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Sa2033 Chronic Constipation: ROME III Criteria and What Patients Think. Are We Talking the Same Language?
AGA Abstracts
CTT or occlusion related to fecaloma. After a one-year follow-up, 17 patients (85 %) were satisfied with at least 1 stool/d, and 3 still had constipation. Conclusion : In patients with severe colonic inertia requiring surgery, morphometric analysis is more sensitive than semiquantitative analysis to detect a defect in ICC In our study, the severity of constipation seems unrelated to the importance of this defect and ICC evaluation has little clinical interests. Clearly, patients with SCI are satisfied after colectomy. Reference Wang et al, Am J Pathol 2008, 32 : 980-5.
Sa2036 A Pooled Analysis of Response to Lubiprostone in Patients With OpioidInduced Constipation Receiving Non-Methadone Opioids Versus Methadone Egilius L. Spierings, Douglas A. Drossman, Byron L. Cryer, Taryn Losch-Beridon, Ryuji Ueno Background: Lubiprostone is indicated in the United States, at a dose of 24 mcg twice daily (BID), to treat opioid-induced constipation (OIC) in adults with chronic non-cancer pain. However, its efficacy has not been established in patients receiving methadone or other opioids of the diphenylheptane class. In non-clinical models, methadone dose-dependently reduces lubiprostone-mediated activation of its molecular target, the ClC-2 chloride channel (Cuppoletti et al. Cell Biochem Biophys. 2013:66:53-63). This analysis examined treatment response in patients receiving non-methadone opioids vs methadone, using pooled pivotal trial data from the lubiprostone OIC development program. Methods: Data were pooled from three phase 3, randomized, double-blind, placebo-controlled, 12-week studies. Patients with ≥9 weeks of non-missing weekly spontaneous bowel movement (SBM) rates were defined as overall responders if they had ≥1 additional SBM compared to baseline for each week data are available and ≥3 SBMs per week for at least 9 weeks. Results: A total of 1300 patients were pooled; 1297 had opioid class data (non-methadone, n=1140; methadone, n=157). In patients receiving non-methadone opioids, 63% were female, the mean±SD age was 50.7±10.6 years, 91% were <65 years old, 81% were white, and 15% were Black/ African American. In patients receiving methadone, 60% were female, the mean±SD age was 49.0±10.5 years, 96% were <65 years old, 87% were white, and 10% were Black/ African American. Among the 1140 patients receiving non-methadone opioids, a significantly greater proportion treated with lubiprostone met response criteria, compared with placebotreated patients (Table). In the 157 patients receiving methadone, the response rate was statistically similar for patients treated with lubiprostone vs placebo (Table). Conclusions: Results of this pooled analysis of OIC pivotal studies demonstrate a statistically significant treatment response with lubiprostone compared with placebo in patients receiving nonmethadone opioids but not in patients receiving methadone. These clinical results are consistent with preclinical studies indicating that methadone dose-dependently reduces the ability of lubiprostone to activate the ClC-2 chloride channel. Response to Lubiprostone and Placebo in Patients Receiving Non-Methadone Opioids vs Methadone
Sa2033 Chronic Constipation: ROME III Criteria and What Patients Think. Are We Talking the Same Language? Dario Gambaccini, Caterina Racale, Stefano Salvadori, Gabrio Bassotti, Filippo Pucciani, Edda Battaglia, Renato Bocchini, Antonio Bove, Pietro Alduini, Santino Marchi, Massimo Bellini Background Chronic constipation is usually diagnosed using Rome III Criteria, but in clinical practice many physicians do not use these criteria and many patients consider themselves constipated while not showing signs or symptoms consistent with these criteria. They require help from their physicians for a "self reported constipation". On the other hand some people could meet the Rome criteria for constipation