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A Randomized, Open Labeled, Multicenter Clinical Trial on the Effectiveness and Safety of the 5-HT3-Receptor Antagonist Ramosetron in Male Patients With Irritable Bowel Syndrome With Diarrhea: Comparison With Mebeverine
Mo1302
AGA Abstracts
A Randomized, Open Labeled, Multicenter Clinical Trial on the Effectiveness and Safety of the 5-HT3-Receptor Antagonist Ramosetron in Male Patients With Irritable Bowel Syndrome With Diarrhea: Comparison With Mebeverine Kwang Jae Lee, Poong-Lyul Rhee
Mo1301
Irritable bowel syndrome (IBS) is characterized by abdominal discomfort and/or pain associated with altered bowel habits. Yet no therapy convincingly controls the multiple symptoms of this syndrome. 5-HT3 receptors are extensively distributed on enteric neurons in the human gastrointestinal tract and play a role in increasing the sensation of pain and affecting bowel habits in patients with IBS. The aim of this study was to evaluate the efficacy and safety of the 5-HT3-receptor antagonist ramosetron hydrochloride in male patients with irritable bowel syndrome with diarrhea (D-IBS). The efficacy and tolerability of the 5-HT3-receptor antagonist ramosetron and the smooth muscle relaxant mebeverine were compared in a double-blind, multicenter, randomized trial with a 1-week run-in period. Two hundred ninety-six male patients with D-IBS meeting the Rome III diagnostic criteria received either 5 microg ramosetron hydrochloride once daily (n=152) or mebeverine 135 mg (n=145) three times daily for 4 weeks. Patients assessed IBS symptoms every 7 days. According to their assessment scores, patients who had complete or considerable relief were defined as weekly responders in that particular week. The weekly responder rates of global IBS symptoms significantly increased throughout the 4 weeks of treatment in both ramosetron and mebeverine groups. The responder rate at the 4 week of ramosetron treatment was 36%. The weekly responder rates of abdominal pain or discomfort and abnormal bowel habits significantly increased throughout the 4 weeks of treatment in both ramosetron and mebeverine groups. The frequency of defecation was significantly reduced by ramosetron treatment (from 2.0 times/day at 1 week to 1.8 times/day at 4 week, p=0.016), whereas it was not significantly altered by mebeverine treatment. Both ramosetron and mebeverine significantly improved urgency, incomplete evacuation sense and quality of life. Ramosetron provided greater improvement in quality of life than mebeverine (p= 0.076). Twelve patients (7.9%) in the ramosetron group and 6 patients (4.1%) in the mebeverine group reported adverse effects (p=0.266) Drug-related adverse events with a frequency greater than 1% in the ramosetron group were constipation and abdominal discomfort. Ischemic colitis and severe constipation were not reported by any patients. Ramosetron hydrochloride 5 microg once daily is an effective and well tolerated treatment for abdominal pain, discomfort and abnormal bowel habits in male patients with D-IBS, compared with mebeverine 135 mg three times daily.
Accuracy of Physician's Assessment of IBS Disease Severity Akriti Dewanwala, Amanda Smith, Andrew Wurl, Jeffrey M. Lackner, Michael D. Sitrin
Mo1303
The analysis reveals that symptoms are endorsed in 4 groups: diarrhea, constipation-related observable signs and symptoms, constipation-related sensations, and pain-related sensations. Blank cells indicate factor loadings <0.4.
