- Email: [email protected]
T1250 Effect of Azithromycin On Small Bowel Motility in Patients with Gastrointestinal Dysmotility
T1248
The Effect of Central Adiposity On Esophageal Acid Exposure and Symptoms of Gastro-Esophageal Reflux Disease Roy Anggiansah, Rami Sweis, Angela Anggiansah, Terry Wong, Mark R. Fox
Pregabalin Prevents Development of Visceral Pain Hypersensitivity (VPH) in a Model of Esophageal Acid Sensitization in Healthy Volunteers Yang C. Chua, Abhishek Sharma, Kee Seong Ng, Jafar Jafari, Etsuro Yazaki, Charles H. Knowles, Qasim Aziz
INTRODUCTION: Epidemiologic evidence suggests a link between gastro-esophageal reflux disease (GERD) and obesity. Studies suggest that this relationship is due to the effects of central adiposity on intragastric pressure with disruption of the gastro-esophageal junction (GEJ) reflux barrier, however the clinical relevance of these findings has not been proven. METHODS: From Aug 2005 to Dec 2006, patients sent to a referral center for physiologic investigation of GERD were studied. Height, weight and waist circumference (WC) were measured. Stationary manometry and 24hr ambulatory pH studies off acid-suppressants were performed and symptom severity was assessed by a validated questionnaire. Linear regression models were used to analyze associations between covariates of interest and Pearson's correlation coefficient (PC) was applied to assess the strength of association. RESULTS: 582/676(86%) consecutive patients (age 48 (range 14-89), 56% female) had complete data for analysis. The prevalence of obesity defined by BMI≥30kg.m-2 in males and females was 16% and 23% (p=ns) respectively. More men had WC≥99cm (M41%:F28%; p<0.001)). %time pH<4 at 5cm above the lower esophageal sphincter (LES) increased with obesity (PC=0.255 and 0.240 for BMI and WC respectively; both p<0.001) and age (PC= 0.162; p<0.001) and was higher in men than women (p=0.014) Increase in %time pH<4 was associated with a reduction in LES pressure and abdominal LES length (PC=-0.327, -0.344 respectively; p<0.001). There was a weak negative association of BMI with LES pressure (PC=-0.140; p=0.005) but no link with abdominal LES length. In contrast, there was a significant negative association of WC with LES pressure (PC=-0.225; p<0.001) and abdominal LES length (PC=-0.213; p<0.001). Overall symptom severity increased with %time pH<4 (PC=0.209; p<0.001); however there was no change in symptom severity with BMI (PC=0.056, p=0.17) and the effect of WC was weak and of borderline significance (PC=0.083, p=0.05). CONCLUSION: In this large cohort of clinical patients referred for investigation of reflux symptoms, gastro-esophageal reflux increased with obesity and was most prevalent in elderly males with central adiposity. WC but not BMI was associated with both reduced LES pressure and abdominal length. These findings confirm the mechanistic link between increasing WC and the risk of reflux via raised intragastric pressure and disruption of the GEJ. In contrast, there was little change in symptom severity despite increased acid exposure in this group. The relative insensitivity to acid reflux may explain the increased prevalence of severe and complicated reflux in obese patients.
Background: Esophageal acid infusion in humans induces primary and secondary hyperalgesia due to peripheral and central sensitization respectively(1). Pregabalin is a centrally acting modulator of voltage-sensitive calcium channels which reduces pain hypersensitivity by attenuating the release of multiple neurotransmitters(2) in the CNS. Its efficacy in reducing acid-induced esophageal VPH has not been explored. Aim: To test the effects of pregabalin on the development of acid induced esophageal VPH in healthy human subjects. Methods: Single center, placebo-controlled, double blind, randomized, two-period, cross-over study was performed in healthy subjects who attended on 3 separate visits. On visit one, after esophageal manometry to determine the location of lower esophageal sphincter, pain thresholds (PT) to esophageal electrical stimulation were determined using bipolar ring electrodes positioned in the proximal and distal esophagus. Thereafter, a 30 minute infusion of hydrochloric acid was performed in the distal esophagus. PT was measured again at both sites at 30 and 90 minutes after the acid infusion. Participants were then given either pregabalin or placebo. During the second visit and third visits, at least 1 and 2 weeks later respectively, esophageal acidification and PT measurements were repeated. The dose of pregabalin used was 75mg twice daily for 3 days, 150mg twice daily for one day and 150mg once daily. Results: To date, 8 subjects have completed all visits (6 male, age range 21-31 years) and are included in this analysis. The mean ‘change in PT' for both time points compared to baseline in the proximal esophagus was -4.85mA after treatment with placebo compared to an increase of 2.65mA after treatment with pregabalin (p=0.0027)Table 1. The baseline PT at placebo and pregabalin visits were not significantly different(p=0.64). Interestingly, there were no differences in the change in PT after acid in the distal esophagus. Conclusion: Pregabalin prevents the development of secondary hyperalgesia in the proximal esophagus after distal esophageal acidification. It has no significant effect on the site of acid exposure, indicating that it acts to reduce central sensitization and does not appear to be analgesic. More detailed studies are required to assess the efficacy of pregabalin in patients with acidinduced esophageal VPH. 1. Sarkar Am J Physiol Gastrointest Liver Physiol 2001 2. Taylor Epilepsy Res 2007 Acknowledgement:Pfizer Ltd, UK Table 1:Mean change in PT after acid infusion
T1247 Effects of Chenodeoxycholic Acid On Gastrointestinal and Colonic Transit and Bowel Function in Healthy Volunteers Suwebatu T. Odunsi, Michael Camilleri, Irene Busciglio, Duane D. Burton, Jesse Lamsam, Sanna McKinzie, Ravinder J. Singh, Alan R. Zinsmeister
T1249 Effect of Two Novel, Selective Alpha4beta2 Nicotinic Receptor Partial Agonists On Restraint Stress-Induced Defecation in Rats Katsuyo Ohashi-Doi, Mitsuhisa Kawai, John B. Furness, Jeremy D. Gale
