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Sa1376 Effect of Linaclotide on Colonic Motility Assessed With Intraluminal Colonic High-Resolution Manometry in Healthy Subjects: Preliminary Results
Sa1375
AGA Abstracts
Medical Management of Constipation: Do New Drugs Truly Offer New Benefits? Klaus Bielefeldt Based on improvements of abdominal pain during treatment, more recently introduced drug treatments for constipation, tegaserod, lubiprotsone and linaclotide, sought and obtained approval for irritable bowel syndrome with constipation (IBS-C) as well. The aim of the current study was to determine whether the observed decreases in pain level were unique effects or a consequence of their laxative properties, which can also be seen in other agents. METHODS: The pubmed databank was searched for clinical trials in constipation and IBSC to identify publications that provided detailed data on changes in bowel movement frequency and pain intensity for time points before and after a therapeutic intervention. The results were abstracted and subjected to a meta-regression analysis. RESULTS: A total of 23 fully reported trials (9 IBS-C) met entry criteria. When normalized to a 5 point scale, pain ratings were higher in IBS-C 2.50 [2.32-2.68] compared to data obtained in studies on constipation (2.15 [1.96-2.33]; P=0.008), while weekly bowel movement frequency were lower in constipation with 1.95 [1.68-2.28] versus 2.75 [2.40-3.11] in IBS-C (P=0.006). Using changes in pain intensity as dependent variable, the meta-regression demonstrated a significant correlation between treatment-induced increases in bowel frequency and decreased pain ratings. CONCLUSION: This analysis of composite data suggests that the effective treatment of constipation decreases discomfort independent of specific drug mechanisms, thus arguing against an additional benefit of newer and often more costly medications.
Figure. Ratio of the baseline value of colonic motility in the right colon, in the left colon and in the rectum. Sa1377 Preserved Colonic Meal Response and Functional Evidence for Anastomotic Nerve Regeneration in Patients With Normal Bowel Function Following Anterior Resection Ryash Vather, Greg O'Grady, Leo K. Cheng, Lukasz Wiklendt, David Rowbotham, Ian P. Bissett, Philip G. Dinning
Meta-regression demonstrating a significant correlation between changes in pain intensity and bowel patterns.
Background: Preservation of normal bowel function after an anterior resection, suggests that normal distal colonic motor patterns are restored. Yet this has never been clearly demonstrated. Using high-resolution fibre-optic manometry, our aim, in patients who had undergone anterior resection and reported normal bowel function, was to define whether these patients exhibited a normal distal colonic meal response, and to establish whether propagating motor patterns travelled across the site of anastomoses. Methods: 15 patients (6 males; median age 68 years; 47-75yr) that had undergone anterior resection >12 months prior, and reported normal bowel function, were included. All patients had had a primary end-to-end colonic anastomosis, located a >5cm above the anorectal junction. After an overnight fast a fibre-optic, high-resolution manometry catheter (36 sensors spaced at 1cm intervals) was positioned via colonoscopy into the distal colon with sensors straddling the site of anastomosis. Manometric recordings were taken 2hrs pre and post a 700cKal meal. These data were compared to 12 healthy controls (5 males; median age 51 yrs; 27-69yr). Spectral analysis was used to determine any dominant frequency of pressure events prior to or after a meal. Propagating motor patterns were defined as i) cyclic (at 2-6/min); ii) short single motor patterns (<1 per min; extent 7 ± 2 cm) , iii) long single motor patterns (<1 per min; amplitude 48 ± 13 mmHg; extent 42 ± 9 cm). The data are expressed as delta values (postprandial count - basal count). Results: Spectral analysis revealed a dominant pressure event frequency of 2-3cpm prior to the meal in the distal colon of both patients and healthy controls. In both groups the amplitude of the pressure events with this frequency increased significantly (P < 0.001) after the meal and this response did not differ between the two groups (p=0.7). Short and long single propagating motor patterns were identified in both groups but the frequency of these events was not influenced by a meal and the count of these events did not differ between the groups. In both patients and controls retrograde cyclic propagating motor patterns increased significantly after the meal (Patients; 2.1 ± 0.7 vs 32.6 ± 8.5 / 2hr; P = 0.0002)(Health; 8.1 ± 3.8 vs 59.1 ± 25.7 / 2hr; P < 0.001). The postprandial delta change in this motor pattern did not differ between the groups (ΔPatients; 30.5 ± 8.1 vs ΔPatients; 50.8 ± 22.4 / 2hr; P = 0.3). Retrograde or antegrade cyclic and short single propagating motor patterns were observed to cross the site of anastomosis in 11/15 patients. Conclusion: These data suggest a restoration of normal motility in the distal colon of patients that had undergone an anterior resection and preserved normal bowel function. Propagation of motor patterns across the site of anastomosis suggests a degree of nerve regeneration.