Introduction:Irritable bowel syndrome (IBS) is a chronic, functional gastrointestinal disorder comprising about 25% of all referrals to gastroenterologists. While physician-determined IBS severity guides clinical decision-making, it is unclear what determines the gastroenterologist's judgment of severity and the concordance between MD and patient ratings. Previously, our group (Lackner, Ma et al., 2009) identified factors predictive of patient rating of IBS severity. In this study, we aimed to determine the degree of agreement between physician and patient assessment of disease severity and to identify clinical factors that influenced MD ratings. Subjects:82 Rome II-diagnosed IBS adults (mean age 46.7 yrs, 86.6% F) completed baseline assessments for an NIH-funded RCT. Methods:Patient questionnaires included:the 2 bloating/ distension and 7 defecation of the GSRS-IBS items and UCLA Pain Scale to assess GI symptoms (abdominal discomfort,defecation, pain); Anxiety Sensitivity Inventory, Brief Symptom Inventory and SF-36 to evaluate emotions (visceral anxiety, depression, fatigue, somatization); IBS Locus of Control (LOC), Coping Strategies Questionnaire, State Trait Anxiety Inventory and Penn State Worry Questionnaire to assess cognitions (LOC, catastrophizing, anxiety, worry). The dependent variables were IBS severity assessed with 2 patient reported measures (UCLA IBS Symptom Severity [UCLA SS], IBS Symptom Severity Scale [IBS-SSS]) and MD rating (CGI Severity) with responses from 'not ill' to 'most extremely ill' on a 7-point Likert scale. Results: Bivariate analysis revealed only a modest correlation between MD rating and patient-reported UCLA SS and IBS-SSS (r=0.49 and 0.45 respectively, p<0.01). In 53.7% of cases, MD rating corresponded with patients' rating while the physician underestimated severity in 31.7% and overestimated in 14.6% of subjects. The disagreement with patients was most prevalent when MD rated IBS as mild. In stepwise linear regression, the blocks of demographic variables, GI symptoms, emotions and cognitions accounted for only 35% of the variance in MD rating in contrast to 57% and 69% on patient scores (UCLA SS and IBS-SSS, respectively). GI symptoms alone explained 16% of variance in MD assessment, while accounting for 49% and 64% of variance in the 2 patient scales (Table 1). Conclusion:Our main finding is a lack of correspondence between MD and patient ratings of severity. This discordance is particularly apparent with IBS patients whom MD rates as being 'mildly ill'. Although GI symptoms, emotions, cognitions and demographic variables, are reasonably good predictors of patient ratings, these only accounted for a third of the variance in physician's rating of IBS severity. Further studies to identify additional factors that influence physician rating of IBS severity are needed. Supported by NIH/NIDDK grants 67878 and 77738 Table 1: Contribution of various factors in physician and patient rating of IBS disease severity
Effects of the Novel 5-HT4 Receptor Partial Agonist RQ-00000010 on Upper and Lower Gastrointestinal Motility in Fasted Dogs Toshinori Yamamoto, Nobuyuki Takahashi, Shuzo Watanabe Background: It is clear that the drugs with 5-HT4 receptor agonistic activity act as a potent prokinetic agent. Some degree of tissue specific activity in the gastrointestinal tract has been described for 5-HT4 agonists, such as cisapride, mosapride and prucalopride. For example, mosapride selectively enhanced upper gastrointestinal (GI) motility in dogs. In contrast, prucalopride has been suggested to selectively stimulate colonic transit in healthy humans. RQ-00000010 (RQ-10) is a potent and highly selective 5-HT4 partial agonist in which there is a low risk of cardiovascular toxicity [DDW2009]. The aim of the present study was to evaluate the effects of RQ-10 on upper and lower GI motility in fasted conscious dogs. Methods: GI motility was assessed by processing the signals from the force transducers implanted in dogs prepared for investigation of motility. Quantitative analysis was performed by calculating the motor index (MI) as the area surrounded by the contraction curve and the baseline. Results: RQ-10 displayed high affinity for the human recombinant 5-HT4d receptor with a Ki value of 0.87 nM, and also showed >2000-fold selectivity against more than 70 GPCRs ion-channels and enzymes. In dogs, RQ-10 long-lasting increased the gastric antral motor activity in dose dependent manner (0.1-10 μg/kg). During the 0 to 2 hour period after oral administration of RQ-10, the measured change in the MI achieved statistical significance at 1 μg/kg, which