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M1864 Immediate-Release Omeprazole Has a More Rapid and More Predictable Absorption Profile Than Delayed-Release Omeprazole in Patients with GERD Associated with Gastroparesis
AGA Abstracts
has been reported that rikkunshito has a prokinetic action on gastric emptying, and its pharmacological action has been shown to be correlated with increased levels of active ghrelin in the plasma, which are known to stimulate gastric motility. Therefore, the findings of the present study suggest that rikkunshito can be considered as a new and effective therapeutic drug for GERD, especially for refractory GERD, as against the antisecretory therapies.
M1865 Effects of Combined Therapy with Esomeprazol and Tegaserod in Patients with Extra-Esophageal GERD Not Responsive to Esomeprazol Mauro Bafutto, Naylé V. Leite, Joffre Rezende Filho Background:Esomeprazol(E),a potent proton pump inhibitor, is commonly indicated for treatment of extra-mesophageal manifestation of GERD, with variable outcome.Tegaserod(T), a partial 5HT4 agonist,has been shown to increase buffers and epidermal growth factor in saliva, to enhance esophageal pre-epithelial defense, and to have prokinetic profiles in esophageal, gastric and intestinal motility. 1,2,3,4.The association of T and E in the treatment of extra-esophageal manifestations in GERD has not been evaluated.Aims: to evaluate the effects of combined theraphy with E and T on extraesophageal symptoms of GERD in patients that not respond previously to E. Patients and methods: At baseline 70 patients with extraesophageal reflux symptoms and signs suggestive of reflux disease at laryngoscopy were included. All patients underwent upper endoscopy and 24-hour pHmetry (Pharyngeal electrode placed 25cm above the lower esophageal sphincter (LES), proximal esophageal electrode - 20cm above the LES, distal esophageal electrode - 5cm above the LES). All patients were initially treated with E 40mg b.i.d. A 4 likert scale symptoms score (max score = 15, min score = 0) was measured at baseline.and after initial treatment. Patients were considered responders (n=38) when the symptom score reduced > 50% and nonresponders (n=32) when the symptom score reduced < 50%.The nonresponders were randomized in two groups:1.T + EGroup(TEG):20 patients were treated with T 6mg b.i.d and E 40mg b.i.d.; 2.E Group(EG):12 patients were treated with E 40mg b.i.d. At 30th day of treatment the symptom score was measured.2 patients from TEG and 2 from EG were excluded.Fisher exact test and paried t test were used for statistical analyses. Results:In TEG,symptom score at 30th day of treatment showed statistically significant reduction as compared to baseline(M 5.78 + SD 2.49 pre treat X M 2.20 + SD 2.24 post treat, (p< 0.0001). In EG, symptom score at 30th day of treatment did not show a statistical significant difference as compared to baseline(M 4.60 + SD 3.27 pre teat X M 4.60 + SD 3.31)(p=1,0).A significant higher proportion of patients in TEG was considered responders(78% of TEG patients X 20% of EG; p=0.005). Conclusion:In patients with extra-esophageal GERD symptoms,not responding to previous treatment with E.,combined therapy with E and T was better than E alone. These results warrant further larger placebo controlled studies.References:1.Majewsky M,Clinical Gastroenterology and Hepatology ,Apr;5(4):430-8,2007.2.Fox M,Aliment PharmacolTher.Oct1;24(7):1017-27,2006.3.Abdulnour-NakhoulS,Diag Dis and Science Vol 53septN9,2008.4. Degen L,NeurogastroenterolMotil Dec,17(6), 2005.