Sa1376 Effect of Linaclotide on Colonic Motility Assessed With Intraluminal Colonic High-Resolution Manometry in Healthy Subjects: Preliminary Results Maura Corsetti, Giuseppe Pagliaro, Silvia Cocca, Eveline Deloose, Ingrid Demedts, Jan F. Tack Polyethylene glycol (PEG), bisacodyl, prucalopride and linaclotide were demonstrated to be superior to placebo for treatment of chronic constipation (Ford AC 2011). Recently we demonstrated that PEG, prucalopride and bisacodyl have distinct effects on colonic phasic activity(Corsetti M, UEGW 2014). While PEG mainly increases low-amplitude phasic activity, bisacodyl mainly induces high amplitude phasic activity and prucalopride has no major effect on colonic phasic activity but increases the amplitude of high-amplitude propagating sequences (HAPSs). Aim of the study: to evaluate the effect of linaclotide as compared to placebo on colonic motility assessed with intraluminal colonic high resolution manometry (HRM). Methods: In 8 volunteers (25±0.7 years) two colonic HRM studies were performed, at least 10 days apart, after an overnight fast and tap water enema. During colonoscopy under conscious sedation the HRM catheter (40 solid state sensors, 2.5 cm spaced) was advanced as far as possible and clipped to the mucosa. After 90 min of basal recording, linaclotide 290 μg or placebo were administered orally in double-blind, randomized, crossover fashion, and the recording continued for 180 min before and after a standardized meal. Colonic motility index (MI; averaged every 15 min in the right and left colon and in the rectum, and expressed as ratio of the baseline value) of four periods (180 minutes before meal, first, second and third hour after the meal) was compared between treatments by means of a mixed models analysis with post-hoc t-tests and Bonferroni correction. Number of HAPSs, of long distance low-amplitude propagating sequences (LDPSs, defined according to Dinning et al 2014) and of pan-colonic pressurizations associated with anal sphincter relaxation (a colonic motor pattern we recently described, Corsetti M et al, FNM 2014) was compared between treatments by means of test student's test. Data are mean±SEM. Results: The catheter was clipped to the right colon mucosa in 10/16 studies, and at least to the splenic flexure in the remaining cases, with no difference according to treatment arm. Baseline MI did not differ between treatments in the right (3.3±0.3 for linaclotide and 4.5±0.4 for placebo, p= 0.26), left colon (3.2±0.7 and 4.4±0.7, p=0.20) and rectum (4.5±0.6 and 4.6±0.8, p= 0.69). At mixed models analysis, no treatment effect was found on the ratio of the baseline value of colonic MI in any of the region of the colon (all p> 0.21) (Figure). Respectively one and two HAPSs were reported in the postprandial period in two healthy subjects only during placebo. The number of pan-colonic pressurizations did not differ between treatments (76±12 for placebo vs 75±14 for linaclotide, p= 0.81) as well as that of LDPSs (3±2 vs 25±14, p= 0.18). Conclusions: In healthy controls, acute administration of linaclotide did not affect colonic motility.