was determined to be the minimum effective dose in this model. The antral motor activity-stimulating effect induced by RQ-10 (1 μg/kg) did not alter with a repeated administration for five consecutive days. The results demonstrated that RQ-10 does not desensitize the receptor at this dose. In the proximal colon, amplitude and frequency of contractions were enhanced by 1 μg/kg of RQ-10. Moreover, RQ-10 facilitated the occurrence of giant migrating contractions after treatment. On the other hand, oral administration of prucalopride (0.1 mg/kg) stimulated gastric antral motility, but did not affect contractions of proximal colon at this dose. Only the high dose treatment (0.3 mg/ kg) of prucalopride enhanced the colonic motor activity, but induced excessive gastroduodenum contractions. Conclusion: A large population of patients with functional bowel disorders have frequently overlapping symptoms that affect both the upper and lower GI tract. For example, IBS is frequently seen in association with GERD. RQ-10 is one of the most potent and selective 5-HT4 agonist, exert stimulatory effects on antral and colonic motility at the same dose; there is no tissue specific activity in the gut. These profiles suggest that RQ-10 could be of valuable and feasible alternative to other prokinetic agents for patients suffering from functional constipation and C-IBS with upper GI symptoms such as dyspepsia or heartburn. Mo1304 Safety and Adverse Event Profiles of Oral Prucalopride Are Similar in Elderly and Adult Patients With Chronic Constipation Michael Camilleri, Patricia Robinson, Rene Kerstens, Lieve M. Vandeplassche INTRODUCTION: Prucalopride (PRU) is a selective, high-affinity 5-HT4 receptor agonist, authorized by the European Medicines Agency for symptomatic treatment of chronic constipation (CC) in women in whom laxatives fail to provide adequate relief. AIM: To compare the adverse event (AE) profile of oral PRU in elderly (≥65 yrs) and adult (18 to 65 yrs)
AGA Abstracts
S-606
AGA Abstracts
A Randomized, Open Labeled, Multicenter Clinical Trial on the Effectiveness and Safety of the 5-HT3-Receptor Antagonist Ramosetron in Male Patients With Irritable Bowel Syndrome With Diarrhea: Comparison With Mebeverine Kwang Jae Lee, Poong-Lyul Rhee
Mo1301
Accuracy of Physician's Assessment of IBS Disease Severity Akriti Dewanwala, Amanda Smith, Andrew Wurl, Jeffrey M. Lackner, Michael D. Sitrin
Mo1303
The analysis reveals that symptoms are endorsed in 4 groups: diarrhea, constipation-related observable signs and symptoms, constipation-related sensations, and pain-related sensations. Blank cells indicate factor loadings <0.4.
Introduction:Irritable bowel syndrome (IBS) is a chronic, functional gastrointestinal disorder comprising about 25% of all referrals to gastroenterologists. While physician-determined IBS severity guides clinical decision-making, it is unclear what determines the gastroenterologist's judgment of severity and the concordance between MD and patient ratings. Previously, our group (Lackner, Ma et al., 2009) identified factors predictive of patient rating of IBS severity. In this study, we aimed to determine the degree of agreement between physician and patient assessment of disease severity and to identify clinical factors that influenced MD ratings. Subjects:82 Rome II-diagnosed IBS adults (mean age 46.7 yrs, 86.6% F) completed baseline assessments for an NIH-funded RCT. Methods:Patient questionnaires included:the 2 bloating/ distension and 7 defecation of the GSRS-IBS items and UCLA Pain Scale to assess GI symptoms (abdominal discomfort,defecation, pain); Anxiety Sensitivity Inventory, Brief Symptom Inventory and SF-36 to evaluate emotions (visceral anxiety, depression, fatigue, somatization); IBS Locus of Control (LOC), Coping Strategies Questionnaire, State Trait Anxiety Inventory and Penn State Worry Questionnaire to assess cognitions (LOC, catastrophizing, anxiety, worry). The dependent variables were IBS severity assessed with 2 patient reported measures (UCLA IBS Symptom Severity [UCLA SS], IBS Symptom Severity Scale [IBS-SSS]) and MD rating (CGI Severity) with responses from 'not ill' to 'most extremely ill' on a 7-point Likert scale. Results: Bivariate analysis revealed only a modest correlation between MD rating and patient-reported UCLA SS and IBS-SSS (r=0.49 and 0.45 respectively, p<0.01). In 53.7% of cases, MD rating corresponded with patients' rating while the physician underestimated severity in 31.7% and overestimated in 14.6% of subjects. The disagreement with patients was most prevalent when MD rated IBS as mild. In stepwise linear regression, the