M1863 The Effect of Baclofen On Sleep Measures and Sleep Related Gastroesophageal Reflux(GER) William C. Orr, Mark Mellow, Uyen Vu, Suanne Goodrich Baclofen, a GABAb agonist, has been shown to inhibit transient LES relaxations, and to reduce 24 hr esophageal acid contact time. Sleep related GER has been shown to be an important variable in the development of esophagitis as well as inducing sleep difficulties. Baclofen has been shown to induce drowsiness and it was felt that it may be an ideal drug to inhibit sleep related GER as well as to enhance quality of sleep. METHODS: Thirteen individuals with nighttime heartburn at least 2 times/wk and an elevated Carlesson GERD questionnaire score were studied. Patients were studied via polysomnography (PSG) for two nights to include simultaneous esophageal pH monitoring. Patients were given 40mg baclofen or placebo in random order prior to sleep. In order to provoke reflux events during sleep, a provocative meal was given 1 hr prior to lights out. Sleep quality was assessed via objective and subjective measures.RESULTS: Acid contact time was reduced, but not significantly (placebo=7.5%, baclofen = 4.0%); Number of reflux events was significantly decreased (placebo = 3.4, baclofen =1.2, P<.05). Sleep was significantly improved on baclofen in terms of reports of total sleep time, sleep quality and number of awakenings (all P<.05). Total sleep time as assessed by PSG was increased on baclofen (placebo=385min., baclofen=438 min, P<.001) as was sleep efficiency (placebo=80%, baclofen=91%, P<.001). CONCLUSIONS: 1) Baclofen is effective in reducing sleep related GER and in markedly improving both subjective and PSG documented quality of sleep in GERD patients; 2) Baclofen would be an ideal adjunct to PPI therapy in GERD patients particularly in those with significant nighttime heartburn and sleep disturbance. M1864 Immediate-Release Omeprazole Has a More Rapid and More Predictable Absorption Profile Than Delayed-Release Omeprazole in Patients with GERD Associated with Gastroparesis John M. Wo, Jennifer Eversmann, Suzanne Mann
M1866 Effect of Concomitant Irritable Bowel Syndrome On Response of GERD Patients to Proton Pump Inhibitors Siavosh Nasseri-Moghaddam, Alireza Abrishami, Hadi Razjouyan, Seyed Maysam Alimohamadi, Mansoureh Mamarabadi, Azadeh Mofid, Shadi Khalili, Shahnaz Tofangchiha, Shahrooz Rashtak, Reza Khaleghnejad, Anahita Ghorbani, Nikoo Fattahi, Reza Malekzadeh
Immediate-release (IR) omeprazole is associated with a more rapid absorption compared to delayed-release (DR) omeprazole in asymptomatic volunteers. IR omeprazole may be especially helpful in patients with gastroparesis because proton pump inhibitors should be taken 30 to 60 min before meals. AIMS: To compare pharmacokinetics between IR and DR omeprazole in patients with GERD associated with gastroparesis. METHODS: Randomized, open-label, cross-over study was performed on patients with symptomatic GERD and delayed gastric scintigraphy (≥60% residual @2-hr or ≥10% residual @4-hr). Patients with esophageal/gastric surgery were excluded. Antireflux and prokinetic drugs were discontinued. Subjects were randomized into: a) IR omeprazole 40 mg oral suspension qam x7 days, wash-out x10-14 days, and DR omeprazole 40 mg capsule qam x7 days; or b) DR omeprazole 40 mg capsule qam x7 days, wash-out x 10-14 days, and IR omeprazole 40 mg oral suspension qam x7 days. Pharmacokinetics were studied on day 7 of each study drug. Subjects fasted overnight and took study drug 60 minutes before a high-fat breakfast (39 gm fat, 84 gm carbohydrate, 21 gm protein). Omeprazole plasma concentrations were obtained before and 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, and 300 min after taking study drug. Patient Assessment of GI Disorders-Symptom Severity Index (PAGI-SYM) was obtained before and after each study drug. Paired t-tests were used. RESULTS: 12 female subjects (mean age 51 yrs, 75% idiopathic) were enrolled. Pharmacokinetic results are shown in table. The tmax was significantly shorter for IR compared to DR omeprazole. AUC0-5hr, Cmax, and tmax for IR omeprazole were less variable among subjects. PAGI-SYM total and subscale scores on heartburn/regurgitation, postprandial fullness/satiety, bloating, and upper abdominal pain significantly improved after IR omeprazole but not after DR omeprazole. CONCLUSIONS: IR omeprazole was associated with a more rapid and more predictable pharmacokinetic profile compared to DR omeprazole in patients with GERD associated with gastroparesis. Heartburn and dyspeptic symptoms significantly improved after 7 days of IR omeprazole.
