Effects of Antidepressants on Gastric Function in Patients with Functional Dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is a highly prevalent functional bowel disorder. The effects of antidepressant therapy (ADTx) on gastric sensorimotor function in FD patients are poorly understood. AIMS: Determine whether FD and subtypes with abnormalities in gastric function respond differently to ADTx compared to those with normal physiology. METHODS: This multicenter, prospective trial randomized FD patients to 12 weeks of amitriptyline (AMI; 50 mg), escitalopram (ESC; 10 mg), or matching placebo. Demographics, symptoms, psychological distress, gastric emptying, and satiation were measured. Gastric accommodation (GA) using single-photon emission computed tomography imaging was performed in a subset of patients. An intent to treat analysis included all randomized subjects. The effect of treatment on gastric emptying was assessed using ANCOVA. A post hoc appraisal of the data was performed categorizing patients according to the Rome III subgrouping (PDS and EPS). RESULTS: In total, 292 subjects were randomized; mean age=44 yrs. 21% had delayed gastric emptying. Neither antidepressant altered gastric emptying, even in those with baseline delayed gastric emptying. GA increased with ADTx (P=0.02). Neither antidepressant affected the maximal-tolerated volume (MTV) of the nutrient drink test although aggregate symptom scores improved compared to placebo (P=0.04). Patients with the combined EPS-PDS subtype (48%) had a lower MTV on the nutrient drink test compared to the EPS group at baseline (P=0.02). Postprandial bloating improved with both AMI (P=0.03) and ESC (P=0.02). CONCLUSIONS: Amitriptyline (50 mg) improves FD symptoms but does not delay gastric emptying, even in patients with baseline delayed gastric emptying. GA improved with low-dose ADTx; the precise mechanism of action is unknown warranting further study.

Associations among binge eating behavior patterns and gastrointestinal symptoms: a population-based study.

BACKGROUND: The psychological symptoms associated with binge eating disorder (BED) have been well documented. However, the physical symptoms associated with BED have not been explored. Gastrointestinal (GI) symptoms such as heartburn and diarrhea are more prevalent in obese adults, but the associations remain unexplained. Patients with bulimia have increased gastric capacity. The objective of the study was to examine if the severity of binge eating episodes would be associated with upper and lower GI symptoms. METHODS: Population-based survey of community residents through a mailed questionnaire measuring GI symptoms, frequency of binge eating episodes and physical activity level. The association of GI symptoms with frequency of binge eating episodes was assessed using logistic regression models adjusting for age, gender, body mass index (BMI) and physical activity level. RESULTS: In 4096 subjects, BED was present in 6.1%. After adjusting for BMI, age, gender, race, diabetes mellitus, socioeconomic status and physical activity level, BED was independently associated with the following upper GI symptoms: acid regurgitation (P<0.001), heartburn (P<0.001), dysphagia (P<0.001), bloating (P<0.001) and upper abdominal pain (P<0.001). BED was also associated with the following lower GI symptoms: diarrhea (P<0.001), urgency (P<0.001), constipation (P<0.01) and feeling of anal blockage (P=0.001). CONCLUSION: BED appears to be associated with the experience of both upper and lower GI symptoms in the general population, independent of the level of obesity. The relationship between increased GI symptoms and physiological responses to increased volume and calorie loads, nutritional selections and rapidity of food ingestion in individuals with BED deserves further study.

Prevalence and risk factors for abdominal bloating and visible distention: a population-based study.

BACKGROUND: Abdominal bloating and visible distention are common yet poorly understood symptoms. Epidemiological data distinguishing visible distention from bloating are not available. We aimed to evaluate the prevalence and potential risk factors for abdominal bloating and visible distention separately in a representative US population, and their association with other functional gastrointestinal disorders (FGIDs). METHODS: The validated Talley Bowel Disease Questionnaire was mailed to a cohort selected at random from the population of Olmsted County, Minnesota. The complete medical records of responders were abstracted; 2259 subjects (53% females; mean age 62 years) provided bloating and distention data. RESULTS: The age and sex-adjusted (US White 2000) overall prevalence per 100 for bloating was 19.0 [95% confidence interval (CI), 16.9 to 21.2] vs 8.9 (95% CI, 7.2 to 10.6) for visible distention. Significantly increased odds for bloating alone and separately for distention (vs neither) were detected in females, and in those with higher overall Somatic Symptom Checklist (SSC) scores and higher scores of each individual SSC item. Further, females [odds ratio (OR), 1.5; 95% CI, 1.0 to 2.1], higher SSC score (OR, 1.4; 95% CI, 1.1 to 1.8), constipation-predominant irritable bowel syndrome (OR, 2.3; 95% CI, 1.3 to 4.1), dyspepsia (OR, 1.9; 95% CI, 1.1 to 3.2), and gastro-intestinal symptom complex overlap (OR, 1.7; 95% CI, 1.1 to 2.7) significantly increased odds for distention over bloating alone. CONCLUSIONS: Bloating and distention are common and have similar risk factors; somatisation probably plays a role.

