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S1083 Effects of the Long Acting Histamine 2 Receptor Antagonists, Lavoltidine, GSK1023911A and GSK1040323B, On Gastric Acid Secretion Measured By pH-Metry in Gastric Fistula Dogs
were lost for follow up examinations. 27/37 (73%) patients showed normal values in pH/ MII under ongoing therapy with 80mg esomeprazole. Baclofen was additionally administered to 7 of the remaining 10 patients with a pathological result. 2 patients refused baclofen therapy due to loss of symptoms under 80 mg esomeprazole, one decided to undergo surgery and was therefore excluded. Normalisation of pH/MII under additive therapy with baclofen was observed in only 2 of the 7 patients treated with baclofen. Conclusion: Doubling the dosage leads to normalization of pathological pH/MII in the majority of all patients with “therapy-refractory” reflux disease despite treatment with 40mg esomeprazole. Additional therapy with baclofen has limited value. S1082 In Vitro and In Vivo Effects of GSK1007066A, a Selective H+/K+-ATPase Inhibitor Colin A. Campbell, Lucy M. Mensah, Stacey L. Wood, Jill Darton, Sarah J. Hadingham, Pamela Gaskin, Emmanuel H. Demont, Mark Bamford, Kevin Lee, Peter McLean Here we describe the In Vitro and In Vivo effects of a novel potassium competitive acid blocker, GSK1007066A, for the treatment of acid related diseases. The activities of GSK1007066A at H+/K+-ATPase and Na+/K+-ATPase were determined using hydrolysis of ATP by pig gastric and dog kidney membranes, respectively. The K+-competitive antagonistic property of GSK1007066A on H+/K+-ATPase activity was assessed at different KCl concentrations and at 1, 2 and 5 times its IC50 value. The ability of GSK1007066A to penetrate parietal cell membrane and inhibit H+/K+-ATPase was assessed using 14C-aminopyrine accumulation in native rat mucosal cells. GSK1007066A was evaluated for onset of action by the ability to inhibit pentagastrin-stimulated gastric acidity levels using a rat gastric aspiration model. GSK1007066A was investigated in the conscious gastric fistula rats. Gastric acid secretion was stimulated by intravenous pentagastrin. Gastric acid samples were collected and the acid content determined every 30 minutes for up to 9 hours post-drug. Gastric fistula dogs were fasted overnight, and instrumented with a subcutaneous catheter, and with an ambulatory infusion pump and pH-metry probe and data-logger held within jackets. Dogs were then administered a liquid meal and a subcutaneous infusion of pentagastrin to stimulate gastric acid secretion. GSK1007066A at doses of 0.3-8mg/kg p.o. were administered 3h following initiation of the pentagastrin infusion. Gastric acidity was monitored for up to a total 24h. The data were collated to measure percentage time post-administration for which the pH was greater than 4. The pIC50 of GSK1007066A was 7.89 ± 0.61 using pig gastric membranes. GSK1007066A generated linear Lineweaver-Burk plots between 1 and 100 mM KCl. The linear regression intersected close to the y-axis suggesting GSK1007066A acts as competitive inhibitor. GSK1007066A was highly selective over its closest family members. In the rat gastric aspiration model, GSK1007066A attenuated the response to pentagastrin within an hour in a dose-dependent manner. In conscious gastric fistula rats, GSK1007066A at 1, 3 & 10mg/kg p.o. inhibited the response to pentagastrin in a dose-dependent manner with an inhibition of acid secretion of 60, 81 and 100%, respectively. In dogs, GSK1007066A induced a dose related increased in percentage time of pH greater than 4 In summary, GSK1007066A has been shown to be a selective, reversible H+/K+-ATPase inhibitor and to be active in In Vivo models of gastric acid secretion.