blocks of demographic variables, GI symptoms, emotions and cognitions accounted for only 35% of the variance in MD rating in contrast to 57% and 69% on patient scores (UCLA SS and IBS-SSS, respectively). GI symptoms alone explained 16% of variance in MD assessment, while accounting for 49% and 64% of variance in the 2 patient scales (Table 1). Conclusion:Our main finding is a lack of correspondence between MD and patient ratings of severity. This discordance is particularly apparent with IBS patients whom MD rates as being 'mildly ill'. Although GI symptoms, emotions, cognitions and demographic variables, are reasonably good predictors of patient ratings, these only accounted for a third of the variance in physician's rating of IBS severity. Further studies to identify additional factors that influence physician rating of IBS severity are needed. Supported by NIH/NIDDK grants 67878 and 77738 Table 1: Contribution of various factors in physician and patient rating of IBS disease severity
Effects of the Novel 5-HT4 Receptor Partial Agonist RQ-00000010 on Upper and Lower Gastrointestinal Motility in Fasted Dogs Toshinori Yamamoto, Nobuyuki Takahashi, Shuzo Watanabe Background: It is clear that the drugs with 5-HT4 receptor agonistic activity act as a potent prokinetic agent. Some degree of tissue specific activity in the gastrointestinal tract has been described for 5-HT4 agonists, such as cisapride, mosapride and prucalopride. For example, mosapride selectively enhanced upper gastrointestinal (GI) motility in dogs. In contrast, prucalopride has been suggested to selectively stimulate colonic transit in healthy humans. RQ-00000010 (RQ-10) is a potent and highly selective 5-HT4 partial agonist in which there is a low risk of cardiovascular toxicity [DDW2009]. The aim of the present study was to evaluate the effects of RQ-10 on upper and lower GI motility in fasted conscious dogs. Methods: GI motility was assessed by processing the signals from the force transducers implanted in dogs prepared for investigation of motility. Quantitative analysis was performed by calculating the motor index (MI) as the area surrounded by the contraction curve and the baseline. Results: RQ-10 displayed high affinity for the human recombinant 5-HT4d receptor with a Ki value of 0.87 nM, and also showed >2000-fold selectivity against more than 70 GPCRs ion-channels and enzymes. In dogs, RQ-10 long-lasting increased the gastric antral motor activity in dose dependent manner (0.1-10 μg/kg). During the 0 to 2 hour period after oral administration of RQ-10, the measured change in the MI achieved statistical significance at 1 μg/kg, which was determined to be the minimum effective dose in this model. The antral motor activity-stimulating effect induced by RQ-10 (1 μg/kg) did not alter with a repeated administration for five consecutive days. The results demonstrated that RQ-10 does not desensitize the receptor at this dose. In the proximal colon, amplitude and frequency of contractions were enhanced by 1 μg/kg of RQ-10. Moreover, RQ-10 facilitated the occurrence of giant migrating contractions after treatment. On the other hand, oral administration of prucalopride (0.1 mg/kg) stimulated gastric antral motility, but did not affect contractions of proximal colon at this dose. Only the high dose treatment (0.3 mg/ kg) of prucalopride enhanced the colonic motor activity, but induced excessive gastroduodenum contractions. Conclusion: A large population of patients with functional bowel disorders have frequently overlapping symptoms that affect both the upper and lower GI tract. For example, IBS is frequently seen in association with GERD. RQ-10 is one of the most potent and selective 5-HT4 agonist, exert stimulatory effects on antral and colonic motility at the same dose; there is no tissue specific activity in the gut. These profiles suggest that RQ-10 could be of valuable and feasible alternative to other prokinetic agents for patients suffering from functional constipation and C-IBS with upper GI symptoms such as dyspepsia or heartburn. Mo1304 Safety and Adverse Event Profiles of Oral Prucalopride Are Similar in Elderly and Adult Patients With Chronic Constipation Michael Camilleri, Patricia Robinson, Rene Kerstens, Lieve M. Vandeplassche INTRODUCTION: Prucalopride (PRU) is a selective, high-affinity 5-HT4 receptor agonist, authorized by the European Medicines Agency for symptomatic treatment of chronic constipation (CC) in women in whom laxatives fail to provide adequate relief. AIM: To compare the adverse event (AE) profile of oral PRU in elderly (≥65 yrs) and adult (18 to 65 yrs)
AGA Abstracts
S-606