Irene Ferber

Association of distinct α2 adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders

Background: The role of genetics in the phenotypic manifestations of irritable bowel syndrome (IBS) is unclear. Our aims were: (1) to compare the prevalence of polymorphisms of alpha 2 (α2) adrenoceptors, norepinephrine transporter, and serotonin transporter protein (soluble carrier protein member 4 (SLC6A4)) promoter in patients with lower functional gastrointestinal disorders (FGID) and in healthy controls; and (2) to test associations of these genetic variations with symptoms of IBS and high somatic symptom scores. Methods: Validated bowel and somatic symptom questionnaires characterised the phenotype: 90 with IBS constipation (IBS-C), 128 IBS diarrhoea, 38 IBS alternating bowel function, and 20 chronic abdominal pain. Logistic regression analyses assessed associations of different polymorphisms for α2 adrenoceptor and SLC6A4 with IBS or chronic abdominal pain phenotypes and high somatic score. Results: Two distinct polymorphisms independently appeared to be associated with the phenotype IBS-C: α2C Del 322–325 (odds ratio (OR) 2.48 (95% confidence interval (CI) 0.98, 6.28); p = 0.05) and α2A −1291 (C→G) (OR 1.66 (95% CI 0.94, 2.92); p = 0.08) relative to wild-type. Overall, the α2C Del 322–325 polymorphism (alone or combined with other polymorphisms) was also significantly associated with a high somatic symptom score (OR 2.2 (95% CI 1.06, 4.64); p = 0.03). Combinations of polymorphisms were also associated with high somatic scores. Conclusion: Functionally distinct α2A and α2C adrenoceptor and serotonin transporter polymorphisms are associated with constipation and high somatic symptoms in patients with lower functional gastrointestinal disorders, although the strength of the genetic contribution to the phenotype is unclear.

Effect of alvimopan and codeine on gastrointestinal transit: A randomized controlled study

UNLABELLED background & aims: Opiate bowel dysfunction is a significant clinical problem. Our aim was to evaluate the ability of a peripheral mu-opioid antagonist, alvimopan, to reverse the effect of codeine on gastric, small-bowel, and colonic transit time in healthy volunteers. METHODS Seventy-four healthy participants (43 women) were randomized in a double-blind, placebo-controlled manner to 1 of 4 groups: alvimopan 12 mg twice daily in the presence and absence of codeine sulfate 30 mg 4 times/day, or codeine or placebo alone. Gastric emptying, small-bowel, and colonic transit were measured by scintigraphy using a 99m-labeled technetium egg meal and 111-labeled indium charcoal delivered to the proximal colon via a delayed-release capsule. The primary end points for colonic transit were geometric center of the colonic counts at 24 hours and time for 50% ascending colon emptying. Analysis of covariance was used to assess the significance of the primary and secondary end points. RESULTS Codeine delayed gastric, small-bowel, proximal, and overall colonic transit (P < .05). Alvimopan reversed codeines effect on small bowel and colon (ascending colon and overall colonic transit). Alvimopan also accelerated overall colonic transit compared with placebo. Thus, the mean colonic geometric center at 24 hours was 2.33 with placebo/placebo, 3.25 with alvimopan/placebo (P < .05), 1.5 with placebo/codeine (P < .05), and 2.63 with alvimopan/codeine. Alvimopan did not reverse codeines delay of gastric emptying. CONCLUSIONS Alvimopan reverses codeines inhibitory effect on small-bowel and colon transit and has potential for treatment of opiate bowel dysfunction. Alvimopan alone accelerates colonic transit, suggesting that mu-opiate mechanisms participate in the physiologic control of colonic transit.