S1080 Physicians Underestimate Symptom Burden and Overestimate Treatment Effects in GERD Patients Hubert Monnikes, Holger Schmitt, Peter Berghoefer, Hubert Doerfler, Robert Heading Introduction: The decision about duration of treatment with PPIs in GERD is mainly based on the severity of remaining symptoms and treatment satisfaction, respectively. However, it is desirable to know if patients and physicians agree when assessing symptom severity. In this study, the clinical endpoints ‘patient treatment satisfaction' and ‘investigator assessment of symptom relief' were compared to symptom assessment with the validated questionnaire ReQuestTM-GI. Methods: In this open, multinational, multicenter study, patients considered by the investigator to have symptoms due to GERD were treated with pantoprazole 40 mg o.d. Endoscopic status was unknown at inclusion into the study. Investigators assessed the control of reflux symptoms and patients assessed their treatment satisfaction at week 4 and 8 on a 3-point Likert scale. Symptomatic response to treatment was defined as the score of the ReQuestTM-GI being below the pre-defined GERD symptom threshold on all 3 consecutive days prior to a visit. Cramer's V was used to analyze the correlations between ReQuestTMGI and the physician's assessment of symptom control and the patient's satisfaction with treatment. Results: A total of 1549 patients (PP) were recruited in 168 centers in 21 countries worldwide. Treatment response rates as assessed by ReQuestTM-GI were 60.6% at Week 4 and 72.6% at Week 8. At both time points the number of patients with symptoms judged as ‘well controlled' by the physician was higher than the number of patients being ‘very satisfied' with treatment (Table). Changes of these numbers over time were similar comparing the two groups. The percentage of patients with ‘not controlled' reflux symptoms and being ‘not satisfied' with treatment were very low at Week 4 and 8. At Week 4, the correlation between ‘treatment response' (ReQuestTM-GI) and ‘treatment satisfaction' was higher than the correlation between ‘treatment response' and ‘control of reflux symptoms' (0.392 vs. 0.335). The same was true for the correlations at Week 8 (0.454 vs. 0.374). Conclusion: Patient-assessed treatment satisfaction corresponds more closely than the physician's assessment of symptom control with response to treatment judged by ReQuestTM-GI. The data suggests that physicians tend to underestimate the patient's symptom burden and to overestimate symptom improvement with treatment. Control of Reflux Symptoms and Treatment Satisfaction after 4 and 8 Weeks (PP)
S1083 Effects of the Long Acting Histamine 2 Receptor Antagonists, Lavoltidine, GSK1023911A and GSK1040323B, On Gastric Acid Secretion Measured By pH-Metry in Gastric Fistula Dogs Colin A. Campbell, Pamela Gaskin, Paul J. Beswick, Kevin Lee, Peter McLean Inhibition of gastric acid secretion is regarded as the primary modality to improve symptoms associated with acid related diseases (ARD). Long acting histamine 2 receptor antagonists (LAH2RA) have been reported to inhibit gastric acid secretion with rapidity of onset (characterised by competitive histamine 2 receptor antagonists) and by duration of action (characterised by proton pump inhibitors due to non-competitive antagonism at the H+/K+-ATPase). Herein we describe the effects of novel LAH2RAs lavoltidine, GSK1023911A and GSK1040323B in pentagastrin stimulated acid secretion in gastric fistula dogs measured by pH-metry. Titanium gastric fistulae were surgically implanted in 4 male dogs (15-21kg). At least 4 weeks recovery was allowed before experimental use. Dogs were fasted overnight, and then on the day of experimentation were instrumented with a subcutaneous catheter, and with an ambulatory infusion pump and pH-metry probe and data-logger held within jackets. Dogs were then administered a liquid meal (Liquivite, Creg Vetfoods, London, UK) and a subcutaneous infusion of pentagastrin (16µg/kg/h for 22h). Lavoltidine, GSK1023911A and GSK1040323B (1 & 3mg/kg p.o.) were randomly administered 3h following initiation of the pentagastrin infusion. Gastric acidity was monitored for up to a total 24h. Inclusion criteria for data required that following the liquid diet and pentagastrin infusion gastric pH either was reduced by at least 3 pH units or that pH was less than 3 at the time of oral dosing and for at least 30 minutes prior to dosing. The data were collated to measure percentage time post-administration for which the pH was greater than 4. Statistical analysis was performed using ANOVA and Dunnetts test. Initial pH values ranged from 1.33 to 8.59 despite the dogs being fasted for the same duration of time. Administration of a liquid diet and pentagastrin infusion resulted in gastric pH reduction to a range of 0.83 to 4.24. Lavoltidine, GSK1023911A and GSK1040323B induced elevations of gastric pH. Lavoltidine, GSK1023911A and GSK1040323B (1 & 3 mg/kg p.o.) induced dose related increases in percentage time of pH greater than 4 of 63±12% (p=0.009) and 69±18% (p=0.002), 41±14% (p=0.061) and 60±6% (p=0.015), and 55±10% (p=0.086) and 80±9% (p=0.002) respectively, compared to control 14±8%. These data show that lavoltidine, GSK1023911A and GSK1040323B reduce the acidity of the stomach in a dose related manner in a model that allows the evaluation of the pharmacodynamic effects in the dog.