Background: GERD is a common and chronic disorder with increasing prevalence in developing countries. Irritable bowel syndrome (IBS) has been reported to co-exist with GERD commonly. We aimed to compare response to treatment of GERD patients with and without IBS. Methods: Patients with clinical GERD from the PARSI database* were assessed. A composite symptom score (CSS) was calculated for each patient considering severity and frequency of major and minor GERD symptoms at enrollment and on follow-ups. IBS was diagnosed using Rome-II criteria. All patients were started on Omeprazole 20mg bid and it was tapered to the lowest dose keeping the patient symptom free according to an algorithm. A more than 75% decrease in CSS was considered as complete response, 25%-75% decrease in CSS as partial response and a <25% decrease in CSS or CSS worsening as non-responders. Each patient was visited thrice (week 0, 4, and 16). Results: Of the 238 patients with GERD (mean age: 39.4+/-14.8, 61.3% female), 145 (60.9%) had IBS. Patients with IBS were slightly younger (38.0 vs. 41.9 p=0.04) and smoked less frequently (15.8% vs. 28.6%, p=0.03). IBS positives had a higher symptom score at base line (55.1 vs. 46.0, p=0.04). Complete responders were more likely to be IBS negative either at the first (52.7% vs. 49.0%, p=0.04) or second (67.7% vs. 54.5%, p=0.01) follow-up. BMI, smoking, age, sex, marital status and presence of esophageal erosion did not affect response to therapy in either group. Average dose of PPI in patients with and without IBS were 30.3 and 28.2mg/day (p=NS) respectively. Among GERD patients who had IBS, those with lower education were more likely to be non-responder (61.5% vs. 31%, p=0.03). Conclusion: According to our data, GERD patients with concomitant IBS have more prominent GERD symptoms and respond less well to PPI therapy. Looking for concomitant IBS helps handling GERD patients more effectively. * Nasseri-Moghaddam S, et al. Prospective Acid Reflux Study of Iran (PARSI): Methodology and study design. BMC Gastroenterology 2007, 7:42. M1867 Efficacy and Tolerability of ADX10059, a Negative Allosteric Modulator of mGluR5, On Gastro-Esophageal Reflux: A pH-Impedance Study in Healthy Subjects Frank Zerbib, Charlotte Keywood Introduction. Animal studies have shown that inhibition of mGluR5 reduces TLESRs and increases LES tone. A preliminary study with ADX10059 in GERD patients demonstrated a reduction in 24 hour esophageal acid exposure and clinical symptoms on a single day of dosing, but with suboptimal tolerability, due to rapid absorption of the compound after oral dosing. The aim of this study was to evalute the pharmacokinetics, tolerability and pharmacodynamics of a modified release formulation of ADX10059. Subjects and methods. Randomized, double-blind placebo-controlled study in 24 healthy male subjects. Three groups of 8 subjects received placebo (n = 2) or ADX10059 (n = 6) at doses of 50, 125 et 250 mg b.i.d. for 6 days. Esophageal pH-impedance was performed pre-treatment on Day -1 and on treatment Day 6, for 1 hour fasting and 4 hours post refluxogenic meal. Traces
Values in means; Area under concentration-time curve (AUC0-5hr); Peak plasma concentration (Cmax); Time to Cmax (tmax).
AGA Abstracts
A-434
has been reported that rikkunshito has a prokinetic action on gastric emptying, and its pharmacological action has been shown to be correlated with increased levels of active ghrelin in the plasma, which are known to stimulate gastric motility. Therefore, the findings of the present study suggest that rikkunshito can be considered as a new and effective therapeutic drug for GERD, especially for refractory GERD, as against the antisecretory therapies.
M1865 Effects of Combined Therapy with Esomeprazol and Tegaserod in Patients with Extra-Esophageal GERD Not Responsive to Esomeprazol Mauro Bafutto, Naylé V. Leite, Joffre Rezende Filho Background:Esomeprazol(E),a potent proton pump inhibitor, is commonly indicated for treatment of extra-mesophageal manifestation of GERD, with variable outcome.Tegaserod(T), a partial 5HT4 agonist,has been shown to increase buffers and epidermal growth factor in saliva, to enhance esophageal pre-epithelial defense, and to have prokinetic profiles in esophageal, gastric and intestinal motility. 1,2,3,4.The association of T and E in the treatment of extra-esophageal manifestations in GERD has not been evaluated.Aims: to evaluate the effects of combined theraphy with E and T on extraesophageal symptoms of GERD in patients that not respond previously to E. Patients and methods: At baseline 70 patients with extraesophageal reflux symptoms and signs suggestive of reflux disease at laryngoscopy were included. All patients underwent upper endoscopy and 24-hour pHmetry (Pharyngeal electrode placed 25cm above the lower esophageal sphincter (LES), proximal esophageal electrode - 20cm above the LES, distal esophageal electrode - 5cm above the LES). All patients were initially treated with E 40mg b.i.d. A 4 likert scale symptoms score (max score = 15, min score = 0) was measured at baseline.and after initial treatment. Patients were considered responders (n=38) when the symptom score reduced > 50% and nonresponders (n=32) when the symptom score reduced < 50%.The nonresponders were randomized in two groups:1.T + EGroup(TEG):20 patients were treated with T 6mg b.i.d and E 40mg b.i.d.; 2.E Group(EG):12 patients were treated with E 40mg b.i.d. At 30th day of treatment the symptom score was measured.2 patients from TEG and 2 from EG were excluded.Fisher exact test and paried t test were used for statistical analyses. Results:In TEG,symptom score at 30th day of treatment showed statistically significant reduction as compared to baseline(M 5.78 + SD 2.49 pre treat X M 2.20 + SD 2.24 post treat, (p< 0.0001). In EG, symptom score at 30th day of treatment did not show a statistical significant difference as compared to baseline(M 4.60 + SD 3.27 pre teat X M 4.60 + SD 3.31)(p=1,0).A significant higher proportion of patients in TEG was considered responders(78% of TEG patients X 20% of EG; p=0.005). Conclusion:In patients with extra-esophageal GERD symptoms,not responding to previous treatment with E.,combined therapy with E and T was better than E alone. These results warrant further larger placebo controlled studies.References:1.Majewsky M,Clinical Gastroenterology and Hepatology ,Apr;5(4):430-8,2007.2.Fox M,Aliment PharmacolTher.Oct1;24(7):1017-27,2006.3.Abdulnour-NakhoulS,Diag Dis and Science Vol 53septN9,2008.4. Degen L,NeurogastroenterolMotil Dec,17(6), 2005.
