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Gastric Stimulation is an Option for Patients With Refractory Cyclical Vomiting Syndrome: One Year Follow up
Tu1389
Interpreting Symptoms Suggesting Gastroparesis in Patients After Gastric and Esophageal Surgeries Irene Sarosiek, Katherine P. Yates, Thomas L. Abell, Gianrico Farrugia, Frank A. Hamilton, William L. Hasler, Kenneth L. Koch, Linda Anh B. Nguyen, Henry P. Parkman, Pankaj J. Pasricha, William J. Snape, James Tonascia, Aynur Unalp-Arida, Richard McCallum
A Double-Blind, Randomized Placebo-Controlled Phase II Study of the Pharmacodynamics, Safety/Tolerability, and Pharmacokinetics of Single Doses of the Motilin Agonist GSK962040, in Patients With Type I Diabetes Mellitus (T1DM) and Gastroparesis Per M. Hellström, Jan F. Tack, Kimberley E. Stephens, Matthew E. Barton, Lakshmi S. Vasist, Duncan B. Richards, Pauline M. Williams, David H. Alpers, George E. Dukes
Background: Post-surgical gastroparesis (PSG) develops in up to 10% of patients who undergo intentional or inadvertent vagotomy and in up to 50% of patients undergoing surgery for gastric outlet obstruction. Dumping syndrome is also a possible outcome from these surgeries. Aim: The aims of this study were to: 1) describe the clinical features of patients presenting with PSG symptoms; 2) identify surgeries associated with PSG; 3) distinguish PSG from a possible Dumping Syndrome. Methods: Medical and surgical history, symptoms assessment (PAGI-SYM,PAGI -QOL, Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), and standardized 4-hour radionuclide gastric emptying test (GET) on patients with at least 12 weeks of gastroparesis (GP) symptoms were performed. Data were analyzed from the ongoing NIDDK GP Registry. All results are presented as percent or mean ± SD. Results: Out of 571 patients, 23 (4 %) qualified as having PSG symptoms. Of these 19 (83%) were F; mean age 48.0±13.2 years; mean BMI 24.7 ±6.5 (61% had a BMI ≤ 24). The mean symptoms duration was 6 years and onset of GP symptoms was associated with the following surgeries: Nissen Fundoplication (52%), partial gastric resection (22%); myotomy or esophago-gastrectomy (9% each); and stomach stapling and vagotomy (4% each). 52% of patients had been hospitalized in the past year and nausea with abdominal pain was the major indication for 78% of these admissions. 52% were on prokinetics, 78% on antiemetics, 78% on PPI / H2 blockers and 26% were on narcotics. None of the patients underwent Botox and 1 had Enterra therapy. The results of GET separated patients with PSG symptoms into: Group A-17(74%) with delayed GET- mean value of 43.3 %± 26% retention at 4h (min-14; max -100% ), and 9 (53%) of them had severely delayed gastric emptying (>35% retention at 4h) and Group B- 6 (26%) without delayed GET, with a mean of 5.3% food retention at 4 h (min-1, max-7%) and with 2 (33%) of these patients meeting the criterion for Dumping Syndrome with ≤30% retention at1h. Overall, the highest mean PAGI-SYM score was for nausea 3.7 ± 1.3(max 5) and early satiety at 3.7±1.3. 17% of all studied patients had severe depression by BDI, 30% had severe STAI score. The average PAGI-QOL score was 2.7±1.1; with the poorest QOL for the diet sub-score (1.6±1.2). There were no statistical differences in symptoms or psychological parameters between the two groups. Conclusions: 1) In the setting of post-gastric and -esophageal surgeries, symptoms associated with delayed, normal or rapid emptying of the stomach are clinically indistinguishable and only GET could guide further medical and therapeutic approaches 2) Nissen Fundoplication is now the major surgery associated with PSG symptoms and could be attributed to “accidental” vagal nerve injury during surgery.