Dihydroxy bile acids cause colonic secretion and high amplitude propagating contractions (HAPC) after infusion of 1mM chenodeoxycholate (CDC) into human colon and 20mM in canine colon. CDC used in gallstone dissolution caused diarrhea. Aim: To evaluate doserelated effects of ileocolonic CDC delivery on gastrointestinal (GI) and colonic transit in health. Methods: This double-blind, placebo-controlled study evaluated effects of 4 days' treatment with CDC in 60 healthy volunteers (17 male, mean age 38.7 y), randomized to oral placebo, 500mg or 1000mg CDC delivered in pH-sensitive, methacrylate-coated capsules. Fasting serum 7α-hydroxy-4-cholesten-3-one (7α-HCO or C4) was measured to assess underlying bile acid malabsorption. GI and colonic transit were measured by scintigraphy during the last 48 h and bowel function by validated daily diaries including Bristol stool form scale. Treatment effects were compared by ANCOVA with age, gender and BMI as covariates. Results: In 94%, baseline serum C4 was normal (<61ng/mL). Gastric emptying t1/2 and colonic filling at 6 h were not significantly affected. There was a significant overall treatment effect of CDC on colonic transit (geometric center at 24 and 48 h, ANCOVA, p= 0.01 and p<0.0001 respectively; see figure); 1000mg was more effective than 500mg dose. There were significant overall treatment effects on stool frequency, consistency (figure), ease of passage and complete evacuation. Most common side effect was loose stools (43 and 57%) or diarrhea (35 and 65% with CDC 500mg and 1000mg respectively, both p<0.001 vs. placebo). No safety issues were identified. Conclusions: CDC accelerates whole colonic transit and loosens stool form. The potential of ileocolonic delivery of CDC in treatment of constipation deserves further study.
INTRODUCTION: Nicotinic acetylcholine receptors (nAChRs) are localised throughout the enteric nervous system (ENS) and have also been shown to modulate pathways associated with physical and psychological responses to stress. Nicotine is known to stimulate the release both of excitatory and inhibitory neurotransmitters in the ENS, including ACh and VIP by activating nAChRs. CP-601927 and CP-601932, bind with high affinity to rat and human alpha4beta2 nAChR subtypes and are selective partial agonists. Stress is well known to affect several gastrointestinal functions. In rat, stress-induced increases in defecation have been used as a model for some features of functional bowel disorders. The study aimed to assess whether partial agonists of alpha4beta2 nAChR were able to modulate stress-induced defecation in the rat. METHODS: Defecation in response to acute restraint stress was measured in non-fasted conscious male Sprague-Dawley rats. Rats were placed in wire-mesh restraint cages while control (non-stressed) rats were placed in large plastic cages. Fecal pellets were collected for 2 hr, and the defecation was expressed as the weight of fecal pellets in each group. RESULTS: Rats exposed to restraint stress for 2 hours showed a significant increase in both the number of fecal pellets and mean fecal wet weight compared with control rats (Stress, 2.93±0.25 g vs. Control, 0.17±0.09 g; p<0.01; n=9-10). CP-601927 (1 - 10 mg/kg, p.o.) produced a dose-dependent decrease in the stress-induced increase in fecal weight (1 mg/kg, 0.2%; 3 mg/kg, 13%; 10 mg/kg, 47% reduction; n=9). Statistical significance was observed in rats treated with 10 mg/kg (p<0.01). CP-601932 (1 and 3 mg/kg, p.o.) had little effect on the stress-induced increase, although the highest dose of 10 mg/kg elicited reduction of fecal weight (10 mg/kg, 79% reduction; n=6) which approached statistical significance (p=0.051). CONCLUSION: The present study demonstrates that oral administration of partial agonists for alpha4beta2 nAChRs have inhibitory effects on stress-induced increases in defecation in rats. The detailed mode of action requires further elucidation. Based on these finding, a partial agonist of alpha4beta2 nAChR might represent a novel compound for the modulation of GI transit and secretion and so may be worthy of investigation in functional GI disorders including IBS. T1250 Effect of Azithromycin On Small Bowel Motility in Patients with Gastrointestinal Dysmotility Payam Chini, Phillip P. Toskes, Wei Hou, Renee McDonald, Baharak Moshiree
Dose-related effect of 500mg and 1000mg CDC on colonic transit, stool frequency and consistency
Background: We have previously demonstrated that Azithromycin (AZI) stimulates antral activity as measured using antroduodenal manometry (ADM) in patients with known gastroparesis (GP) similar to erythromycin (EES) - the current most potent prokinetic available(Am J Gastro 2005; 100: S-326). Although EES does not induce phase III migrating motor complexes (MMCs) in the small bowel, we do not yet know the effect of AZI-a semi-synthetic macrolide-on small bowel activity in patients with documented small bowel dysmotility. Aim: Our study investigates the effect of AZI as compared to EES on duodenal activity in
A-531
AGA Abstracts
AGA Abstracts
T1246
AGA Abstracts
patients with gastrointestinal dysmotility (GID). Method: We evaluated a consecutive series of 21 patients referred to our Clinical Motility Lab for evaluation of chronic abdominal pain or suspected GID undergoing 24 hour ADM. Only those patients with GP and small bowel dysmotility were included. All patients had pressure profiles recorded in three stages: baseline period (BL), fed state after a standardized meal, and postprandial after administration of EES (250 mg IV) and AZI (250 mg IV). The measured parameters include the characteristics of the MMCs and AFs such as site of origin (antrum versus duodenum), duration of phase III activity, amplitude of phase III MMCs in duodenum and number of cycles per minute. The data were analyzed using a repeated measures analysis of variance for comparison of each medication. Results: Overall comparison of AZI and EES showed that AZI induced more MMCs in the duodenum with origin of AFs in the antrum than did EES (18 patients with AZI versus 10 patients with EES, p value = 0.0299). The average duration of MMCs and antral AFs were also longer in AZI group as compared with EES (AZI mean = 18.5 min, EES mean = 9.7 min, SEM 3.6 min, p value = 0.0172). Further comparison of pressure profiles seen at BL in the duodenum with AZI given in the postprandial state showed statistically significant improvement in the number of MMCs (BL mean = 1.2, AZI mean = 2.4, SEM = 0.42, p value = 0.0055) and number of AFs in the antrum (p value = 0.0256). No significant difference between AZI and BL fasting state was seen with respect to the duration of MMCs or number of cycles per minute. Conclusions: AZI induces AFs followed by duodenal contractions more frequently than EES, even in patients with GID. Furthermore, analysis of the duodenal MMC and AF characteristics indicates that the average duration of affect is also longer with AZI as compared to EES. Clearly, AZI is a promising prokinetic in patients with gastric and small bowel dysmotility but whether these findings translate into symptom improvement remains to be seen.