M1863 The Effect of Baclofen On Sleep Measures and Sleep Related Gastroesophageal Reflux(GER) William C. Orr, Mark Mellow, Uyen Vu, Suanne Goodrich Baclofen, a GABAb agonist, has been shown to inhibit transient LES relaxations, and to reduce 24 hr esophageal acid contact time. Sleep related GER has been shown to be an important variable in the development of esophagitis as well as inducing sleep difficulties. Baclofen has been shown to induce drowsiness and it was felt that it may be an ideal drug to inhibit sleep related GER as well as to enhance quality of sleep. METHODS: Thirteen individuals with nighttime heartburn at least 2 times/wk and an elevated Carlesson GERD questionnaire score were studied. Patients were studied via polysomnography (PSG) for two nights to include simultaneous esophageal pH monitoring. Patients were given 40mg baclofen or placebo in random order prior to sleep. In order to provoke reflux events during sleep, a provocative meal was given 1 hr prior to lights out. Sleep quality was assessed via objective and subjective measures.RESULTS: Acid contact time was reduced, but not significantly (placebo=7.5%, baclofen = 4.0%); Number of reflux events was significantly decreased (placebo = 3.4, baclofen =1.2, P<.05). Sleep was significantly improved on baclofen in terms of reports of total sleep time, sleep quality and number of awakenings (all P<.05). Total sleep time as assessed by PSG was increased on baclofen (placebo=385min., baclofen=438 min, P<.001) as was sleep efficiency (placebo=80%, baclofen=91%, P<.001). CONCLUSIONS: 1) Baclofen is effective in reducing sleep related GER and in markedly improving both subjective and PSG documented quality of sleep in GERD patients; 2) Baclofen would be an ideal adjunct to PPI therapy in GERD patients particularly in those with significant nighttime heartburn and sleep disturbance. M1864 Immediate-Release Omeprazole Has a More Rapid and More Predictable Absorption Profile Than Delayed-Release Omeprazole in Patients with GERD Associated with Gastroparesis John M. Wo, Jennifer Eversmann, Suzanne Mann
M1866 Effect of Concomitant Irritable Bowel Syndrome On Response of GERD Patients to Proton Pump Inhibitors Siavosh Nasseri-Moghaddam, Alireza Abrishami, Hadi Razjouyan, Seyed Maysam Alimohamadi, Mansoureh Mamarabadi, Azadeh Mofid, Shadi Khalili, Shahnaz Tofangchiha, Shahrooz Rashtak, Reza Khaleghnejad, Anahita Ghorbani, Nikoo Fattahi, Reza Malekzadeh
Immediate-release (IR) omeprazole is associated with a more rapid absorption compared to delayed-release (DR) omeprazole in asymptomatic volunteers. IR omeprazole may be especially helpful in patients with gastroparesis because proton pump inhibitors should be taken 30 to 60 min before meals. AIMS: To compare pharmacokinetics between IR and DR omeprazole in patients with GERD associated with gastroparesis. METHODS: Randomized, open-label, cross-over study was performed on patients with symptomatic GERD and delayed gastric scintigraphy (≥60% residual @2-hr or ≥10% residual @4-hr). Patients with esophageal/gastric surgery were excluded. Antireflux and prokinetic drugs were discontinued. Subjects were randomized into: a) IR omeprazole 40 mg oral suspension qam x7 days, wash-out x10-14 days, and DR omeprazole 40 mg capsule qam x7 days; or b) DR omeprazole 40 mg capsule qam x7 days, wash-out x 10-14 days, and IR omeprazole 40 mg oral suspension qam x7 days. Pharmacokinetics were studied on day 7 of each study drug. Subjects fasted overnight and took study drug 60 minutes before a high-fat breakfast (39 gm fat, 84 gm carbohydrate, 21 gm protein). Omeprazole plasma concentrations were obtained before and 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, and 300 min after taking study drug. Patient Assessment of GI Disorders-Symptom Severity Index (PAGI-SYM) was obtained before and after each study drug. Paired t-tests were used. RESULTS: 12 female subjects (mean age 51 yrs, 75% idiopathic) were enrolled. Pharmacokinetic results are shown in table. The tmax was significantly shorter for IR compared to DR omeprazole. AUC0-5hr, Cmax, and tmax for IR omeprazole were less variable among subjects. PAGI-SYM total and subscale scores on heartburn/regurgitation, postprandial fullness/satiety, bloating, and upper abdominal pain significantly improved after IR omeprazole but not after DR omeprazole. CONCLUSIONS: IR omeprazole was associated with a more rapid and more predictable pharmacokinetic profile compared to DR omeprazole in patients with GERD associated with gastroparesis. Heartburn and dyspeptic symptoms significantly improved after 7 days of IR omeprazole.