Background: GSK962040 (040), a small molecule selective motilin agonist, significantly enhanced gastric emptying (GE) in healthy volunteers when given as oral single (50-150mg) or repeat doses (50-125mg) for 14 days (Dukes G, Neurogastroenterol Motil 2009 & 2010). The current study (MOT111809) evaluated the effect of oral single doses on GE in T1DM subjects with gastroparesis, as well as the safety/tolerability and pharmacokinetics (PK) of 040 in this patient population. Methods: T1DM patients (males (n=1) and females (n=7)) with at least a 3 month history of symptoms of gastroparesis and a previous diagnosis of gastroparesis by scintigraphy or breath test were randomly assigned to receive placebo and 2 of 3 doses (25, 50, or 125 mg) in a 3-period incomplete block cross-over design. GE was assessed by the [13C]-octanoic acid breath method for a 4-hr post-meal period, beginning 90 min post-dose. Primary endpoint was half-emptying time of GE (GET½). Results: GSK962040 was generally well-tolerated with no serious drug-related adverse events (AEs) or changes in ECG/chemistry values. The least squares mean GET½ following placebo was 154.85 min (95% CI 110.66, 199.03) (ULN=109 min) and was significantly (p<0.05) shorter following a 125 mg dose (55.32 min; 95% CI 3.50, 107.13). GSK962040 produced a mean within-subject decrease in GET½ from placebo of 30% for the 25 and 50 mg doses and 64% for the 125 mg dose. Three of 5 subjects who received 25 mg, 3/5 who received 50 mg, and 6/6 who received 125 mg decreased their GET½ to values below ULN. Fasting glucose levels did not adversely affect the ability of the drug to enhance GE. The 040 PK parameters were generally consistent with those observed in healthy volunteers with greater variability in absorption, yet enhancement of GE vs. AUC was consistent with a positive exposure/response relationship. Conclusion: GSK962040, given as single oral doses up to 125 mg, was generally well-tolerated, exhibited favorable oral PK, and enhanced GE in T1DM patients with gastroparesis. Compared with placebo, there was a significant increase in the rate of GE following single doses of 125 mg.
Tu1388
Tu1390
Gastric Stimulation is an Option for Patients With Refractory Cyclical Vomiting Syndrome: One Year Follow up Inderpreet Grover, Shivangi Kothari, Archana Kedar, Christopher J. Lahr, David R. Fleisher, Thomas L. Abell, Danielle C. Spree
Motility Parameters and Luminal pH Does Not Correlate With Small Intestinal Bacterial Overgrowth in Patients With Chronic Idiopathic Constipation Laura A. Buchanan, Shilpa C. Reddy, Meagan Gray, Jennifer Eversmann, John M. Wo Constipation has been reported to increase intestinal gas production in small bowel. However, pathophysiologic mechanism for this is unclear. Aim: To identify the risk factors for developing small intestinal bacterial overgrowth (SIBO) in patients with chronic idiopathic constipation. Methods: Prospective study was performed on patients with chronic idiopathic constipation by Rome III criteria (GI surgery and secondary constipation were excluded). All prokinetics, probiotics, antibiotics and treatment for constipation was withheld for 4 weeks. After an overnight fast, lactulose breath test was performed with 10 cc oral lactulose; breath samples were obtained every 15 min for 3 hrs. A rise of >20 ppm in either hydrogen (H2) or methane (CH4) concentration within first 90 min was considered positive. Wireless motility capsule (SmartPill®) using the standard method was obtained after breath testing. Potential physiologic and diagnostic parameters that may be associated with SIBO were defined prospectively (motility index, contraction frequency, segment transit time and luminal pH). These parameters were determined in the entire small bowel, distal small bowel [30 min before ileocecal junction (ICJ)], cecum (30 min after ICJ) and entire colon. Comparisons were made between subjects without and with SIBO. Mann-Whitney U test for unpaired non-parametric data were utilized with SPSS. Results: 20 constipation subjects (mean age 46 yrs, 85% F, mean BMI 27.4) were enrolled. 40% of subjects had SIBO (30% by H2; 10% by CH4). 35% of subjects had delayed small bowel transit and 40% had delayed colon transit; 1 subject (5%) had both. Motility results are shown in box plots below. There were no significant differences in any motility parameters between the two groups. pH data were also similar. Median (25th-75th percentile) pH was 7.29 (7.21-7.57) and 7.49 (7.147.60) in distal small bowel from subjects with SIBO (-) and SIBO (+), respectively (p=0.76). Median (25th-75th percentile) pH was 6.34 (5.53-6.94) and 6.24 (6.03-6.54) in cecum from subjects with SIBO (-) and SIBO (+), respectively (p=0.87). Conclusions: 1) SIBO was common in patients with constipation. 2) Presence of SIBO was not associated with motility or pH parameters in small bowel or colon. 3) Further studies are needed to determine pathophysiologic correlates of SIBO in patients with constipation.