A nutrient drink test to assess maximum tolerated volume and postprandial symptoms: effects of gender, body mass index and age in health

Abstract   To assess the effects of age, gender and body mass index on the maximum tolerated volume of a nutrient drink and postprandial symptoms in health. Healthy adolescents (15 M, 15 F, aged 13–17 years) and adults (15 M, 25 F, aged 19–51 years) ingested Ensure®(1 kcal mL−1) at a rate of 30 mL min−1. The maximum tolerated volume was recorded. Thirty minutes later, bloating, fullness, nausea and pain were rated using visual analogue scales. The Mann–Whitney test was used for comparisons between groups using body mass index and maximum tolerated volume as covariates. Age‐related differences in maximum tolerated volume were noted between adolescents and adults, and were observed in both genders. Adults had higher scores for bloating and pain, and lower scores for fullness. Gender‐related differences in maximum tolerated volume were noted in the group as a whole, and separately for adolescents and adults. Females had higher scores for nausea and pain. Gender and age‐related differences in the maximum tolerated volume of a nutrient drink and postprandial symptoms should be considered in future studies of upper gastrointestinal symptoms in disease. Body mass index does not appear to influence maximum tolerated volume beyond its association with age and gender.

Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo-controlled study.

Abstract  Cannabinoid receptor (CBR) stimulation inhibits motility and increases food intake in rodents. Effects of CBR stimulation in human gastrointestinal (GI) tract are unclear. We compared effects of dronabinol (DRO) and placebo (PLA) on GI transit, gastric volume and satiation in humans. In a double‐blind, randomized study, 30 healthy volunteers were randomly assigned to DRO 5 mg b.i.d. or PLA for three doses. We measured GI functions noninvasively: day 0, Ensure® satiation test to measure maximum tolerated volume (MTV) and 30‐min post‐Ensure® symptoms; day 1, scintigraphic transit (111In‐egg meal) and fasting and postprandial gastric volume (99Tcm‐SPECT); day 2, 24‐h colonic transit and repeat satiation test. ancova was used to compare treatment groups with gender, age, and, for the satiation test, the baseline MTV, as covariates. A log‐rank test was used to assess treatment effects on gastric emptying. Planned sample size had 80% power to detect 25–30% differences in primary end points. There was an overall retardation of gastric emptying with DRO (P = 0.018); this was more pronounced in females (P = 0.011), than in males (P = 0.184). No significant treatment differences were detected for gastric volumes, MTV, post‐Ensure® symptoms, small bowel and colonic transit. Fasting gastric volume was greater in males receiving DRO compared with PLA (238 ± 17 vs 185 ± 16, P = 0.04). DRO retards gastric emptying in humans; effects are gender‐related. Dronabinol also increases fasting gastric volumes in males.

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

Abstract  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.

Effect of Gastric Volume or Emptying on Meal-Related Symptoms After Liquid Nutrients in Obesity: A Pharmacologic Study

BACKGROUND & AIMS Altered postprandial satiation influences food intake in obesity. The aim of this study was to evaluate the contribution of gastric motor functions to intra- and postprandial symptoms in obese, otherwise healthy, people. METHODS In a randomized, parallel-group, double-blind design, 40 obese (body mass index>30 kg/m2) healthy volunteers (n=10/group) received intravenous saline (placebo), atropine (.02 mg/kg), or erythromycin (1 or 3 mg/kg) to alter gastric volume and emptying after liquid nutrient meals, measured by validated imaging methods. The nutrient drink test assessed the volume ingested at maximum satiation, and intra- and early postprandial symptoms. Relationships between gastric motor functions, meal size, and symptoms were assessed by using multiple regression. Circulating levels of candidate upper-gut hormones involved in satiation were measured. RESULTS Relative to placebo, atropine retarded gastric emptying and increased gastric volumes; erythromycin accelerated gastric emptying and reduced gastric volumes during fasting. Although similar maximal tolerated volumes were recorded across treatments, intra- and immediate postprandial symptoms were increased by these perturbations, particularly nausea and bloating. Upper-gut hormonal profiles generally reflected changes in gastric emptying. Regression analysis showed that fasting predrug gastric volume was a significant predictor of intra- and postprandial bloating. Change in gastric volume postdrug or postmeal did not contribute additionally to predicting intra- or postprandial symptoms. There was significant (negative) association between gastric emptying and fullness score, and significant (positive) association with hunger score 30 minutes postprandially. CONCLUSIONS In obese individuals, fasting gastric volumes and gastric emptying, but not postprandial gastric volumes, were associated with intra- and postprandial symptoms. Understanding the determinants of gastric volume may provide insights on mechanisms controlling satiation.