Biliary events and an increased risk of new onset irritable bowel syndrome: a population-based cohort study.

BACKGROUND: Prospective data are lacking to determine if irritable bowel syndrome (IBS) is a risk factor for cholecystectomy, or if biliary disease and cholecystectomy predisposes to the development of IBS. AIM: To test the hypothesis that IBS and biliary tract disease are associated. METHODS: Validated symptom surveys sent to cohorts of Olmsted County, MN, (1988-1994) with follow-up in 2003. Medical histories were reviewed to determine any 'biliary events' (defined by gallstones or cholecystectomy). Analyses examined were: (i) time to a biliary event post-initial survey and separately and (ii) risk of IBS (Rome II) in those with vs. without a prior biliary event. RESULTS: A total of 1908 eligible subjects were mailed a follow-up survey. For analysis (i) of the 726 without IBS at initial survey, 44 (6.1%) had biliary events during follow up, in contrast to 5 of 93 (5.4%) with IBS at initial survey (HR 0.8, 95% CI 0.3-2.1). For analysis (ii) of the 59 subjects with a biliary event at initial survey, 10 (17%) reported new IBS on the follow-up survey, while in 682 without a biliary event up to 1.5 years prior to the second survey, 58 (8.5%) reported IBS on follow-up (OR = 2.2, 95% CI 1.1-4.6, P = 0.03). CONCLUSION: There is an increased risk of new IBS in community subjects who have been diagnosed as having a biliary event.

The effect of short-term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying: a double-blind, randomized, placebo-controlled trial.

Antidepressants are commonly prescribed for patients with functional dyspepsia. However, the effect of tricyclic antidepressants on satiation and gastric emptying remains unclear, and there are no data for tetracyclic compounds. To compare the effects of nortriptyline (maximum dose: 50 mg daily) and mirtazapine (30 mg daily) vs placebo on gastric emptying, gastric satiation and postprandial symptoms after a nutrient load in healthy volunteers. Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 14 days of nortriptyline (n = 13), mirtazapine (n = 13), or placebo (n = 14) in healthy volunteers. Validated methods were used to study gastric emptying ((13)C-octanoate) and satiation postnutrient drink test. The three arms were comparable with regard to age, gender, body mass index and hospital anxiety/depression scale. There were no statistically significant effects of mirtazapine or nortriptyline on gastric emptying compared to placebo (P = 0.34). Maximum tolerated volume was similar on drug and placebo (P = 0.56). Aggregate symptom score 30 min postmaximum tolerated volume after nutrient drink challenge on placebo was 132 (+/-21), vs 165 (+/-21) on mirtazapine, and 126 (+/-21) on nortriptyline 50 mg respectively (P = 0.28). Tricyclic and tetracyclic antidepressant agents do not appear to have significant effects on gastric motor or satiation postnutrient challenge in healthy individuals at the doses tested.

An exploratory study of the association of adrenergic and serotonergic genotype and gastrointestinal motor functions.