Sa1378 Reduction of Breath Methane Using Rifaximin Shortens Colon Transit Time and Improves Constipation: A Randomized Double-Blind Placebo Controlled Trial Uday C. Ghoshal, Deepakshi Srivastava, Asha Misra Objective: Gut microbe-derived methane may slow transit causing chronic constipation (CC) and its reduction with antibiotic may improve it. Effect of rifaximin on methaneassociated slow transit CC was evaluated. Method: Bristol stool form, frequency, colon transit time (CTT) and breath methane were evaluated in 23 patients with CC (Rome III) and methane production compared with 68 non-constipating IBS. Methane-producing CC
AGA Abstracts
S-308
AGA Abstracts
Medical Management of Constipation: Do New Drugs Truly Offer New Benefits? Klaus Bielefeldt Based on improvements of abdominal pain during treatment, more recently introduced drug treatments for constipation, tegaserod, lubiprotsone and linaclotide, sought and obtained approval for irritable bowel syndrome with constipation (IBS-C) as well. The aim of the current study was to determine whether the observed decreases in pain level were unique effects or a consequence of their laxative properties, which can also be seen in other agents. METHODS: The pubmed databank was searched for clinical trials in constipation and IBSC to identify publications that provided detailed data on changes in bowel movement frequency and pain intensity for time points before and after a therapeutic intervention. The results were abstracted and subjected to a meta-regression analysis. RESULTS: A total of 23 fully reported trials (9 IBS-C) met entry criteria. When normalized to a 5 point scale, pain ratings were higher in IBS-C 2.50 [2.32-2.68] compared to data obtained in studies on constipation (2.15 [1.96-2.33]; P=0.008), while weekly bowel movement frequency were lower in constipation with 1.95 [1.68-2.28] versus 2.75 [2.40-3.11] in IBS-C (P=0.006). Using changes in pain intensity as dependent variable, the meta-regression demonstrated a significant correlation between treatment-induced increases in bowel frequency and decreased pain ratings. CONCLUSION: This analysis of composite data suggests that the effective treatment of constipation decreases discomfort independent of specific drug mechanisms, thus arguing against an additional benefit of newer and often more costly medications.
Figure. Ratio of the baseline value of colonic motility in the right colon, in the left colon and in the rectum. Sa1377 Preserved Colonic Meal Response and Functional Evidence for Anastomotic Nerve Regeneration in Patients With Normal Bowel Function Following Anterior Resection Ryash Vather, Greg O'Grady, Leo K. Cheng, Lukasz Wiklendt, David Rowbotham, Ian P. Bissett, Philip G. Dinning
Meta-regression demonstrating a significant correlation between changes in pain intensity and bowel patterns.
Background: Preservation of normal bowel function after an anterior resection, suggests that normal distal colonic motor patterns are restored. Yet this has never been clearly demonstrated. Using high-resolution fibre-optic manometry, our aim, in patients who had undergone anterior resection and reported normal bowel function, was to define whether these patients exhibited a normal distal colonic meal response, and to establish whether propagating motor patterns travelled across the site of anastomoses. Methods: 15 patients (6 males; median age 68 years; 47-75yr) that had undergone anterior resection >12 months prior, and reported normal bowel function, were included. All patients had had a primary end-to-end colonic anastomosis, located a >5cm above the anorectal junction. After an overnight fast a fibre-optic, high-resolution manometry catheter (36 sensors spaced at 1cm intervals) was positioned via colonoscopy into the distal colon with sensors straddling the site of anastomosis. Manometric recordings were taken 2hrs pre and post a 700cKal meal. These data were compared to 12 healthy controls (5 males; median age 51 yrs; 27-69yr). Spectral analysis was used to determine any dominant frequency of pressure events prior to or after a meal. Propagating motor patterns were defined as i) cyclic (at 2-6/min); ii) short single motor patterns (<1 per min; extent 7 ± 2 cm) , iii) long single motor patterns (<1 per min; amplitude 48 ± 13 mmHg; extent 42 ± 9 cm). The data are expressed as delta values (postprandial count - basal count). Results: Spectral analysis revealed a dominant pressure event frequency of 2-3cpm prior to the meal in the distal colon of both patients and healthy controls. In both groups the amplitude of the pressure events with this frequency increased significantly (P < 0.001) after the meal and this response did not differ between the two groups (p=0.7). Short and long single propagating motor patterns were identified in both groups but the frequency of these events was not influenced by a meal and the count of these events did not differ between the groups. In both patients and controls retrograde cyclic propagating motor patterns increased significantly after the meal (Patients; 2.1 ± 0.7 vs 32.6 ± 8.5 / 2hr; P = 0.0002)(Health; 8.1 ± 3.8 vs 59.1 ± 25.7 / 2hr; P < 0.001). The postprandial delta change in this motor pattern did not differ between the groups (ΔPatients; 30.5 ± 8.1 vs ΔPatients; 50.8 ± 22.4 / 2hr; P = 0.3). Retrograde or antegrade cyclic and short single propagating motor patterns were observed to cross the site of anastomosis in 11/15 patients. Conclusion: These data suggest a restoration of normal motility in the distal colon of patients that had undergone an anterior resection and preserved normal bowel function. Propagation of motor patterns across the site of anastomosis suggests a degree of nerve regeneration.