Effects of asimadoline, a κ-opioid agonist, on satiation and postprandial symptoms in health

Aim:  To evaluate the effect of single administrations of asimadoline, a κ‐opioid agonist, on satiation volume, postprandial symptoms and gastric volumes.

Effect of atilmotin on gastrointestinal transit in healthy subjects: a randomized, placebo‐controlled study

Abstract  We studied effects of i.v. atilmotin (BAX‐ACC‐1638, a novel motilin agonist, circulating t1/2 <10 min) on gastrointestinal transit in humans using a randomized, parallel‐group, dose‐response double‐blind study of i.v. atilmotin, 6, 30, 60 μg or vehicle (placebo) given 2 min after standardized breakfast, lunch and dinner. The breakfast meal contained 99mTc‐eggs and 111In‐milk. Full gastrointestinal transit was measured by scintigraphy. Primary endpoints were % gastric emptying (GE) at 30 min, GE t1/2, colonic filling (CF) at 6 h, and geometric centre of colonic transit at 24 h. Analysis included adjustment for age, gender and body mass index, with Bonferroni correction applied for multiple comparisons. A significant treatment effect of atilmotin was detected for GE (%) at 30 min for solids and liquids (P < 0.01 for both). There were no significant effects on CF or CT and no significant adverse clinical events. Thus, atilmotin accelerates GE of solids and liquids in healthy humans. These data suggest that, at the doses tested, atilmotin should be considered for treatment of stomach motility disorders.

Other clinical studyThe integrity of the cholecystokinin receptor gene in gallbladder disease and obesity

Cholesterol gallstone disease and obesity are common and often associated disorders that could be affected by dysfunction of the receptor for cholecystokinin (CCK). Extending earlier studies that identified a defect at the level of receptor-G protein coupling in cholesterol gallstone disease, we characterized the primary structure of the gallbladder CCK receptor in patients undergoing a cholecystectomy. Represented were patients with cholesterol gallstones, as well as controls with pigment gallstones or without gallbladder disease. Both groups were composed of the range of body habitus from lean to morbidly obese. No evidence of any sequence mutation or polymorphism in the CCK receptor gene was found in any patient. This should lead future investigations of the pathogenesis of these problems toward the possible contribution of the plasmalemmal environment in affecting the association between normal receptors and G proteins.

Adrenergic and serotonergic polymorphisms: Association with symptom phenotype and psychosomatic scores in lower functional bowel disorders

Using a gas challenge test we have previously shown that patients complaining of abdominal bloating exhibit impaired gas tolerance and develop retention. Our present aim was to identify the gut compartment responsible for gas retention in these patients. METHODS. In 12 IBS patients with abdominal bloating, and 10 healthy subjects, gut transit of radiolabelled gas was measured by scintigraphy, as follows. A gas nuxture (NI, CO2, Ox in venous proportions) was infused at 24 ml/min into the jejunum for 2 h, while gas outflow was collected via an mtrarectal cannula. After 1 h, a 74 mBq bolus of t33Xe was added to the gas mixture, and anterior and posterior scans were simultaneously obtained by means of a large held-of-view dual head gammacamera at 60 s intervals for the following hour. Segmental gas tramit was measured by a region of interest program. At the end of the study we measured gas retention, as gas volume infused minus evacuated, and perception by a 0-6 scale. RESULTS. [n patients total gut transit of gas was delayed (T~0 42 +/-4 rain vs 31 +/3 rnm in health; p<0.05) and this was associated to gas retention (589+A194 ml by the end of the study vs -72+A18 ml in health; p<0.05) and abdominal symptoms (score 3.5 +/-0.6 vs 1.3 +/-0.3 in health; p<0.05). Segmental transit analysis showed that impaired gas clearance was related to delayed gas transit through the small intestine (Tso 21 +/-3 min vs 1).+/-3 min in health; p<0,05), whereas colonic transit was normal (T~0 20+/-2 min and 19 +/-2 rain in health; N.S.). No gaseous back flow was detected in any study. CONCLUSION. Small bowel incompetence to propulse gas is responsible for gas intolerance and retention in patients complaining of abdominal bloating