Adrenergic and serotonergic mechanisms alter human gut motor functions. Genotype variation influences phenotype. Our aim was to test the hypothesis that variation in genes that control these functions is associated with gastrointestinal (GI) motor functions in humans with functional GI disorders (FGID). A database of 251 people was assembled by combining genotype data with measurements of gut transit and gastric volumes. Genetic variations evaluated were: alpha(2A) adrenergic (C-1291G), alpha(2C) (Del 332-325), 5-HT transporter (SLC6A4) and GNbeta3 (C825T). We sought associations between motor function or disease groups and genotypes, adjusting for age, gender and body mass index. Among 251 participants, 82 were healthy, 20 with irritable bowel syndrome (IBS) with mixed bowel habit, 49 with constipation-predominant IBS, 67 with diarrhoea-predominant IBS and 33 with functional dyspepsia. For all candidate genes, there was no significant association between motor function and wildtype vs non-wildtype gene status. There were significant interactions between genotype and motility phenotype, specifically GNbeta3 and alpha(2A) and gastric emptying at 4 h. Borderline associations were noted for SCL6A4 and alpha(2A) and postprandial gastric volume, and for alpha(2C) and gastric emptying at 2 h. We conclude that genotype variation may affect gastric motor functions in different FGID phenotypes. However, these candidate genes account for only a limited amount of the variance in gastric function of patients with FGID.

A pharmacological challenge predicts reversible rectal sensorimotor dysfunctions in women with fecal incontinence.

BACKGROUND: In order to understand the pathophysiology of rectal sensorimotor dysfunctions in women with fecal incontinence (FI) and rectal urgency, we evaluated the effects of a muscarinic antagonist and an adrenergic α2 agonist on these parameters. METHODS: Firstly, rectal distensibility and sensation were evaluated with a barostat and sinusoidal oscillation at baseline and after randomization to intravenous saline or atropine in 16 healthy controls and 44 FI patients. Thereafter, FI patients were randomized to placebo or clonidine for 4 wk; rectal compliance and sensation were revaluated thereafter. The effect of atropine and clonidine on rectal functions and the relationship between them were evaluated. RESULTS: At baseline, compared to controls, rectal capacity was lower (P = .03) while the mean pressure (P = .02) and elastance (P = .01) during sinusoidal oscillation were greater, signifying reduced distensibility, in FI. Compared to placebo, atropine increased (P ≤ .02) the heart rate in controls and FI and reduced (P = .03) the variability in rectal pressures during sinusoidal oscillation in controls. Clonidine increased rectal compliance (P = .04) and reduced rectal capacity (P = .03) in FI. The effects of atropine and clonidine on compliance (r = .44, P = .003), capacity (r = .34, P = .02), pressures during sinusoidal oscillation (r = .3, P = .057), pressure (r = .6, P < .0001), and volume sensory thresholds (r = .48, P = .003) were correlated. CONCLUSIONS: The effects of atropine and clonidine on rectal distensibility and sensation were significantly correlated. A preserved response to atropine suggests that reduced rectal distensibility is partly reversible, mediated by cholinergic mechanisms, and may predict the response to clonidine, providing a pharmacological challenge.

Reproducibility of gastric emptying assessed with scintigraphy in patients with upper GI symptoms.

BACKGROUND: The reproducibility of gastric emptying (GE) measured with scintigraphy in patients is poorly understood. Our aims were to assess the intra and inter-individual reproducibility of these parameters in patients with upper gastrointestinal symptoms. METHODS: Sixty patients (21 diabetics, 39 non-diabetics) with upper gastrointestinal symptoms underwent scintigraphic-assessment of GE of a solid meal (296 kcal, 30% fat) over 4 hours on two occasions at an average interval of 15 days. The concordance correlation coefficient (CCC), intra and inter-individual coefficients of variation (COV) of GE endpoints were analyzed. RESULTS: The GE t1/2 was 134 ± 8 minutes (mean ± SEM) for the first and 128 ± 6 minutes for the second study. The mean (95% CI) CCC between the two studies was 0.79 (0.67, 0.87) for GE at 1 hour, 0.83 (0.75, 0.9) for GE at 2 hours, 0.54 (0.34, 0.7) for GE at 4 hours, and 0.79 (0.68, 0.86) for GE t1/2 . However, in 18 of 60 patients (30%), the characterization of GE as normal, delayed, or rapid differed between the first and second studies. For gastric empting t1/2 , the inter-individual coefficients of variation was 40%; the intra-individual COV was 20%, comparable in diabetics and non-diabetics, and greater in patients with rapid (28%) than delayed (18%) or normal GE (12%). CONCLUSIONS & INFERENCES: Among patients with upper gastrointestinal symptoms, GE measured with scintigraphy is relatively reproducible. In 30% of cases, the interpretation was different between the two assessments. Hence, a diagnosis of gastroparesis based on a single study may occasionally be inaccurate.