Oral AZD7371 (1, 3, 10 or 30 μmol/kg, n=7-8 per dose) inhibited visceromotor responses to CRD in a dose-related manner, with an ED50 of 14 μmol/kg. In telemetrized rats, AZD7371 (100 or 300 nmol/kg, iv, n=4 for each) inhibited the visceromotor response to CRD, but did not affect the rise in HR and BP in response to CRD. When administered icv, AZD7371 (1 μmol/rat, n=7) did not affect visceromotor responses to CRD, while it, as expected, inhibited micturition. None of the doses tested induced visible gross-side effects. Conclusions: AZD7371, likely acting at a peripheral and/or spinal site, inhibited the visceromotor, but not the autonomic cardiovascular, responses to visceral pain in the CRD model in rats. While agents effective on multiple pain-related readouts in the rat CRD model (e.g. pregabalin or clonidine) have alleviated IBS symptoms in clinical trials, data with compounds like AZD7371, effective on only one pseudo-affective readout during CRD in rats, need to be interpreted cautiously as it relates to its clinical translational value. These results question whether AZD7371-induced inhibition of visceromotor responses during CRD in rats reflects a true analgesic activity of the compound. T1253 Sumatriptan Inhibits the Colonic Response to Intragastric, But Not Intraduodenal, Nutrient Administration Sebastien Kindt, Rita Vos, Maura Corsetti, Jan F. Tack The gastrocolonic response consists of a tonic and phasic contractile response of the colon to meal-induced mechano- and chemoreceptor-activation in the stomach and duodenum. Besides cholinergic pathways, serotonin (5-HT)3 receptors have been implicated. Sumatriptan (Suma), a 5-HT1D receptor agonist, enhances gastric accommodation and delays gastric emptying, hereby modifying meal-induced mechano- and chemoreceptor activation. Our aim was to study the influence of sumatriptan on the colonic response to feeding. Methods: Twelve healthy subjects (8 men) underwent two colonic barostat studies, at least one week apart, with administration of Suma or placebo in a double-blind cross-over fashion. After cleansing with water enema, a combined manometry and barostat assembly was positioned in the descending colon. After a 30 minute adaptation period, intra-balloon pressure was set at operating pressure (lowest pressure inducing intra-balloon volume >30 ml) +2 mmHg. Suma 6 mg or saline were administered s.c. after 60 min, followed by oral (n=7) or intraduodenal (via nasoduodenal tube, 1.5 ml/min, n=5) administration of a liquid meal (Nutridrink 200 ml, 1.5kcal/ml). Changes in balloon volume before and after the meal, and at 5-min intervals, were compared using paired t-tests and repeated-measures ANOVA with Bonferroni post-hoc test. Results: Baseline colonic intra-balloon volumes were comparable under all study conditions. Suma significantly inhibited the meal-induced decrease of colonic balloon volumes (mean change -30.3±8.6 vs. 2.4±11.8 ml, p=0.04; ANOVA p=0.05), with a significant difference at 15 (-39.4±10.9 vs. 2.8±12.4 ml), 35 (-28.7±14.8 vs. 5.8±14.2 ml) and 50 (-39.2±17.0 vs. 9.3±15.3 ml) minutes postprandially on post-hoc testing (all p<0.05). Suma did not alter the colonic response to intraduodenal nutrient administration (mean change 5.05±31.0 vs. -0.5±10.7 ml, p=NS). Conclusion: The colonic contractile response to nutrient ingestion, the so-called gastrocolonic reflex, depends on the presence of intragastric nutrients. Administration of sumatriptan prior to nutrient ingestion inhibits this reflex.