Sa1376 Effect of Linaclotide on Colonic Motility Assessed With Intraluminal Colonic High-Resolution Manometry in Healthy Subjects: Preliminary Results Maura Corsetti, Giuseppe Pagliaro, Silvia Cocca, Eveline Deloose, Ingrid Demedts, Jan F. Tack Polyethylene glycol (PEG), bisacodyl, prucalopride and linaclotide were demonstrated to be superior to placebo for treatment of chronic constipation (Ford AC 2011). Recently we demonstrated that PEG, prucalopride and bisacodyl have distinct effects on colonic phasic activity(Corsetti M, UEGW 2014). While PEG mainly increases low-amplitude phasic activity, bisacodyl mainly induces high amplitude phasic activity and prucalopride has no major effect on colonic phasic activity but increases the amplitude of high-amplitude propagating sequences (HAPSs). Aim of the study: to evaluate the effect of linaclotide as compared to placebo on colonic motility assessed with intraluminal colonic high resolution manometry (HRM). Methods: In 8 volunteers (25±0.7 years) two colonic HRM studies were performed, at least 10 days apart, after an overnight fast and tap water enema. During colonoscopy under conscious sedation the HRM catheter (40 solid state sensors, 2.5 cm spaced) was advanced as far as possible and clipped to the mucosa. After 90 min of basal recording, linaclotide 290 μg or placebo were administered orally in double-blind, randomized, crossover fashion, and the recording continued for 180 min before and after a standardized meal. Colonic motility index (MI; averaged every 15 min in the right and left colon and in the rectum, and expressed as ratio of the baseline value) of four periods (180 minutes before meal, first, second and third hour after the meal) was compared between treatments by means of a mixed models analysis with post-hoc t-tests and Bonferroni correction. Number of HAPSs, of long distance low-amplitude propagating sequences (LDPSs, defined according to Dinning et al 2014) and of pan-colonic pressurizations associated with anal sphincter relaxation (a colonic motor pattern we recently described, Corsetti M et al, FNM 2014) was compared between treatments by means of test student's test. Data are mean±SEM. Results: The catheter was clipped to the right colon mucosa in 10/16 studies, and at least to the splenic flexure in the remaining cases, with no difference according to treatment arm. Baseline MI did not differ between treatments in the right (3.3±0.3 for linaclotide and 4.5±0.4 for placebo, p= 0.26), left colon (3.2±0.7 and 4.4±0.7, p=0.20) and rectum (4.5±0.6 and 4.6±0.8, p= 0.69). At mixed models analysis, no treatment effect was found on the ratio of the baseline value of colonic MI in any of the region of the colon (all p> 0.21) (Figure). Respectively one and two HAPSs were reported in the postprandial period in two healthy subjects only during placebo. The number of pan-colonic pressurizations did not differ between treatments (76±12 for placebo vs 75±14 for linaclotide, p= 0.81) as well as that of LDPSs (3±2 vs 25±14, p= 0.18). Conclusions: In healthy controls, acute administration of linaclotide did not affect colonic motility.
Sa1378 Reduction of Breath Methane Using Rifaximin Shortens Colon Transit Time and Improves Constipation: A Randomized Double-Blind Placebo Controlled Trial Uday C. Ghoshal, Deepakshi Srivastava, Asha Misra Objective: Gut microbe-derived methane may slow transit causing chronic constipation (CC) and its reduction with antibiotic may improve it. Effect of rifaximin on methaneassociated slow transit CC was evaluated. Method: Bristol stool form, frequency, colon transit time (CTT) and breath methane were evaluated in 23 patients with CC (Rome III) and methane production compared with 68 non-constipating IBS. Methane-producing CC
AGA Abstracts
S-308