Background: GERD is a common and chronic disorder with increasing prevalence in developing countries. Irritable bowel syndrome (IBS) has been reported to co-exist with GERD commonly. We aimed to compare response to treatment of GERD patients with and without IBS. Methods: Patients with clinical GERD from the PARSI database* were assessed. A composite symptom score (CSS) was calculated for each patient considering severity and frequency of major and minor GERD symptoms at enrollment and on follow-ups. IBS was diagnosed using Rome-II criteria. All patients were started on Omeprazole 20mg bid and it was tapered to the lowest dose keeping the patient symptom free according to an algorithm. A more than 75% decrease in CSS was considered as complete response, 25%-75% decrease in CSS as partial response and a <25% decrease in CSS or CSS worsening as non-responders. Each patient was visited thrice (week 0, 4, and 16). Results: Of the 238 patients with GERD (mean age: 39.4+/-14.8, 61.3% female), 145 (60.9%) had IBS. Patients with IBS were slightly younger (38.0 vs. 41.9 p=0.04) and smoked less frequently (15.8% vs. 28.6%, p=0.03). IBS positives had a higher symptom score at base line (55.1 vs. 46.0, p=0.04). Complete responders were more likely to be IBS negative either at the first (52.7% vs. 49.0%, p=0.04) or second (67.7% vs. 54.5%, p=0.01) follow-up. BMI, smoking, age, sex, marital status and presence of esophageal erosion did not affect response to therapy in either group. Average dose of PPI in patients with and without IBS were 30.3 and 28.2mg/day (p=NS) respectively. Among GERD patients who had IBS, those with lower education were more likely to be non-responder (61.5% vs. 31%, p=0.03). Conclusion: According to our data, GERD patients with concomitant IBS have more prominent GERD symptoms and respond less well to PPI therapy. Looking for concomitant IBS helps handling GERD patients more effectively. * Nasseri-Moghaddam S, et al. Prospective Acid Reflux Study of Iran (PARSI): Methodology and study design. BMC Gastroenterology 2007, 7:42. M1867 Efficacy and Tolerability of ADX10059, a Negative Allosteric Modulator of mGluR5, On Gastro-Esophageal Reflux: A pH-Impedance Study in Healthy Subjects Frank Zerbib, Charlotte Keywood Introduction. Animal studies have shown that inhibition of mGluR5 reduces TLESRs and increases LES tone. A preliminary study with ADX10059 in GERD patients demonstrated a reduction in 24 hour esophageal acid exposure and clinical symptoms on a single day of dosing, but with suboptimal tolerability, due to rapid absorption of the compound after oral dosing. The aim of this study was to evalute the pharmacokinetics, tolerability and pharmacodynamics of a modified release formulation of ADX10059. Subjects and methods. Randomized, double-blind placebo-controlled study in 24 healthy male subjects. Three groups of 8 subjects received placebo (n = 2) or ADX10059 (n = 6) at doses of 50, 125 et 250 mg b.i.d. for 6 days. Esophageal pH-impedance was performed pre-treatment on Day -1 and on treatment Day 6, for 1 hour fasting and 4 hours post refluxogenic meal. Traces
Values in means; Area under concentration-time curve (AUC0-5hr); Peak plasma concentration (Cmax); Time to Cmax (tmax).
AGA Abstracts
A-434