Normal values for assessment of anal sphincter morphology, anorectal motion, and pelvic organ prolapse with MRI in healthy women.

BACKGROUND: Endoanal MRI and MR defecography are used to identify anal sphincter injury and disordered defecation. However, few studies have evaluated findings in asymptomatic healthy people. The effects of BMI and parity on rectoanal motion and evacuation are unknown. METHODS: In 113 asymptomatic females (age 50 ± 17 years, Mean ± SD) without risk factors for anorectal trauma, anal sphincter appearance, anorectal motion, and pelvic organ prolapse were evaluated with MRI. The relationship between age, BMI, and parity and structural findings were evaluated with parametric and non-parametric tests. RESULTS: The anal sphincters and puborectalis appeared normal in over 90% of women. During dynamic MRI, the anorectal angle was 100 ± 1º (Mean ± SEM) at rest, 70 ± 2° at squeeze, and 120 ± 2° during defecation. The change in anorectal angle during squeeze (r = -.25, P < .005), but not during evacuation (r = .13, P = .25) was associated with age. In the multivariable models, BMI (P < .01) and parity (P < .01) were, respectively, independently associated with the intersubject variation in the anorectal angle at rest and the angle change during squeeze. Ten percent or fewer women had had descent of the bladder base or uterus 4 cm or more below the pubococcygeal line or a rectocele measuring 4 cm or larger. Only 5% had a patulous anal canal. CONCLUSIONS: In addition to age, BMI and parity also affect anorectal motion in asymptomatic women. These findings provide age-adjusted normal values for rectoanal anatomy and pelvic floor motion.

1,25-Dihydroxyvitamin D stimulation test for osteoblast function in normal and osteoporotic postmenopausal women.

The cause of bone loss in postmenopausal osteoporosis--decreased bone formation or increased bone resorption--is controversial. Synthesis of bone--Gla protein (BGP), a specific osteoblast product, is stimulated by 1,25-dihydroxyvitamin D3 [1,25(OH)2D] in vitro. Thus, increases in serum BGP levels during 1,25(OH)2D administration might provide a useful dynamic index of osteoblast function. We compared 14 postmenopausal osteoporotic women with 12 age-matched postmenopausal normal women before and during 6 d of 1,25(OH)2D administration (2.0 micrograms/d). Serum BGP levels were similar at baseline and increased during treatment in both groups (P less than 0.001). However, trend analysis showed a greater (P less than 0.01) increase in the osteoporotic women. These data do not support the hypothesis that defective osteoblast function is the major cause of bone loss in postmenopausal osteoporosis.

Epidemiology of slow and fast colonic transit using a scale of stool form in a community.

BACKGROUND: Measurement of gastrointestinal transit is commonly performed in the clinic, but data on transit in the community are lacking. AIM: To estimate the prevalence of slow and fast colonic transit using stool form, and potential risk factors. METHODS: A validated self-reported gastrointestinal symptom questionnaire was mailed to 4196 randomly selected members of the community (response rate 54%). One question asked the subject to self-report their stool form using the Bristol Stool Scale. RESULTS: Overall, 18%, 9% and 73% met stool form criteria for slow, fast or normal colonic transit, respectively. Increased odds for slow transit were observed with a higher Somatic Symptom Checklist score (OR = 1.6; 1.3-2.0), while a decreased odds for slow transit was observed in males relative to females (OR = 0.6; 0.5-0.8). An increased odds for fast transit was observed with higher Somatic Symptom Checklist score (OR = 2.3; 1.7-2.9) and a history of cholecystectomy (OR = 1.8; 1.2-2.8). Increasing body mass index (per 5 units) was associated with decreased odds for slow (OR = 0.85; 0.78-0.93), and an increased odds for fast (OR = 1.1; 1.04-1.24) colonic transit. CONCLUSION: Based on stool form assessment, nearly one in five community members may have slow colonic transit and one in 12 have accelerated colonic transit.

The changing incidence of oesophageal and gastric adenocarcinoma by anatomic sub-site.