inv=investigator-assessed, pat=patient-assessed, PP=per protocol, N=number of patients S1081 High-Dose Esomeprazole in Combination with Baclofen in the Treatment of Symptomatic Refractory Gastroesophageal Reflux Disease — a pH-Metry/ Impedance Controlled Study Monther Bajbouj, Valentin Becker, Roland M. Schmid, Alexander Meining Background: Combined 24h-pH-monitoring/intraluminal-multi-channel-impedance-measurement (pH/MII) is an useful method for determination of gastroesophageal reflux despite ongoing therapy with proton-pump-inhibitors. Aim of our study was to evaluate the influence of an escalating medical anti-reflux-therapy with 40mg esomeprazole, followed by 80mg esomeprazole, followed by 80mg esomeprazol with additive baclofen on refractory pathological reflux as determined by pH/MII. Methods: We examined 130 patients with persistent reflux-symptoms despite ongoing therapy with 40mg esomeprazole by the means of combined 24h pH/MII. Patients with normal values in pH/MII (<73 weakly-, non- or acidic mixed refluxepisodes) were excluded from further evaluation at that time. All others received 80mg esomeprazole for another 4 weeks. Thereafter, treatment effect was again controlled by pH/ MII. In the case of persistent pathological reflux, therapy was further escalated by adding baclofen with dosage stepwise increased up to 60mg/d. A final pH/MII was performed in these patients after 3 months. Results: 40 of 130 (30.8%) patients showed pathological findings in pH/MII despite ongoing therapy with 40mg esomeprazole. 3/40 (7.5%) patients
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AGA Abstracts
AGA Abstracts
genotype status was associated with the symptomatic recurrence of GERD during maintenance therapy with a PPI. Methods: This is the prospective study performed during 2004 and 2007. Patients with endoscopically proven GERD were invited and enrolled to the study after cure of mucosal breaks and symptoms by a treatment with lansoprazole 30 mg/D for 8 weeks. Cure of mucosal breaks was diagnosed by endoscopy. They were treated with lansoprazole 30 mg after cure of mucosal breaks. When incidence of reflux symptoms became no more than once per week, the dose of lansoprazole was decreased to 15 mg/D. The reflux symptoms were interviewed every 2 — 4 weeks. When reflux symptoms occurred more than twice per week, the dose of lansoprazole was restored to 30 mg/D. CYP2C19 genotypes were analyzed with DNAs extracted from leucocytes and were classified into rapid metabolizer (RM: *1/*1), intermediate metabolizer (IM: *1/*X) and poor metabolizer (PM: *X/*X) (*X = *2 or *3). Results: Patients consisted of 54 RMs, 56 IMs and 14 PMs. Of 124 patients, 18 RMs, 28 IMs and 8 PMs were treated with lansopraozle 15 mg. During treatment with lansoprazole 15 mg/D, 88.9% (16/18) of RMs, 78.6%( 22/28) of IMs and 50% (4/8) of PMs (50%) experienced symptomatic recurrence and a dose of lansoprazole was restored to 30 mg/D. The hazard ratio of symptomatic recurrence of GERD in RMs in comparison with PMs was 4.82 (95%C.I.:1.36 — 17.02, P = 0.015). Finally, 96.3% of RMs, 85.7% of IMs and 71.4% of PMs were continuously treated with lansopraozle 30 mg/D as the maintenance therapy (P = 0.018). Conclusion: When dose of a PPI is decreased, GERD patients with RM genotype of CYP2C19 are at higher risk of symptomatic recurrence. The CYP2C19 genotyping test seems a useful marker to determine the optimal dose of a PPI in the maintenance therapy of GERD.