Purpose: Cyclic vomiting syndrome (CVS) is a migraine variant which manifests as severe episodes of nausea and vomiting that can be refractory to other therapies. Gastric electrical stimulation (GES) is a proven therapy for nausea and vomiting, but is untried in CVS. We previously reported that GES can be helpful for refractory CVS patients. (DDW abstract 2010). Patients: We studied 11 consecutive patients (4 white males, 4 white females, 3 black males; mean age 38 yrs; 6 with concomitant glucose intolerance) with drug refractory CVS. All patients met Rome criteria and NASPGHAN consensus classification, and underwent temporary GES (tGES) placement prior to permanent GES (pGES) implantation. Methods: All patients received temporary and permanent GES devices using previously described protocols (GIE, 61:455-461, 2005). Standardized symptom tools and physiologic evaluations were used to obtain measures at baseline, with tGES, and with pGES for GET and EGG (cutaneous, mucosal, and serosal), and for patient-reported outcomes, using a Likert scale (0-4, none-worst) tool for Nausea (N), Vomiting (V), Bloating (Bl), Abdominal pain (AP), and Early Satiety (ES), with values summed to produce a Total Symptom Score (TSS) (020). Hospital admissions per year were assessed at baseline, at temporary GES, and after implantation of permanent GES for one year. Results were compared by paired t-tests and reported as mean ± SD. Patients had an overall improvement in symptoms during both temporary and permanent GES as well as fewer hospital admissions. Findings were statistically significant in terms of fewer hospitalizations and decreased vomiting intensity/frequency when followed over a period of one year. (See details in the table below) Conclusions: In a small group of drug refractory CVS patients, temporary and permanent GES reduced symptom occurrence and hospital admissions. GES may be a viable option for some patents with refractory CVS. Hospitalization and Vomiting: Before and After PERM
Motility index, contraction frequency and segment transit times in patients without and with SIBO: Horizontal line (median), box (25th-75th percentile) & bar (5th-95th percentile).
S-813
AGA Abstracts
AGA Abstracts
Tu1387
Interpreting Symptoms Suggesting Gastroparesis in Patients After Gastric and Esophageal Surgeries Irene Sarosiek, Katherine P. Yates, Thomas L. Abell, Gianrico Farrugia, Frank A. Hamilton, William L. Hasler, Kenneth L. Koch, Linda Anh B. Nguyen, Henry P. Parkman, Pankaj J. Pasricha, William J. Snape, James Tonascia, Aynur Unalp-Arida, Richard McCallum
A Double-Blind, Randomized Placebo-Controlled Phase II Study of the Pharmacodynamics, Safety/Tolerability, and Pharmacokinetics of Single Doses of the Motilin Agonist GSK962040, in Patients With Type I Diabetes Mellitus (T1DM) and Gastroparesis Per M. Hellström, Jan F. Tack, Kimberley E. Stephens, Matthew E. Barton, Lakshmi S. Vasist, Duncan B. Richards, Pauline M. Williams, David H. Alpers, George E. Dukes
Background: Post-surgical gastroparesis (PSG) develops in up to 10% of patients who undergo intentional or inadvertent vagotomy and in up to 50% of patients undergoing surgery for gastric outlet obstruction. Dumping syndrome is also a possible outcome from these surgeries. Aim: The aims of this study were to: 1) describe the clinical features of patients presenting with PSG symptoms; 2) identify surgeries associated with PSG; 3) distinguish PSG from a possible Dumping Syndrome. Methods: Medical and surgical history, symptoms assessment (PAGI-SYM,PAGI -QOL, Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), and standardized 4-hour radionuclide gastric emptying test (GET) on patients with at least 12 weeks of gastroparesis (GP) symptoms were performed. Data were analyzed from the ongoing NIDDK GP Registry. All results are presented as percent or mean ± SD. Results: Out of 571 patients, 23 (4 %) qualified as having PSG symptoms. Of these 19 (83%) were F; mean age 48.0±13.2 years; mean BMI 24.7 ±6.5 (61% had a BMI ≤ 24). The mean symptoms duration was 6 years and onset of GP symptoms was associated with the following surgeries: Nissen Fundoplication (52%), partial gastric resection (22%); myotomy or esophago-gastrectomy (9% each); and stomach stapling and vagotomy (4% each). 