while considering themselves perfectly "normal". Aim To evaluate the correlation between the self reported constipation, functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) diagnosed according Rome III criteria. Methods 934 patients referred for gastroenterological visit and 980 carers were asked if they considered themselves to be affected with chronic constipation. Afterward they were invited to record anonymously their demographic data and symptoms in order to verify if they could be diagnosed as FC or IBS-C or not (self perceived constipation "SPC"). The overall score of PAC-QoL, ODS score and CSI of these patients were also recorded. Subjects with known or suspected severe organic diseases potentially causing constipation or assuming potentially constipating drugs were excluded. Results Data from 1914 subjects (patients and carers) were obtained (38.2% M; 61.8% F; mean age 50.6 ± SD 15.8). Among these 661/1914 (34.5%) subjects considered themselves to be constipated and 1253 (65.5%) not to be constipated (p<0.001). Among the "constipated" group (661 subjects) Rome III criteria for FC were satisfied in 290 (44%), Rome III criteria for IBS-c in 282 (43%); the Rome III criteria were not satisfied in 89 (13%) subjects (SPC patients). The ODS score was lower (p<0.05) in SPC than in subjects with a ROME III positive diagnosis. In 1253 subjects that not considered themselves to be constipated, diagnosis of FC and IBS-c according to Rome III criteria were feasible in 163 (13%) and 76 (6%) subjects. PAC-QoL and ODS score were lower than in patients which considered themselves to be constipated. No difference in ODS score was founded between subjects with FC and IBSC. A measure of agreement between ROME III criteria (FC and IBS-c) and patients conception of constipation was reported (K Cohen 0.64). Conclusions There is a substantial but not a total agreement between ROME III criteria (IBS-C and FC) and what patients call constipation. FC, IBS-C and SCP are not easily separable conditions in clinical practice. Patients tend often to define "constipation" the combination of different symptoms that are not usually included in Rome III criteria for the diagnosis of constipation. QoL is similar between FC, IBS but is lower in patients that consider themselves to be constipated and higher in SPC. Is it time for a revision of Rome Criteria for constipation?
Sa2037 Effect of DA-6886 on Gastrointestinal Transit and Defecation in Mice Kang Hun Cho, Min Jung Lee, Hyun Min Park, Weonbin Im, Sunghak Choi Purpose: Gastrointestinal prokinetics have been considered the therapeutic option of choice for functional gastrointestinal disorders. DA-6886, the gastrointestinal prokinetic agent is a potent 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation. The aim of the present study was to investigate the effects of DA-6886 on gastrointestinal transit and defecation in conscious mice. Methods: Effect of DA-6886 on gastrointestinal transit was assessed by the whole gastrointestinal transit in mice. The whole gastrointestinal transit was measured the excretion time of fecal pellet containing with dye following treatment of DA-6686 by intraperitoneal(ip) injection and administration of dye meal by gavage, simultaneously. To demonstrate the effect of DA-6886 on defecation, fecal pellets were collected each 1 h for the 3 h following drug oral administration. The number of fecal pellets was counted and fecal dry weight was measured. Results: DA-6886 was significantly enhanced gastrointestinal transit in a dosedependent manner (0.02 ~ 0.5 mg/kg, ip). The number of fecal pellets and fecal dry weight were increased by oral administration of DA-6886 (0.3mg/kg), similar to 10mg/kg of tegaserod. 1mg/kg of DA-6886 was significantly increased defecation compared to vehicle control. Conclusions: DA-6886 is a potent 5-HT4 agonist with increased gastrointestinal transit activity and enhanced defecation in mice, which may be effective for the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation.