S1080 Physicians Underestimate Symptom Burden and Overestimate Treatment Effects in GERD Patients Hubert Monnikes, Holger Schmitt, Peter Berghoefer, Hubert Doerfler, Robert Heading Introduction: The decision about duration of treatment with PPIs in GERD is mainly based on the severity of remaining symptoms and treatment satisfaction, respectively. However, it is desirable to know if patients and physicians agree when assessing symptom severity. In this study, the clinical endpoints ‘patient treatment satisfaction' and ‘investigator assessment of symptom relief' were compared to symptom assessment with the validated questionnaire ReQuestTM-GI. Methods: In this open, multinational, multicenter study, patients considered by the investigator to have symptoms due to GERD were treated with pantoprazole 40 mg o.d. Endoscopic status was unknown at inclusion into the study. Investigators assessed the control of reflux symptoms and patients assessed their treatment satisfaction at week 4 and 8 on a 3-point Likert scale. Symptomatic response to treatment was defined as the score of the ReQuestTM-GI being below the pre-defined GERD symptom threshold on all 3 consecutive days prior to a visit. Cramer's V was used to analyze the correlations between ReQuestTMGI and the physician's assessment of symptom control and the patient's satisfaction with treatment. Results: A total of 1549 patients (PP) were recruited in 168 centers in 21 countries worldwide. Treatment response rates as assessed by ReQuestTM-GI were 60.6% at Week 4 and 72.6% at Week 8. At both time points the number of patients with symptoms judged as ‘well controlled' by the physician was higher than the number of patients being ‘very satisfied' with treatment (Table). Changes of these numbers over time were similar comparing the two groups. The percentage of patients with ‘not controlled' reflux symptoms and being ‘not satisfied' with treatment were very low at Week 4 and 8. At Week 4, the correlation between ‘treatment response' (ReQuestTM-GI) and ‘treatment satisfaction' was higher than the correlation between ‘treatment response' and ‘control of reflux symptoms' (0.392 vs. 0.335). The same was true for the correlations at Week 8 (0.454 vs. 0.374). Conclusion: Patient-assessed treatment satisfaction corresponds more closely than the physician's assessment of symptom control with response to treatment judged by ReQuestTM-GI. The data suggests that physicians tend to underestimate the patient's symptom burden and to overestimate symptom improvement with treatment. Control of Reflux Symptoms and Treatment Satisfaction after 4 and 8 Weeks (PP)
S1083 Effects of the Long Acting Histamine 2 Receptor Antagonists, Lavoltidine, GSK1023911A and GSK1040323B, On Gastric Acid Secretion Measured By pH-Metry in Gastric Fistula Dogs Colin A. Campbell, Pamela Gaskin, Paul J. Beswick, Kevin Lee, Peter McLean Inhibition of gastric acid secretion is regarded as the primary modality to improve symptoms associated with acid related diseases (ARD). Long acting histamine 2 receptor antagonists (LAH2RA) have been reported to inhibit gastric acid secretion with rapidity of onset (characterised by competitive histamine 2 receptor antagonists) and by duration of action (characterised by proton pump inhibitors due to non-competitive antagonism at the H+/K+-ATPase). Herein we describe the effects of novel LAH2RAs lavoltidine, GSK1023911A and GSK1040323B in pentagastrin stimulated acid secretion in gastric fistula dogs measured by pH-metry. Titanium gastric fistulae were surgically implanted in 4 male dogs (15-21kg). At least 4 weeks recovery was allowed before experimental use. Dogs were fasted overnight, and then on the day of experimentation were instrumented with a subcutaneous catheter, and with an ambulatory infusion pump and pH-metry probe and data-logger held within jackets. Dogs were then administered a liquid meal (Liquivite, Creg Vetfoods, London, UK) and a subcutaneous infusion of pentagastrin (16µg/kg/h for 22h). Lavoltidine, GSK1023911A and GSK1040323B (1 & 3mg/kg p.o.) were randomly administered 3h following initiation of the pentagastrin infusion. Gastric acidity was monitored for up to a total 24h. Inclusion criteria for data required that following the liquid diet and pentagastrin infusion gastric pH either was reduced by at least 3 pH units or that pH was less than 3 at the time of oral dosing and for at least 30 minutes prior to dosing. The data were collated to measure percentage time post-administration for which the pH was greater than 4. Statistical analysis was performed using ANOVA and Dunnetts test. Initial pH values ranged from 1.33 to 8.59 despite the dogs being fasted for the same duration of time. Administration of a liquid diet and pentagastrin infusion resulted in gastric pH reduction to a range of 0.83 to 4.24. Lavoltidine, GSK1023911A and GSK1040323B induced elevations of gastric pH. Lavoltidine, GSK1023911A and GSK1040323B (1 & 3 mg/kg p.o.) induced dose related increases in percentage time of pH greater than 4 of 63±12% (p=0.009) and 69±18% (p=0.002), 41±14% (p=0.061) and 60±6% (p=0.015), and 55±10% (p=0.086) and 80±9% (p=0.002) respectively, compared to control 14±8%. These data show that lavoltidine, GSK1023911A and GSK1040323B reduce the acidity of the stomach in a dose related manner in a model that allows the evaluation of the pharmacodynamic effects in the dog.