T1251 Effects of STW 5 and Some of Its Components On Spontaneous Contractions in Mouse Ileum In Vitro Katrin Wald, Daniela Hagelauer, Bettina R. Vinson, Olaf Kelber, Dieter Weiser, Helmut Heinle INTRODUCTION: As several clinical studies have shown, STW 5 (Iberogast®) is effective in functional gastrointestinal diseases (1). Pharmacological studies have demonstrated its influence on gastric and intestinal smooth muscle (2, 3, 4) and were recently also confirmed by clinical pharmacological studies (5). As a phytomedicinal combination of nine herbal extracts, STW 5 is a multicomponent remedy, as are phytomedicines in general, irrespective whether they are based on single herbal extracts or combinations thereof. OBJECTIVES: It is therefore relevant to explore the contributions of the components of STW 5 to its effects by studying the extracts contained and even their single phytochemical components in pharmacological models In Vitro. METHODS: STW 5, the different extracts contained, and selected of their chemical components were studied. Rings of the ileum were mounted in a perfused organ bath and longitudinal spontaneous muscle activity and tonus were recorded. RESULTS: The ileum showed very stable spontaneous contractions (mean amplitude 3.4±2mN; mean frequency 21.6±4/minute). All plant extracts were applied in a dilution of 1:100, the chemical compounds in concentrations corresponding to those in the extracts. STW 5 decreased tone and amplitude of the contraction most distinctly, whereas the single plant extracts influenced contractility in different ways: peppermint, chamomile and angelica root strongly inhibited the characteristics of spontaneous contractility, whereas liquorice root and melissa showed minor effects on these parameters (2). None of the selected chemical compounds had significant effects on amplitude or frequency when applied in concentrations present in the genuine extracts. α-bisabolol (chamomilla), rosmarinic acid, citral, citronellal (all lemon balm) and kaempferol (Iberis amara) decreased amplitude and increased frequency significantly in concentrations above 300 μM CONCLUSION: These results suggest that the effects of STW 5 can not be simply deduced from those of their components and leads to the conclusion, that, like also in other phytomedicines, not single phytochemical components, but the extracts, as complex compositions of these, respective their combination are the active substances in this medicine. REFERENCES: 1. Schmulson M. Nature Clin Pract Gastro Hepatol 2008, 5, 136-137; 2. Schemann M et al. Phytomedicine 2006, 13, S V, 90-99; 3. Heinle H et al. Phytomedicine 2006, 13, S V, 75-79; 4. Okpanyi SN et al. Acta Hort 1993, 332, 227-235; 5. Pilichiewicz AN et al. Am J Gastro 2007, 102, 1-8; 6. Hagelauer D. Thesis, 2007, University of Tuebingen, Germany; 7. Wagner H. Phytomedicine 2006, 13, S V, 122-129
T1254 Chronic Psychological Stress Induces Abnormal Colonic Motility and Wood Creosote Prevents Its Abnormality in Unrestrained Conscious Rats Koji Ataka, Mineko Fujimiya BACKGROUND Psychological stress induces anxiety, increases blood pressure and heart rate, induces diarrhea and constipation, and has a close relationship with irritable bowel syndrome. Communication box is a device to provoke psychological stress in conscious rats; however its influence on colonic motility has not been examined. Wood creosote is an oral herbal medicine for treatment of acute diarrhea in Asia for more than a century. Our recent study has shown that wood creosote suppresses the colonic motor activity accelerated by corticotropin-releasing factor, a key brain mediator in the stress response. OBJECTIVE We aimed to examine the effects of psychological stress on the colonic motility measured by manometric methods, and examine the effects of wood creosote on abnormal colonic motility induced by stress. METHODS Male Wistar rats were exposed to chronic psychological stress one hour per day, for 5 successive days. Manometric tracing of colonic motility was recorded in unrestrained conscious rats implanted with a cannula for intravenous (i.v.) injection. % motor index (%MI) of proximal and distal colon, during and after stress exposure was calculated. Wood creosote or vehicle was injected i.v. at 10 min before stress exposure on day 5. RESULTS In the proximal colon, %MI was increased during stress exposure on day 5 (stress rats; 119.5 ± 8.5%, non-stress rats; 92.7 ± 4.3%, p < 0.05, n = 7) but decreased after stress exposure (stress rats; 82.8 ± 5.6%, non-stress rats; 102.8 ± 4.7%, p < 0.05, n = 7). In the distal colon, on the other hand, %MI was not changed both during and after stress procedure. %MI of proximal and distal colon in rats received only a single stress exposure remained unchanged. I.v. injection of wood creosote prevented changes in %MI of proximal colon, both during and after stress exposure. CONCLUSIONS The results suggest that chronic, but not acute, psychological stress may induce abnormal colonic motility and wood creosote may be beneficial for the treatment or prevention of stress-induced abnormal colonic motility.
T1252 The Selective 5-HT1A Antagonist, AZD7371 (Robalzotan Tartrate Monohydrate), Inhibits Pain-Related Visceromotor, But Not Autonomic Cardiovascular, Responses to Colorectal Distension in Rats Erik Lindström, Anna Ravnefjord, Mikael Brusberg, Stephan Hjorth, Håkan Larsson, Vicente Martinez Background: 5-hydroxytrypamine 1A (5-HT1A) receptors have been suggested as a potential target for the treatment of IBS. However, a recent clinical trial investigating the efficacy and safety of the selective 5-HT1A antagonist AZD7371 (Robalzotan tartrate monohydrate, NAD299) showed no symptomatic improvement in IBS patients, leading to discontinuation of development (Am J Gastroent 103:2562, 2008). Aim: We characterized the mechanisms mediating potential analgesic effects of AZD7371 in a model of colorectal distension (CRD)induced visceral pain in rats to understand its mechanism of action and the lack of clinical efficacy. Methods: Visceromotor (activity of the abdominal musculature) and autonomic cardiovascular responses (blood pressure, BP; and heart rate, HR; using telemetry) were assessed in conscious rats during repetitive noxious CRD (12 distensions at 80 mmHg). Effects of AZD7371 (3-300 nmol/kg, iv and 1-30 μmol/kg, po) and the reference 5-HT1A antagonist, WAY 100635 (3-300 nmol/kg, iv), were assessed. Effects of intracerebroventricular (icv) AZD7371 on CRD-evoked pain and micturition were also evaluated. Results: Isobaric CRD (80 mmHg) induced visceromotor responses and cardiovascular changes (increase in HR and BP) indicative of visceral pain. AZD7371 and WAY 100635 (3, 10, 30, 100 or 300 nmol/kg, iv, n=4-8 for each dose and compound) inhibited the visceromotor response to CRD in a dose-related manner, with ED50s of 203 and 231 nmol/kg, respectively.