BACKGROUND: The incidence rates of gastric and oesophageal adenocarcinoma are changing significantly, but little is known about specific sub-sites. AIM: To use a population-based approach to describe the trends in the site-specific incidence of oesophageal and gastric adenocarcinoma. METHODS: Using the Rochester Epidemiology Project, all cases of gastric and oesophageal adenocarcinoma among Olmsted County, Minnesota, residents first diagnosed between 1971 and 2000 were identified (n = 186). Complete in-patient and out-patient records were reviewed and site determined from pathological, surgical, endoscopic and radiological reports. RESULTS: Between the decades of 1971-1980 and 1991-2000, the incidence of oesophageal adenocarcinoma increased significantly from 0.4 to 2.5 per 100 000 person-years. The incidence of adenocarcinoma of the oesophagogastric junction also increased from a rate of 0.6 to 2.2 per 100 000 person-years. The incidence rate of cancer involving the gastric cardia was stable but the incidence of adenocarcinoma involving distal gastric sites declined. Combined oesophageal and oesophagogastric junction adenocarcinoma (4.7 per 1 000 000 person-years) was as common as gastric adenocarcinoma (3.4 per 100 000 person-years) in 1991-2000. CONCLUSIONS: The incidence rates of adenocarcinoma involving proximal gastric sub-sites do not appear to be increasing in a manner similar to those involving oesophageal sub-sites.

Overlap of gastro-oesophageal reflux disease and irritable bowel syndrome: prevalence and risk factors in the general population.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) and irritable bowel syndrome may occur more often than expected by chance, but little community data exists and risk factors are unknown. AIM: To determine prevalence and risk factors for overlap of GERD and irritable bowel disease. METHODS: Population-based, cross-sectional survey was conducted by mailing a valid symptom questionnaire to eligible residents of Olmsted County, MN, aged 30-95 years. Irritable bowel syndrome were defined by Rome III; GERD was defined by weekly or more frequent heartburn and/or acid regurgitation. RESULTS: 2298 questionnaires returned (women 52%, 55% response). Irritable bowel syndrome and GERD occurred together more commonly than expected by chance; the prevalence of irritable bowel syndrome-GERD overlap, GERD alone and irritable bowel syndrome alone were 3%, 15% and 5% in men, and 4%, 14% and 10% in women, respectively. Predictors of irritable bowel syndrome-GERD overlap vs. irritable bowel syndrome alone, and separately, GERD alone, were insomnia (OR 1.3, 95% CI: 1.06-1.70; OR 1.5, 95% CI: 1.13-1.90, respectively) and frequent abdominal pain (OR 3.9, 2.2-6.7; OR 1.8, 1.02-3.2, respectively). An additional predictor of irritable bowel syndrome-GERD overlap vs. GERD alone was higher somatization (OR 1.7, 1.1-2.4) and for irritable bowel syndrome-GERD overlap vs. irritable bowel syndrome alone was a higher body mass index (OR 1.0, 1.003-1.07). CONCLUSIONS: Irritable bowel syndrome and GERD overlap is common in the population and does not occur by chance.

Age at onset of inflammatory bowel disease and the risk of surgery for non-neoplastic bowel disease.

BACKGROUND: There is conflicting data regarding the response to medical and surgical therapy for inflammatory bowel disease with respect to age at disease onset. AIM: To determine if the age at onset of Crohn's disease and ulcerative colitis is a risk factor for surgery for non-neoplastic bowel disease. METHODS: This was a case-control study of patients evaluated between 1998 and 2001. Cases had undergone an initial operation for bowel disease. Controls were matched 1:1 for gender, disease subtype, date of first visit (+/-2 years), time from diagnosis prior to first visit (+/-3 years) and duration of follow-up. Association with age, disease extent, smoking history, medication use and co-morbidities vs. case/control status was assessed using multiple variable conditional logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (CI) for undergoing surgery. RESULTS: Among 132 Crohn's patients, older patients had lower odds for surgery (OR per 5 years, 0.86; 95% CI: 0.75-0.98). The rate of surgery for non-neoplastic bowel disease was not significantly associated with disease distribution, co-morbidities or cigarette smoking. Among 234 ulcerative colitis patients, the rate of surgery was unrelated to age, disease extent, co-morbidities or cigarette smoking, CONCLUSIONS: For Crohn's disease, but not ulcerative colitis, the risk of surgery for non-neoplastic bowel disease decreases with increasing age at diagnosis, irrespective of disease distribution and history of cigarette smoking.

Risk factors for chronic constipation and a possible role of analgesics.