Sa2034 Accurate Interpretation of Breath Test Results Depends on Measuring Hydrogen Sulfide in Non-Methane Excretors Benjamin J. Burnett, Prashanth Setty, Sudha B. Singh, Henry C. Lin Breath tests are widely used to detect excessive fermentation by gut bacteria. Since fermentation by hydrogenogenic microbes is the sole source of hydrogen (H2) appearing in the exhaled breath, a low peak breath hydrogen concentration, e.g., <20 parts per million (ppm) after lactulose administration has been interpreted as a negative result for excessive fermentation, a finding often used to rule out bacterial overgrowth. However, H2 production is balanced by H2 consumption via 1 of 3 microbial pathways (methanogens converting H2 to methane (CH4), sulfate-reducing bacteria (SRB) converting H2 to hydrogen sulfide (H2S) and acetogens converting H2 to acetate). Since commercially available clinical gas analyzers measure only H2 and CH4, excessive fermentation may be missed in non-methane excretors leading to a false-negative test result when excessive H2 production is masked by conversion of H2 to H2S, a gas that is not routinely measured. Aim: In this study, we tested the hypothesis that detection of excessive fermentation may depend on measuring H2S in non-methane excretors. Methods: To test this hypothesis, we measured H2S concentration in parts per billion (OralChroma) and H2 and CH4 concentrations in ppm (Quintron SC) excreted by rats that are housed in metabolic cages over 180 min. Twenty-eight rats were randomized into 1 of 4 treatments, each consisting of a single gavage of a lactulose and mannitol solution with saline with varying load of SRB (Desulfovibrio vulgaris): 0 (No SRB), 10^8 (Low SRB), 10^9 (Mid SRB), or 10^10 (High SRB). H2 concentrations were measured and rats were categorized as Positive for excessive fermentation if peak [H2] > 20 ppm and Negative for excessive fermentation if peak [H2 ] ≤ 20 ppm. H2S concentrations were also measured. If H2S were to be detected but peak [H2 ] ≤ 20 ppm, the result was considered a false negative as the peak [H2] alone would have been interpreted as negative for excessive fermentation. Experimental results were assigned a value of 0 for correctly assessed result (no error) and a value of 1 for incorrectly assessed result (false negative) and mean values +/- SE were compared using a one-way ANOVA. Results: 1. All groups contained some false negative breath test results (No SRB: 0.285 +/- 0.18, Low SRB: 0.429 +/- 0.20, Mid SRB: 0.429 +/- 0.20, and High SRB: 0.571 +/- 0.20) (p=0.791). 2. CH4 was not detected in this population of rats demonstrating that H2 consumption depended on conversion to H2S. Conclusion: Hydrogen sulfide measurement is required for accurate interpretation of lactulose breath test results in non-methane excretors
AGA Abstracts
Sa2038 Effect of DA-9701 in Opioid-Induced Bowel Dysfunction Model of Guinea Pig Kwangwon Rhee, Young Ju Lee, Hyojin Park Background and aim DA9701, a prokinetic agent for gastric emptying, is known to have agonist effect of 5-HT4 receptor. However, it is unclear whether DA9701 also has a prokinetic effect on colon. This study is aimed at assessing the effect of DA 9701 on morphineattenuated bowel movement of guinea pig to verify its efficacy in opioid induced bowel dysfunction. Subjects and methods Distal colon and ileum were removed from male guinea pigs, weighing approximately 300g. Bowel was electrically stimulated at 7.5 Hz with 50V in tissue bath, which was filled with Kreb-Henseleit solution, 1uM morphine, and 1, 5, 10ug/ml of DA 9701. To assess colonic transit time, artificial feces were inserted into the oral side of the colonic lumen, of which both ends were fixed in Kreb-Henseleit-filled chamber. The time taken for the feces to move to the anal side was measured. Results Morphine successfully suppressed muscular contractility in ileum and colon, 41% and 45% of the control, respectively. 10ug/ml of DA9701 restored muscular contractility to 80% of control in ileum but not in colon. Colonic transit was delayed to 64% of control with subcutaneous injection of 10uM morphine but the delay was not normalized with DA 9701 Conclusion In opioid induced bowel dysfunction model of guinea pig, DA 9701 reverses the effect of morphine in ileum but not in colon. Therefore, DA 9701 seems to be an enteroprokinetics but not colo-prokinetics.