52% of patients had been hospitalized in the past year and nausea with abdominal pain was the major indication for 78% of these admissions. 52% were on prokinetics, 78% on antiemetics, 78% on PPI / H2 blockers and 26% were on narcotics. None of the patients underwent Botox and 1 had Enterra therapy. The results of GET separated patients with PSG symptoms into: Group A-17(74%) with delayed GET- mean value of 43.3 %± 26% retention at 4h (min-14; max -100% ), and 9 (53%) of them had severely delayed gastric emptying (>35% retention at 4h) and Group B- 6 (26%) without delayed GET, with a mean of 5.3% food retention at 4 h (min-1, max-7%) and with 2 (33%) of these patients meeting the criterion for Dumping Syndrome with ≤30% retention at1h. Overall, the highest mean PAGI-SYM score was for nausea 3.7 ± 1.3(max 5) and early satiety at 3.7±1.3. 17% of all studied patients had severe depression by BDI, 30% had severe STAI score. The average PAGI-QOL score was 2.7±1.1; with the poorest QOL for the diet sub-score (1.6±1.2). There were no statistical differences in symptoms or psychological parameters between the two groups. Conclusions: 1) In the setting of post-gastric and -esophageal surgeries, symptoms associated with delayed, normal or rapid emptying of the stomach are clinically indistinguishable and only GET could guide further medical and therapeutic approaches 2) Nissen Fundoplication is now the major surgery associated with PSG symptoms and could be attributed to “accidental” vagal nerve injury during surgery.
Background: GSK962040 (040), a small molecule selective motilin agonist, significantly enhanced gastric emptying (GE) in healthy volunteers when given as oral single (50-150mg) or repeat doses (50-125mg) for 14 days (Dukes G, Neurogastroenterol Motil 2009 & 2010). The current study (MOT111809) evaluated the effect of oral single doses on GE in T1DM subjects with gastroparesis, as well as the safety/tolerability and pharmacokinetics (PK) of 040 in this patient population. Methods: T1DM patients (males (n=1) and females (n=7)) with at least a 3 month history of symptoms of gastroparesis and a previous diagnosis of gastroparesis by scintigraphy or breath test were randomly assigned to receive placebo and 2 of 3 doses (25, 50, or 125 mg) in a 3-period incomplete block cross-over design. GE was assessed by the [13C]-octanoic acid breath method for a 4-hr post-meal period, beginning 90 min post-dose. Primary endpoint was half-emptying time of GE (GET½). Results: GSK962040 was generally well-tolerated with no serious drug-related adverse events (AEs) or changes in ECG/chemistry values. The least squares mean GET½ following placebo was 154.85 min (95% CI 110.66, 199.03) (ULN=109 min) and was significantly (p<0.05) shorter following a 125 mg dose (55.32 min; 95% CI 3.50, 107.13). GSK962040 produced a mean within-subject decrease in GET½ from placebo of 30% for the 25 and 50 mg doses and 64% for the 125 mg dose. Three of 5 subjects who received 25 mg, 3/5 who received 50 mg, and 6/6 who received 125 mg decreased their GET½ to values below ULN. Fasting glucose levels did not adversely affect the ability of the drug to enhance GE. The 040 PK parameters were generally consistent with those observed in healthy volunteers with greater variability in absorption, yet enhancement of GE vs. AUC was consistent with a positive exposure/response relationship. Conclusion: GSK962040, given as single oral doses up to 125 mg, was generally well-tolerated, exhibited favorable oral PK, and enhanced GE in T1DM patients with gastroparesis. Compared with placebo, there was a significant increase in the rate of GE following single doses of 125 mg.