Constipation has an estimated prevalence of 15% in the general population. However, the etiopathogenesis of this condition remains relatively obscure. This study sought to identify potentially novel risk factors for chronic constipation. A valid self-report questionnaire was mailed to an age- and gender-stratified random sample of Olmsted County, Minnesota residents aged 30-64 years. A logistic regression model that adjusted for age, gender and somatic symptom score (SSC) was used to identify factors associated with chronic constipation. People reporting symptoms of irritable bowel syndrome (IBS) were excluded. Of the 892 eligible subjects, 653 (73%) returned the survey. Among the 523 subjects not reporting IBS symptoms, chronic constipation was reported by 93 (18%) of the respondents. Chronic constipation was significantly associated with use of acetaminophen [>or=7 tablets per week, OR = 2.7 (1.1-6.6)]; aspirin [OR = 1.7 (1.0-2.7)]; non-steroidal anti-inflammatory drugs [OR = 1.8 (1.1-3.0)]; and SSC. No association was detected for age, gender, body mass index, marital status, smoking, alcohol, coffee, education level, food allergy, exposure to pets, stress, emotional support, or water supply. Chronic constipation is associated with use of acetaminophen, aspirin and non-steroidal anti-inflammatory drugs. The explanation of these associations requires further investigation.

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.

Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans.

ATI-7505, an investigational 5-HT(4) receptor agonist, was designed to have similar activity as cisapride without the cardiac adverse effects, i.e. without QT prolongation. In addition, ATI-7505 is not metabolized by CYP450. The aim of the study was to assess the effect of ATI-7505 on gastrointestinal (GI) and colonic transit in healthy humans. A randomized, parallel-group, double-blind, placebo-controlled study evaluated effects of 9-day treatment with ATI-7505 (3, 10 or 20 mg t.i.d.) on scintigraphic GI and colonic transit in healthy volunteers (12 per group). Primary endpoints were gastric-emptying (GE) T(1/2), colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T(1/2). Daily stool diaries were kept. Analysis of covariance assessed overall treatment group differences, followed by post hoc unadjusted pairwise comparisons. There were borderline overall treatment effects (decrease) on GE T(1/2) (P = 0.154); the 20 mg t.i.d. of ATI-7505-accelerated GE vs placebo (P = 0.038). ATI-7505 increased colonic transit (GC24, P = 0.031) with fastest transit at 10 mg t.i.d. vs placebo (P = 0.065). ATI-7505 accelerated AC emptying T(1/2) (overall P = 0.075) with 10 mg dose vs placebo (P = 0.042). There was looser stool (Bristol stool form scale, overall P = 0.056) with the 10 and 20 mg t.i.d. doses. No safety issues were identified. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.

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.

Effects of glucagon-like peptide-1 and sympathetic stimulation on gastric accommodation in humans.

In humans, glucagon-like peptide-1 (GLP-1) delays gastric emptying by inhibiting vagal activity and also increases gastric volumes, by unclear mechanisms. Because GLP-1 inhibits intestinal motility by stimulating the sympathetic nervous system in rats, we assessed the effects of a GLP-1 agonist and yohimbine, an alpha(2)-adrenergic antagonist, on gastric volumes in humans. In this double-blind study, 32 healthy volunteers were randomized to placebo, a GLP-1 agonist, yohimbine or GLP-1 and yohimbine. Gastric volumes (fasting predrug and postdrug, and postprandial postdrug) were measured by (99m)Tc single photon emission computed tomography imaging. Plasma catecholamines and haemodynamic parameters were assessed. Compared with placebo, GLP-1 increased (P = 0.03) but yohimbine did not affect fasting gastric volume. However, GLP-1 plus yohimbine increased (P < 0.001) postprandial gastric accommodation vs placebo and vs GLP-1 alone [postprandial volume change = 542 +/- 29 mL (mean +/- SEM, placebo), 605 +/- 31 mL (GLP-1), 652 +/- 54 mL (yohimbine) and 810 +/- 37 mL (GLP-1 and yohimbine)]. Plasma noradrenaline and dihydroxyphenylglycol concentrations were higher for yohimbine vs placebo and for GLP-1 and yohimbine vs GLP-1. Yohimbine stimulates central sympathetic activity and in combination with GLP-1, augments postprandial accommodation in humans.

Effect of the NK(3) 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.