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CTT or occlusion related to fecaloma. After a one-year follow-up, 17 patients (85 %) were satisfied with at least 1 stool/d, and 3 still had constipation. Conclusion : In patients with severe colonic inertia requiring surgery, morphometric analysis is more sensitive than semiquantitative analysis to detect a defect in ICC In our study, the severity of constipation seems unrelated to the importance of this defect and ICC evaluation has little clinical interests. Clearly, patients with SCI are satisfied after colectomy. Reference Wang et al, Am J Pathol 2008, 32 : 980-5.
Sa2036 A Pooled Analysis of Response to Lubiprostone in Patients With OpioidInduced Constipation Receiving Non-Methadone Opioids Versus Methadone Egilius L. Spierings, Douglas A. Drossman, Byron L. Cryer, Taryn Losch-Beridon, Ryuji Ueno Background: Lubiprostone is indicated in the United States, at a dose of 24 mcg twice daily (BID), to treat opioid-induced constipation (OIC) in adults with chronic non-cancer pain. However, its efficacy has not been established in patients receiving methadone or other opioids of the diphenylheptane class. In non-clinical models, methadone dose-dependently reduces lubiprostone-mediated activation of its molecular target, the ClC-2 chloride channel (Cuppoletti et al. Cell Biochem Biophys. 2013:66:53-63). This analysis examined treatment response in patients receiving non-methadone opioids vs methadone, using pooled pivotal trial data from the lubiprostone OIC development program. Methods: Data were pooled from three phase 3, randomized, double-blind, placebo-controlled, 12-week studies. Patients with ≥9 weeks of non-missing weekly spontaneous bowel movement (SBM) rates were defined as overall responders if they had ≥1 additional SBM compared to baseline for each week data are available and ≥3 SBMs per week for at least 9 weeks. Results: A total of 1300 patients were pooled; 1297 had opioid class data (non-methadone, n=1140; methadone, n=157). In patients receiving non-methadone opioids, 63% were female, the mean±SD age was 50.7±10.6 years, 91% were <65 years old, 81% were white, and 15% were Black/ African American. In patients receiving methadone, 60% were female, the mean±SD age was 49.0±10.5 years, 96% were <65 years old, 87% were white, and 10% were Black/ African American. Among the 1140 patients receiving non-methadone opioids, a significantly greater proportion treated with lubiprostone met response criteria, compared with placebotreated patients (Table). In the 157 patients receiving methadone, the response rate was statistically similar for patients treated with lubiprostone vs placebo (Table). Conclusions: Results of this pooled analysis of OIC pivotal studies demonstrate a statistically significant treatment response with lubiprostone compared with placebo in patients receiving nonmethadone opioids but not in patients receiving methadone. These clinical results are consistent with preclinical studies indicating that methadone dose-dependently reduces the ability of lubiprostone to activate the ClC-2 chloride channel. Response to Lubiprostone and Placebo in Patients Receiving Non-Methadone Opioids vs Methadone
Sa2033 Chronic Constipation: ROME III Criteria and What Patients Think. Are We Talking the Same Language? Dario Gambaccini, Caterina Racale, Stefano Salvadori, Gabrio Bassotti, Filippo Pucciani, Edda Battaglia, Renato Bocchini, Antonio Bove, Pietro Alduini, Santino Marchi, Massimo Bellini Background Chronic constipation is usually diagnosed using Rome III Criteria, but in clinical practice many physicians do not use these criteria and many patients consider themselves constipated while not showing signs or symptoms consistent with these criteria. They require help from their physicians for a "self reported constipation". On the other hand some people could meet the Rome criteria for constipation while considering themselves perfectly "normal". Aim To