AGA Abstracts
A-532
The Effect of Central Adiposity On Esophageal Acid Exposure and Symptoms of Gastro-Esophageal Reflux Disease Roy Anggiansah, Rami Sweis, Angela Anggiansah, Terry Wong, Mark R. Fox
Pregabalin Prevents Development of Visceral Pain Hypersensitivity (VPH) in a Model of Esophageal Acid Sensitization in Healthy Volunteers Yang C. Chua, Abhishek Sharma, Kee Seong Ng, Jafar Jafari, Etsuro Yazaki, Charles H. Knowles, Qasim Aziz
INTRODUCTION: Epidemiologic evidence suggests a link between gastro-esophageal reflux disease (GERD) and obesity. Studies suggest that this relationship is due to the effects of central adiposity on intragastric pressure with disruption of the gastro-esophageal junction (GEJ) reflux barrier, however the clinical relevance of these findings has not been proven. METHODS: From Aug 2005 to Dec 2006, patients sent to a referral center for physiologic investigation of GERD were studied. Height, weight and waist circumference (WC) were measured. Stationary manometry and 24hr ambulatory pH studies off acid-suppressants were performed and symptom severity was assessed by a validated questionnaire. Linear regression models were used to analyze associations between covariates of interest and Pearson's correlation coefficient (PC) was applied to assess the strength of association. RESULTS: 582/676(86%) consecutive patients (age 48 (range 14-89), 56% female) had complete data for analysis. The prevalence of obesity defined by BMI≥30kg.m-2 in males and females was 16% and 23% (p=ns) respectively. More men had WC≥99cm (M41%:F28%; p<0.001)). %time pH<4 at 5cm above the lower esophageal sphincter (LES) increased with obesity (PC=0.255 and 0.240 for BMI and WC respectively; both p<0.001) and age (PC= 0.162; p<0.001) and was higher in men than women (p=0.014) Increase in %time pH<4 was associated with a reduction in LES pressure and abdominal LES length (PC=-0.327, -0.344 respectively; p<0.001). There was a weak negative association of BMI with LES pressure (PC=-0.140; p=0.005) but no link with abdominal LES length. In contrast, there was a significant negative association of WC with LES pressure (PC=-0.225; p<0.001) and abdominal LES length (PC=-0.213; p<0.001). Overall symptom severity increased with %time pH<4 (PC=0.209; p<0.001); however there was no change in symptom severity with BMI (PC=0.056, p=0.17) and the effect of WC was weak and of borderline significance (PC=0.083, p=0.05). CONCLUSION: In this large cohort of clinical patients referred for investigation of reflux symptoms, gastro-esophageal reflux increased with obesity and was most prevalent in elderly males with central adiposity. WC but not BMI was associated with both reduced LES pressure and abdominal length. These findings confirm the mechanistic link between increasing WC and the risk of reflux via raised intragastric pressure and disruption of the GEJ. In contrast, there was little change in symptom severity despite increased acid exposure in this group. The relative insensitivity to acid reflux may explain the increased prevalence of severe and complicated reflux in obese patients.
Background: Esophageal acid infusion in humans induces primary and secondary hyperalgesia due to peripheral and central sensitization respectively(1). Pregabalin is a centrally acting modulator of voltage-sensitive calcium channels which reduces pain hypersensitivity by attenuating the release of multiple neurotransmitters(2) in the CNS. Its efficacy in reducing acid-induced esophageal VPH has not been explored. Aim: To test the effects of pregabalin on the development of acid induced esophageal VPH in healthy human subjects. Methods: Single center, placebo-controlled, double blind, randomized, two-period, cross-over study was performed in healthy subjects who attended on 3 separate visits. On visit one, after esophageal manometry to determine the location of lower esophageal sphincter, pain thresholds (PT) to esophageal electrical stimulation were determined using bipolar ring electrodes positioned in the proximal and distal esophagus. Thereafter, a 30 minute infusion of hydrochloric acid was performed in the distal esophagus. PT was measured again at both sites at 30 and 90 minutes after the acid infusion. Participants were then given either pregabalin or placebo. During the second visit and third visits, at least 1 and 2 weeks later respectively, esophageal acidification and PT measurements were repeated. The dose of pregabalin used was 75mg twice daily for 3 days, 150mg twice daily for one day and 150mg once daily. Results: To date, 8 subjects have completed all visits (6 male, age range 21-31 years) and are included in this analysis. The mean ‘change in PT' for both time points compared to baseline in the proximal esophagus was -4.85mA after treatment with placebo compared to an increase of 2.65mA after treatment with pregabalin (p=0.0027)Table 1. The baseline PT at placebo and pregabalin visits were not significantly different(p=0.64). Interestingly, there were no differences in the change in PT after acid in the distal esophagus. Conclusion: Pregabalin prevents the development of secondary hyperalgesia in the proximal esophagus after distal esophageal acidification. It has no significant effect on the site of acid exposure, indicating that it acts to reduce central sensitization and does not appear to be analgesic. More detailed studies are required to assess the efficacy of pregabalin in patients with acidinduced esophageal VPH. 1. Sarkar Am J Physiol Gastrointest Liver Physiol 2001 2. Taylor Epilepsy Res 2007 Acknowledgement:Pfizer Ltd, UK Table 1:Mean change in PT after acid infusion
T1247 Effects of Chenodeoxycholic Acid On Gastrointestinal and Colonic Transit and Bowel Function in Healthy Volunteers Suwebatu T. Odunsi, Michael Camilleri, Irene Busciglio, Duane D. Burton, Jesse Lamsam, Sanna McKinzie, Ravinder J. Singh, Alan R. Zinsmeister
T1249 Effect of Two Novel, Selective Alpha4beta2 Nicotinic Receptor Partial Agonists On Restraint Stress-Induced Defecation in Rats Katsuyo Ohashi-Doi, Mitsuhisa Kawai, John B. Furness, Jeremy D. Gale