Tu1388
Tu1390
Gastric Stimulation is an Option for Patients With Refractory Cyclical Vomiting Syndrome: One Year Follow up Inderpreet Grover, Shivangi Kothari, Archana Kedar, Christopher J. Lahr, David R. Fleisher, Thomas L. Abell, Danielle C. Spree
Motility Parameters and Luminal pH Does Not Correlate With Small Intestinal Bacterial Overgrowth in Patients With Chronic Idiopathic Constipation Laura A. Buchanan, Shilpa C. Reddy, Meagan Gray, Jennifer Eversmann, John M. Wo Constipation has been reported to increase intestinal gas production in small bowel. However, pathophysiologic mechanism for this is unclear. Aim: To identify the risk factors for developing small intestinal bacterial overgrowth (SIBO) in patients with chronic idiopathic constipation. Methods: Prospective study was performed on patients with chronic idiopathic constipation by Rome III criteria (GI surgery and secondary constipation were excluded). All prokinetics, probiotics, antibiotics and treatment for constipation was withheld for 4 weeks. After an overnight fast, lactulose breath test was performed with 10 cc oral lactulose; breath samples were obtained every 15 min for 3 hrs. A rise of >20 ppm in either hydrogen (H2) or methane (CH4) concentration within first 90 min was considered positive. Wireless motility capsule (SmartPill®) using the standard method was obtained after breath testing. Potential physiologic and diagnostic parameters that may be associated with SIBO were defined prospectively (motility index, contraction frequency, segment transit time and luminal pH). These parameters were determined in the entire small bowel, distal small bowel [30 min before ileocecal junction (ICJ)], cecum (30 min after ICJ) and entire colon. Comparisons were made between subjects without and with SIBO. Mann-Whitney U test for unpaired non-parametric data were utilized with SPSS. Results: 20 constipation subjects (mean age 46 yrs, 85% F, mean BMI 27.4) were enrolled. 40% of subjects had SIBO (30% by H2; 10% by CH4). 35% of subjects had delayed small bowel transit and 40% had delayed colon transit; 1 subject (5%) had both. Motility results are shown in box plots below. There were no significant differences in any motility parameters between the two groups. pH data were also similar. Median (25th-75th percentile) pH was 7.29 (7.21-7.57) and 7.49 (7.147.60) in distal small bowel from subjects with SIBO (-) and SIBO (+), respectively (p=0.76). Median (25th-75th percentile) pH was 6.34 (5.53-6.94) and 6.24 (6.03-6.54) in cecum from subjects with SIBO (-) and SIBO (+), respectively (p=0.87). Conclusions: 1) SIBO was common in patients with constipation. 2) Presence of SIBO was not associated with motility or pH parameters in small bowel or colon. 3) Further studies are needed to determine pathophysiologic correlates of SIBO in patients with constipation.
Purpose: Cyclic vomiting syndrome (CVS) is a migraine variant which manifests as severe episodes of nausea and vomiting that can be refractory to other therapies. Gastric electrical stimulation (GES) is a proven therapy for nausea and vomiting, but is untried in CVS. We previously reported that GES can be helpful for refractory CVS patients. (DDW abstract 2010). Patients: We studied 11 consecutive patients (4 white males, 4 white females, 3 black males; mean age 38 yrs; 6 with concomitant glucose intolerance) with drug refractory CVS. All patients met Rome criteria and NASPGHAN consensus classification, and underwent temporary GES (tGES) placement prior to permanent GES (pGES) implantation. Methods: All patients received temporary and permanent GES devices using previously described protocols (GIE, 61:455-461, 2005). Standardized symptom tools and physiologic evaluations were used to obtain measures at baseline, with tGES, and with pGES for GET and EGG (cutaneous, mucosal, and serosal), and for patient-reported outcomes, using a Likert scale (0-4, none-worst) tool for Nausea (N), Vomiting (V), Bloating (Bl), Abdominal pain (AP), and Early Satiety (ES), with values summed to produce a Total Symptom Score (TSS) (020). Hospital admissions per year were assessed at baseline, at temporary GES, and after implantation of permanent GES for one year. Results were compared by paired t-tests and reported as mean ± SD. Patients had an overall improvement in symptoms during both temporary and permanent GES as well as fewer hospital admissions. Findings were statistically significant in terms of fewer hospitalizations and decreased vomiting intensity/frequency when followed over a period of one year. (See details in the table below) Conclusions: In a small group of drug refractory CVS patients, temporary and permanent GES reduced symptom occurrence and hospital admissions. GES may be a viable option for some patents with refractory CVS. Hospitalization and Vomiting: Before and After PERM
Motility index, contraction frequency and segment transit times in patients without and with SIBO: Horizontal line (median), box (25th-75th percentile) & bar (5th-95th percentile).
S-813
AGA Abstracts
AGA Abstracts
Tu1387