inv=investigator-assessed, pat=patient-assessed, PP=per protocol, N=number of patients S1081 High-Dose Esomeprazole in Combination with Baclofen in the Treatment of Symptomatic Refractory Gastroesophageal Reflux Disease — a pH-Metry/ Impedance Controlled Study Monther Bajbouj, Valentin Becker, Roland M. Schmid, Alexander Meining Background: Combined 24h-pH-monitoring/intraluminal-multi-channel-impedance-measurement (pH/MII) is an useful method for determination of gastroesophageal reflux despite ongoing therapy with proton-pump-inhibitors. Aim of our study was to evaluate the influence of an escalating medical anti-reflux-therapy with 40mg esomeprazole, followed by 80mg esomeprazole, followed by 80mg esomeprazol with additive baclofen on refractory pathological reflux as determined by pH/MII. Methods: We examined 130 patients with persistent reflux-symptoms despite ongoing therapy with 40mg esomeprazole by the means of combined 24h pH/MII. Patients with normal values in pH/MII (<73 weakly-, non- or acidic mixed refluxepisodes) were excluded from further evaluation at that time. All others received 80mg esomeprazole for another 4 weeks. Thereafter, treatment effect was again controlled by pH/ MII. In the case of persistent pathological reflux, therapy was further escalated by adding baclofen with dosage stepwise increased up to 60mg/d. A final pH/MII was performed in these patients after 3 months. Results: 40 of 130 (30.8%) patients showed pathological findings in pH/MII despite ongoing therapy with 40mg esomeprazole. 3/40 (7.5%) patients
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AGA Abstracts
AGA Abstracts
genotype status was associated with the symptomatic recurrence of GERD during maintenance therapy with a PPI. Methods: This is the prospective study performed during 2004 and 2007. Patients with endoscopically proven GERD were invited and enrolled to the study after cure of mucosal breaks and symptoms by a treatment with lansoprazole 30 mg/D for 8 weeks. Cure of mucosal breaks was diagnosed by endoscopy. They were treated with lansoprazole 30 mg after cure of mucosal breaks. When incidence of reflux symptoms became no more than once per week, the dose of lansoprazole was decreased to 15 mg/D. The reflux symptoms were interviewed every 2 — 4 weeks. When reflux symptoms occurred more than twice per week, the dose of lansoprazole was restored to 30 mg/D. CYP2C19 genotypes were analyzed with DNAs extracted from leucocytes and were classified into rapid metabolizer (RM: *1/*1), intermediate metabolizer (IM: *1/*X) and poor metabolizer (PM: *X/*X) (*X = *2 or *3). Results: Patients consisted of 54 RMs, 56 IMs and 14 PMs. Of 124 patients, 18 RMs, 28 IMs and 8 PMs were treated with lansopraozle 15 mg. During treatment with lansoprazole 15 mg/D, 88.9% (16/18) of RMs, 78.6%( 22/28) of IMs and 50% (4/8) of PMs (50%) experienced symptomatic recurrence and a dose of lansoprazole was restored to 30 mg/D. The hazard ratio of symptomatic recurrence of GERD in RMs in comparison with PMs was 4.82 (95%C.I.:1.36 — 17.02, P = 0.015). Finally, 96.3% of RMs, 85.7% of IMs and 71.4% of PMs were continuously treated with lansopraozle 30 mg/D as the maintenance therapy (P = 0.018). Conclusion: When dose of a PPI is decreased, GERD patients with RM genotype of CYP2C19 are at higher risk of symptomatic recurrence. The CYP2C19 genotyping test seems a useful marker to determine the optimal dose of a PPI in the maintenance therapy of GERD.