Dihydroxy bile acids cause colonic secretion and high amplitude propagating contractions (HAPC) after infusion of 1mM chenodeoxycholate (CDC) into human colon and 20mM in canine colon. CDC used in gallstone dissolution caused diarrhea. Aim: To evaluate doserelated effects of ileocolonic CDC delivery on gastrointestinal (GI) and colonic transit in health. Methods: This double-blind, placebo-controlled study evaluated effects of 4 days' treatment with CDC in 60 healthy volunteers (17 male, mean age 38.7 y), randomized to oral placebo, 500mg or 1000mg CDC delivered in pH-sensitive, methacrylate-coated capsules. Fasting serum 7α-hydroxy-4-cholesten-3-one (7α-HCO or C4) was measured to assess underlying bile acid malabsorption. GI and colonic transit were measured by scintigraphy during the last 48 h and bowel function by validated daily diaries including Bristol stool form scale. Treatment effects were compared by ANCOVA with age, gender and BMI as covariates. Results: In 94%, baseline serum C4 was normal (<61ng/mL). Gastric emptying t1/2 and colonic filling at 6 h were not significantly affected. There was a significant overall treatment effect of CDC on colonic transit (geometric center at 24 and 48 h, ANCOVA, p= 0.01 and p<0.0001 respectively; see figure); 1000mg was more effective than 500mg dose. There were significant overall treatment effects on stool frequency, consistency (figure), ease of passage and complete evacuation. Most common side effect was loose stools (43 and 57%) or diarrhea (35 and 65% with CDC 500mg and 1000mg respectively, both p<0.001 vs. placebo). No safety issues were identified. Conclusions: CDC accelerates whole colonic transit and loosens stool form. The potential of ileocolonic delivery of CDC in treatment of constipation deserves further study.
INTRODUCTION: Nicotinic acetylcholine receptors (nAChRs) are localised throughout the enteric nervous system (ENS) and have also been shown to modulate pathways associated with physical and psychological responses to stress. Nicotine is known to stimulate the release both of excitatory and inhibitory neurotransmitters in the ENS, including ACh and VIP by activating nAChRs. CP-601927 and CP-601932, bind with high affinity to rat and human alpha4beta2 nAChR subtypes and are selective partial agonists. Stress is well known to affect several gastrointestinal functions. In rat, stress-induced increases in defecation have been used as a model for some features of functional bowel disorders. The study aimed to assess whether partial agonists of alpha4beta2 nAChR were able to modulate stress-induced defecation in the rat. METHODS: Defecation in response to acute restraint stress was measured in non-fasted conscious male Sprague-Dawley rats. Rats were placed in wire-mesh restraint cages while control (non-stressed) rats were placed in large plastic cages. Fecal pellets were collected for 2 hr, and the defecation was expressed as the weight of fecal pellets in each group. RESULTS: Rats exposed to restraint stress for 2 hours showed a significant increase in both the number of fecal pellets and mean fecal wet weight compared with control rats (Stress, 2.93±0.25 g vs. Control, 0.17±0.09 g; p<0.01; n=9-10). CP-601927 (1 - 10 mg/kg, p.o.) produced a dose-dependent decrease in the stress-induced increase in fecal weight (1 mg/kg, 0.2%; 3 mg/kg, 13%; 10 mg/kg, 47% reduction; n=9). Statistical significance was observed in rats treated with 10 mg/kg (p<0.01). CP-601932 (1 and 3 mg/kg, p.o.) had little effect on the stress-induced increase, although the highest dose of 10 mg/kg elicited reduction of fecal weight (10 mg/kg, 79% reduction; n=6) which approached statistical significance (p=0.051). CONCLUSION: The present study demonstrates that oral administration of partial agonists for alpha4beta2 nAChRs have inhibitory effects on stress-induced increases in defecation in rats. The detailed mode of action requires further elucidation. Based on these finding, a partial agonist of alpha4beta2 nAChR might represent a novel compound for the modulation of GI transit and secretion and so may be worthy of investigation in functional GI disorders including IBS. T1250 Effect of Azithromycin On Small Bowel Motility in Patients with Gastrointestinal Dysmotility Payam Chini, Phillip P. Toskes, Wei Hou, Renee McDonald, Baharak Moshiree
Dose-related effect of 500mg and 1000mg CDC on colonic transit, stool frequency and consistency
Background: We have previously demonstrated that Azithromycin (AZI) stimulates antral activity as measured using antroduodenal manometry (ADM) in patients with known gastroparesis (GP) similar to erythromycin (EES) - the current most potent prokinetic available(Am J Gastro 2005; 100: S-326). Although EES does not induce phase III migrating motor complexes (MMCs) in the small bowel, we do not yet know the effect of AZI-a semi-synthetic macrolide-on small bowel activity in patients with documented small bowel dysmotility. Aim: Our study investigates the effect of AZI as compared to EES on duodenal activity in
A-531
AGA Abstracts
AGA Abstracts
T1246
AGA Abstracts
patients with gastrointestinal dysmotility (GID). Method: We evaluated a consecutive series of 21 patients referred to our Clinical Motility Lab for evaluation of chronic abdominal pain or suspected GID undergoing 24 hour ADM. Only those patients with GP and small bowel dysmotility were included. All patients had pressure profiles recorded in three stages: baseline period (BL), fed state after a standardized meal, and postprandial after administration of EES (250 mg IV) and AZI (250 mg IV). The measured parameters include the characteristics of the MMCs and AFs such as site of origin (antrum versus duodenum), duration of phase III activity, amplitude of phase III MMCs in duodenum and number of cycles per minute. The data were analyzed using a repeated measures analysis of variance for comparison of each medication. Results: Overall comparison of AZI and EES showed that AZI induced more MMCs in the duodenum with origin of AFs in the antrum than did EES (18 patients with AZI versus 10 patients with EES, p value = 0.0299). The average duration of MMCs and antral AFs were also longer in AZI group as compared with EES (AZI mean = 18.5 min, EES mean = 9.7 min, SEM 3.6 min, p value = 0.0172). Further comparison of pressure profiles seen at BL in the duodenum with AZI given in the postprandial state showed statistically significant improvement in the number of MMCs (BL mean = 1.2, AZI mean = 2.4, SEM = 0.42, p value = 0.0055) and number of AFs in the antrum (p value = 0.0256). No significant difference between AZI and BL fasting state was seen with respect to the duration of MMCs or number of cycles per minute. Conclusions: AZI induces AFs followed by duodenal contractions more frequently than EES, even in patients with GID. Furthermore, analysis of the duodenal MMC and AF characteristics indicates that the average duration of affect is also longer with AZI as compared to EES. Clearly, AZI is a promising prokinetic in patients with gastric and small bowel dysmotility but whether these findings translate into symptom improvement remains to be seen.