evaluate the correlation between the self reported constipation, functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) diagnosed according Rome III criteria. Methods 934 patients referred for gastroenterological visit and 980 carers were asked if they considered themselves to be affected with chronic constipation. Afterward they were invited to record anonymously their demographic data and symptoms in order to verify if they could be diagnosed as FC or IBS-C or not (self perceived constipation "SPC"). The overall score of PAC-QoL, ODS score and CSI of these patients were also recorded. Subjects with known or suspected severe organic diseases potentially causing constipation or assuming potentially constipating drugs were excluded. Results Data from 1914 subjects (patients and carers) were obtained (38.2% M; 61.8% F; mean age 50.6 ± SD 15.8). Among these 661/1914 (34.5%) subjects considered themselves to be constipated and 1253 (65.5%) not to be constipated (p<0.001). Among the "constipated" group (661 subjects) Rome III criteria for FC were satisfied in 290 (44%), Rome III criteria for IBS-c in 282 (43%); the Rome III criteria were not satisfied in 89 (13%) subjects (SPC patients). The ODS score was lower (p<0.05) in SPC than in subjects with a ROME III positive diagnosis. In 1253 subjects that not considered themselves to be constipated, diagnosis of FC and IBS-c according to Rome III criteria were feasible in 163 (13%) and 76 (6%) subjects. PAC-QoL and ODS score were lower than in patients which considered themselves to be constipated. No difference in ODS score was founded between subjects with FC and IBSC. A measure of agreement between ROME III criteria (FC and IBS-c) and patients conception of constipation was reported (K Cohen 0.64). Conclusions There is a substantial but not a total agreement between ROME III criteria (IBS-C and FC) and what patients call constipation. FC, IBS-C and SCP are not easily separable conditions in clinical practice. Patients tend often to define "constipation" the combination of different symptoms that are not usually included in Rome III criteria for the diagnosis of constipation. QoL is similar between FC, IBS but is lower in patients that consider themselves to be constipated and higher in SPC. Is it time for a revision of Rome Criteria for constipation?
Sa2037 Effect of DA-6886 on Gastrointestinal Transit and Defecation in Mice Kang Hun Cho, Min Jung Lee, Hyun Min Park, Weonbin Im, Sunghak Choi Purpose: Gastrointestinal prokinetics have been considered the therapeutic option of choice for functional gastrointestinal disorders. DA-6886, the gastrointestinal prokinetic agent is a potent 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation. The aim of the present study was to investigate the effects of DA-6886 on gastrointestinal transit and defecation in conscious mice. Methods: Effect of DA-6886 on gastrointestinal transit was assessed by the whole gastrointestinal transit in mice. The whole gastrointestinal transit was measured the excretion time of fecal pellet containing with dye following treatment of DA-6686 by intraperitoneal(ip) injection and administration of dye meal by gavage, simultaneously. To demonstrate the effect of DA-6886 on defecation, fecal pellets were collected each 1 h for the 3 h following drug oral administration. The number of fecal pellets was counted and fecal dry weight was measured. Results: DA-6886 was significantly enhanced gastrointestinal transit in a dosedependent manner (0.02 ~ 0.5 mg/kg, ip). The number of fecal pellets and fecal dry weight were increased by oral administration of DA-6886 (0.3mg/kg), similar to 10mg/kg of tegaserod. 1mg/kg of DA-6886 was significantly increased defecation compared to vehicle control. Conclusions: DA-6886 is a potent 5-HT4 agonist with increased gastrointestinal transit activity and enhanced defecation in mice, which may be effective for the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation.
Sa2034 Accurate Interpretation of Breath Test Results Depends on Measuring Hydrogen Sulfide in Non-Methane Excretors Benjamin J. Burnett, Prashanth Setty, Sudha B. Singh, Henry C. Lin Breath tests are widely used to detect excessive fermentation by gut bacteria. Since fermentation by hydrogenogenic microbes is the sole source of hydrogen (H2) appearing in the exhaled breath, a low peak breath hydrogen concentration, e.g., <20 parts per million (ppm) after lactulose administration has been interpreted as a negative result for excessive fermentation, a finding often used to rule out bacterial overgrowth. However, H2 production is balanced by H2 consumption via 1 of 3 microbial pathways (methanogens converting H2 to methane (CH4), sulfate-reducing bacteria (SRB) converting H2 to hydrogen sulfide (H2S) and acetogens converting H2 to acetate). Since commercially available clinical gas analyzers measure only H2 and CH4, excessive fermentation may be missed in non-methane excretors leading to a false-negative test result when excessive H2 production is masked by conversion of H2 to H2S, a gas that is not routinely measured. Aim: In this study, we tested the hypothesis that detection of excessive fermentation may depend on measuring H2S in non-methane excretors. Methods: To test this hypothesis, we measured H2S concentration in parts per billion (OralChroma) and H2 and CH4 concentrations in ppm (Quintron SC) excreted by rats that are housed in metabolic cages over 180 min. Twenty-eight rats were randomized into 1 of 4 treatments, each consisting of a single gavage of a lactulose and mannitol solution with saline with varying load of SRB (Desulfovibrio vulgaris): 0 (No SRB), 10^8 (Low SRB), 10^9 (Mid SRB), or 10^10 (High SRB). H2 concentrations were measured and rats were categorized as Positive for excessive fermentation if peak [H2] > 20 ppm and Negative for excessive fermentation if peak [H2 ] ≤ 20 ppm. H2S concentrations were also measured. If H2S were to be detected but peak [H2 ] ≤ 20 ppm, the result was considered a false negative as the peak [H2] alone would have been interpreted as negative for excessive fermentation. Experimental results were assigned a value of 0 for correctly assessed result (no error) and a value of 1 for incorrectly assessed result (false negative) and mean values +/- SE were compared using a one-way ANOVA. Results: 1. All groups contained some false negative breath test results (No SRB: 0.285 +/- 0.18, Low SRB: 0.429 +/- 0.20, Mid SRB: 0.429 +/- 0.20, and High SRB: 0.571 +/- 0.20) (p=0.791). 2. CH4 was not detected in this population of rats demonstrating that H2 consumption depended on conversion to H2S. Conclusion: Hydrogen sulfide measurement is required for accurate interpretation of lactulose breath test results in non-methane excretors
AGA Abstracts
Sa2038 Effect of DA-9701 in Opioid-Induced Bowel Dysfunction Model of Guinea Pig Kwangwon Rhee, Young Ju Lee, Hyojin Park Background and aim DA9701, a prokinetic agent for gastric emptying, is known to have agonist effect of 5-HT4 receptor. However, it is unclear whether DA9701 also has a prokinetic effect on colon. This study is aimed at assessing the effect of DA 9701 on morphineattenuated bowel movement of guinea pig to verify its efficacy in opioid induced bowel dysfunction. Subjects and methods Distal colon and ileum were removed from male guinea pigs, weighing approximately 300g. Bowel was electrically stimulated at 7.5 Hz with 50V in tissue bath, which was filled with Kreb-Henseleit solution, 1uM morphine, and 1, 5, 10ug/ml of DA 9701. To assess colonic transit time, artificial feces were inserted into the oral side of the colonic lumen, of which both ends were fixed in Kreb-Henseleit-filled chamber. The time taken for the feces to move to the anal side was measured. Results Morphine successfully suppressed muscular contractility in ileum and colon, 41% and 45% of the control, respectively. 10ug/ml of DA9701 restored muscular contractility to 80% of control in ileum but not in colon. Colonic transit was delayed to 64% of control with subcutaneous injection of 10uM morphine but the delay was not normalized with DA 9701 Conclusion In opioid induced bowel dysfunction model of guinea pig, DA 9701 reverses the effect of morphine in ileum but not in colon. Therefore, DA 9701 seems to be an enteroprokinetics but not colo-prokinetics.
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