Oral AZD7371 (1, 3, 10 or 30 μmol/kg, n=7-8 per dose) inhibited visceromotor responses to CRD in a dose-related manner, with an ED50 of 14 μmol/kg. In telemetrized rats, AZD7371 (100 or 300 nmol/kg, iv, n=4 for each) inhibited the visceromotor response to CRD, but did not affect the rise in HR and BP in response to CRD. When administered icv, AZD7371 (1 μmol/rat, n=7) did not affect visceromotor responses to CRD, while it, as expected, inhibited micturition. None of the doses tested induced visible gross-side effects. Conclusions: AZD7371, likely acting at a peripheral and/or spinal site, inhibited the visceromotor, but not the autonomic cardiovascular, responses to visceral pain in the CRD model in rats. While agents effective on multiple pain-related readouts in the rat CRD model (e.g. pregabalin or clonidine) have alleviated IBS symptoms in clinical trials, data with compounds like AZD7371, effective on only one pseudo-affective readout during CRD in rats, need to be interpreted cautiously as it relates to its clinical translational value. These results question whether AZD7371-induced inhibition of visceromotor responses during CRD in rats reflects a true analgesic activity of the compound. T1253 Sumatriptan Inhibits the Colonic Response to Intragastric, But Not Intraduodenal, Nutrient Administration Sebastien Kindt, Rita Vos, Maura Corsetti, Jan F. Tack The gastrocolonic response consists of a tonic and phasic contractile response of the colon to meal-induced mechano- and chemoreceptor-activation in the stomach and duodenum. Besides cholinergic pathways, serotonin (5-HT)3 receptors have been implicated. Sumatriptan (Suma), a 5-HT1D receptor agonist, enhances gastric accommodation and delays gastric emptying, hereby modifying meal-induced mechano- and chemoreceptor activation. Our aim was to study the influence of sumatriptan on the colonic response to feeding. Methods: Twelve healthy subjects (8 men) underwent two colonic barostat studies, at least one week apart, with administration of Suma or placebo in a double-blind cross-over fashion. After cleansing with water enema, a combined manometry and barostat assembly was positioned in the descending colon. After a 30 minute adaptation period, intra-balloon pressure was set at operating pressure (lowest pressure inducing intra-balloon volume >30 ml) +2 mmHg. Suma 6 mg or saline were administered s.c. after 60 min, followed by oral (n=7) or intraduodenal (via nasoduodenal tube, 1.5 ml/min, n=5) administration of a liquid meal (Nutridrink 200 ml, 1.5kcal/ml). Changes in balloon volume before and after the meal, and at 5-min intervals, were compared using paired t-tests and repeated-measures ANOVA with Bonferroni post-hoc test. Results: Baseline colonic intra-balloon volumes were comparable under all study conditions. Suma significantly inhibited the meal-induced decrease of colonic balloon volumes (mean change -30.3±8.6 vs. 2.4±11.8 ml, p=0.04; ANOVA p=0.05), with a significant difference at 15 (-39.4±10.9 vs. 2.8±12.4 ml), 35 (-28.7±14.8 vs. 5.8±14.2 ml) and 50 (-39.2±17.0 vs. 9.3±15.3 ml) minutes postprandially on post-hoc testing (all p<0.05). Suma did not alter the colonic response to intraduodenal nutrient administration (mean change 5.05±31.0 vs. -0.5±10.7 ml, p=NS). Conclusion: The colonic contractile response to nutrient ingestion, the so-called gastrocolonic reflex, depends on the presence of intragastric nutrients. Administration of sumatriptan prior to nutrient ingestion inhibits this reflex.
T1251 Effects of STW 5 and Some of Its Components On Spontaneous Contractions in Mouse Ileum In Vitro Katrin Wald, Daniela Hagelauer, Bettina R. Vinson, Olaf Kelber, Dieter Weiser, Helmut Heinle INTRODUCTION: As several clinical studies have shown, STW 5 (Iberogast®) is effective in functional gastrointestinal diseases (1). Pharmacological studies have demonstrated its influence on gastric and intestinal smooth muscle (2, 3, 4) and were recently also confirmed by clinical pharmacological studies (5). As a phytomedicinal combination of nine herbal extracts, STW 5 is a multicomponent remedy, as are phytomedicines in general, irrespective whether they are based on single herbal extracts or combinations thereof. OBJECTIVES: It is therefore relevant to explore the contributions of the components of STW 5 to its effects by studying the extracts contained and even their single phytochemical components in pharmacological models In Vitro. METHODS: STW 5, the different extracts contained, and selected of their chemical components were studied. Rings of the ileum were mounted in a perfused organ bath and longitudinal spontaneous muscle activity and tonus were recorded. RESULTS: The ileum showed very stable spontaneous contractions (mean amplitude 3.4±2mN; mean frequency 21.6±4/minute). All plant extracts were applied in a dilution of 1:100, the chemical compounds in concentrations corresponding to those in the extracts. STW 5 decreased tone and amplitude of the contraction most distinctly, whereas the single plant extracts influenced contractility in different ways: peppermint, chamomile and angelica root strongly inhibited the characteristics of spontaneous contractility, whereas liquorice root and melissa showed minor effects on these parameters (2). None of the selected chemical compounds had significant effects on amplitude or frequency when applied in concentrations present in the genuine extracts. α-bisabolol (chamomilla), rosmarinic acid, citral, citronellal (all lemon balm) and kaempferol (Iberis amara) decreased amplitude and increased frequency significantly in concentrations above 300 μM CONCLUSION: These results suggest that the effects of STW 5 can not be simply deduced from those of their components and leads to the conclusion, that, like also in other phytomedicines, not single phytochemical components, but the extracts, as complex compositions of these, respective their combination are the active substances in this medicine. REFERENCES: 1. Schmulson M. Nature Clin Pract Gastro Hepatol 2008, 5, 136-137; 2. Schemann M et al. Phytomedicine 2006, 13, S V, 90-99; 3. Heinle H et al. Phytomedicine 2006, 13, S V, 75-79; 4. Okpanyi SN et al. Acta Hort 1993, 332, 227-235; 5. Pilichiewicz AN et al. Am J Gastro 2007, 102, 1-8; 6. Hagelauer D. Thesis, 2007, University of Tuebingen, Germany; 7. Wagner H. Phytomedicine 2006, 13, S V, 122-129
T1254 Chronic Psychological Stress Induces Abnormal Colonic Motility and Wood Creosote Prevents Its Abnormality in Unrestrained Conscious Rats Koji Ataka, Mineko Fujimiya BACKGROUND Psychological stress induces anxiety, increases blood pressure and heart rate, induces diarrhea and constipation, and has a close relationship with irritable bowel syndrome. Communication box is a device to provoke psychological stress in conscious rats; however its influence on colonic motility has not been examined. Wood creosote is an oral herbal medicine for treatment of acute diarrhea in Asia for more than a century. Our recent study has shown that wood creosote suppresses the colonic motor activity accelerated by corticotropin-releasing factor, a key brain mediator in the stress response. OBJECTIVE We aimed to examine the effects of psychological stress on the colonic motility measured by manometric methods, and examine the effects of wood creosote on abnormal colonic motility induced by stress. METHODS Male Wistar rats were exposed to chronic psychological stress one hour per day, for 5 successive days. Manometric tracing of colonic motility was recorded in unrestrained conscious rats implanted with a cannula for intravenous (i.v.) injection. % motor index (%MI) of proximal and distal colon, during and after stress exposure was calculated. Wood creosote or vehicle was injected i.v. at 10 min before stress exposure on day 5. RESULTS In the proximal colon, %MI was increased during stress exposure on day 5 (stress rats; 119.5 ± 8.5%, non-stress rats; 92.7 ± 4.3%, p < 0.05, n = 7) but decreased after stress exposure (stress rats; 82.8 ± 5.6%, non-stress rats; 102.8 ± 4.7%, p < 0.05, n = 7). In the distal colon, on the other hand, %MI was not changed both during and after stress procedure. %MI of proximal and distal colon in rats received only a single stress exposure remained unchanged. I.v. injection of wood creosote prevented changes in %MI of proximal colon, both during and after stress exposure. CONCLUSIONS The results suggest that chronic, but not acute, psychological stress may induce abnormal colonic motility and wood creosote may be beneficial for the treatment or prevention of stress-induced abnormal colonic motility.
T1252 The Selective 5-HT1A Antagonist, AZD7371 (Robalzotan Tartrate Monohydrate), Inhibits Pain-Related Visceromotor, But Not Autonomic Cardiovascular, Responses to Colorectal Distension in Rats Erik Lindström, Anna Ravnefjord, Mikael Brusberg, Stephan Hjorth, Håkan Larsson, Vicente Martinez Background: 5-hydroxytrypamine 1A (5-HT1A) receptors have been suggested as a potential target for the treatment of IBS. However, a recent clinical trial investigating the efficacy and safety of the selective 5-HT1A antagonist AZD7371 (Robalzotan tartrate monohydrate, NAD299) showed no symptomatic improvement in IBS patients, leading to discontinuation of development (Am J Gastroent 103:2562, 2008). Aim: We characterized the mechanisms mediating potential analgesic effects of AZD7371 in a model of colorectal distension (CRD)induced visceral pain in rats to understand its mechanism of action and the lack of clinical efficacy. Methods: Visceromotor (activity of the abdominal musculature) and autonomic cardiovascular responses (blood pressure, BP; and heart rate, HR; using telemetry) were assessed in conscious rats during repetitive noxious CRD (12 distensions at 80 mmHg). Effects of AZD7371 (3-300 nmol/kg, iv and 1-30 μmol/kg, po) and the reference 5-HT1A antagonist, WAY 100635 (3-300 nmol/kg, iv), were assessed. Effects of intracerebroventricular (icv) AZD7371 on CRD-evoked pain and micturition were also evaluated. Results: Isobaric CRD (80 mmHg) induced visceromotor responses and cardiovascular changes (increase in HR and BP) indicative of visceral pain. AZD7371 and WAY 100635 (3, 10, 30, 100 or 300 nmol/kg, iv, n=4-8 for each dose and compound) inhibited the visceromotor response to CRD in a dose-related manner, with ED50s of 203 and 231 nmol/kg, respectively.
AGA Abstracts
A-532