- Email: [email protected]
Oral cysteamine bitartrate, an alternative to pentagastrin for gastric acid secretion testing
with P[21. (Table) Sumraary: Variations in gastric pH over a 24-hour period are non-random and the observed degree of long-term correlation is greater after both 1 and 2 weeks of PPl administration. Conclusinns: The modulation of gastric acidity is a non-linear process; quantification of long-term correlations and their response to experimental interventions, such as acid suppression, will allow more detailed study of the mechanisms underlying the control of gastric acid secretion. Support: DeGroote Foundation & NSERC Canada.
Tgo0
H2-recepter antagonist at night with proton pump inhibitor enhances gastric acid neutralization before and after phase llI activity Yukihiko Koizumi, Motoyasu Kusano, Masaki Maeda, Yasuyuki Shimoyama, Testuya Higuchi, Shikou Kuribayashi, Masatomo Mort
Correlation Indices (a ~,~mean+_SD) Electrode location
PEA
OMI
PC 1.206~0.057 1.2730.059 = DC 1 243~0.060 1.305~0.044b AN 1A03 fl.073 1.2080.069= (paired 24ai1~1,Student t-test ~;, a: p<0.02, b: p
Nocturnal gastric acid breakthrough (NAB) has been defined as a gastric pH<4 for more than one hour during sleep despite protom pump inhibitor (PH) therapy Administration of an H2-receptor antagonist (H2A) before sleep with a PH suppresses the onset of NAB, although the precise effect of H2A therapy on NAB is still unknown The aim of this study was to measure the gastric motor activity and pH simultaneously in order to investigate the mechanism of NAB and the effect of H2A on gastric motor activity, which is considered to have an important role in gastric acid regulation. METHODS: In eight healthy volunteers (mean age 24.6 y., 5 men and 3 women with negative IgG antibody, for H. pylori), gastric motility was measured with a 3-channel strain gauge transducer, and the pH at 5 cm above an d 10 cm below the LES was measured with a 2-channel antimony electrode. The stud)" was performed fi'om 17:00 p.m until 8:30 a.m with a standard dinner (788 Kcal) and breakfast (391 Kcal). NAB was defined as explain e d above, while sleep which was confirnled by a body position sensor. All vohmteers underwent the manometry study four times: without medicines, with PH alone (rabeprazole 20 rag, 2X a day'), with PPI + H2A (raintidine 150 mg before sleep), and with P H + s ele ctive 5-HT4 agonist (mosapride 15 rag, 3X a day'). The mean gastric pH tor each 30-rain period was calculated by computer software (Mull igram) before and after first gastric phase III activity. RESULTS: NAB was found in all subjects. Adding H2A to PPI the rapy abolished NAB in 6 out of 8 subjects. Changes of the gastric pH are shown in the table. The gastric pH was significantly (p<0.0 5) higher after the phase II1 activity than before. Gastric acid neutralization after phase llI was strongest and longest with PPI + H2A therapy. The antral motility index in phase lll was highest with PPI + H2A therapy, but there was no significant difference. CONCLUSIONS: Gastric phase III activity is closely related to changes of the gastric pH. It is considered that suppression of NAB by adding H2A therapy is due to enhancement of gastric acid neutralization after gastric phase lll activity.
OM2 1.266~0.047" 1.313-~0.053 b 1.25(] 0.040~
T898 Oral Cysteamine Bitartrate, an Ahernative to Pentagastrin for Gastric Acid Secretion Testing R~njan Dohil, Jerry A. ~hneider Previously, studies have demonstrated that cysteamine causes gastric acid-hy~0ersecretion in laboratory animals. Until recently" the efik'ct of cysteamine in human subjects had not been well documented. We have reported the effect of oral cysteamine bitartrate on children with cystinosis wbo are required to take cysteamine every 6 hours, eveD" day of their lives, and as a result frequently develop SyTnptoms such as vomiting, pain, anorexia and heartburn. Gastric acid output studies in these children demonstrated a mean 3 fold rise in peak acid production compared with baseline (PAO v's BAO 728.2 v's 256.5 uEqH +/kg/hr respectively, P < 0.001); children with cystinosis have a higher mean BAO than age-matched normal controls (40-67 uEqH +/kg/hr). Gastric acid stimulation following sub-cutaneous pentagastrin (6ug/kg), in normal children, resulted in a 5-8 fold increase in acid output. Children with cystinosis were show'n also to have a mean baseline serum gastrin level of 48.1 pg/ml (compared with 14.8 - 20.9 pg/ml in normal control children over 3 yrs of age) and a mean peak gastrin level of 73.9 pg/ral (P < 0.01) following a single oral dose of cysteamine bitartrate (mean dose 15 mg/kg). Cysteamine is such a powerful stimulant of acid secretion that when the output studies were repeated whilst receiving regular omeprazole therapy (mean dose 1.3 mg/kg~ a mean 1.8 fold increase in maximal acid production above baseline was still observed. Cysteamine, administered orally, appears therefore to cause a similar gastric acid output profile to that seen following subcutaneous pentagastrin administration. Pentagastrin-induced gastric acid output measurements have been useful in differentiating between appropriate and non-appropriate causes of fasting hyqpergastrinemia such as Zollinger-Efiisun syndrome Appropriate hypergastrinem/a is usually due to reduced acid production that might be seen in gastric atrophy ( e g , pemicions anemia or H.pylori infection) or with gasmc acid anti-secretory therapy. Pentagastrin is hOVeunavailable in the USA. Oral cysteamine may provide a sale alternative to pentagastrin; it is FDA approved for the treatment of cystinosis and is currently available by mail-ordan The dose of cysteamine for acid secretion testing in adults is yet to be established, but 3-5 mg/kg may be appropriate. *The study of GI disease in children with cystinosis was sponsored by"AstraZeneca, Wilmington, DE. and by NIH grant MO1RR00827.
Changes of gastrlc pH before and after phase m act~'ity
RAB 10 mg OME 20 m9 *p
62.0 51.0
Intragaslrlc pH >3 and >4 in DuodenalUlcer Patients
62.6" 39.4
2&h 62.5* 47.6
56.4* 39.1
40.6* 28.8
r 1.4 2.6
+60 1.7 3.9
+90 1,8 4.4
+120 1.8 4.9
§ 1.4 4.8
+180 mln 1.4 47
PPI~H2A
4.3
4.7
6.0
6.3
6.0
PPI~SHT4
3,3
2.8
2.8
3,7
3,7
6.0
6.3
6.6
4,2
4.t
3.5
Introduction: An ongoing study is evaluating the safety and efficacy of oral pantoprazole (PAN) in patients with ZES. We enrolled 35 patients aged 30 to 74 years (8 patients aged 65 or older; 63% were men; 91% were white) in a 36-month, opendabel, PAN-only, multicenter study to evaluate AO control; 26 had ZES (74%) and 9 had idiopathic hypersecretion (IH; 26%). Six had multiple endocrine neoplasia type 1 (MEN 1). Eleven had had acidreducing surgeD, (ARS). AO measurements and endoscopy were performed at 3 and 6 month intervals, respectively. Methods: The initial PAN dose was 40 or 80 rag twice daily (BID), at the investigator's discretion. Doses (all BID) at 36 months were 40 mg (n=25), 80 mg (n=8), and 120 mg (n=2), titrated to maintain AO at < 10 mEq/hr (< 5 mEq/hr in patients with prior ARS). Results: To date, 13 patients (ages 32-68; all with ZES, including the 6 with MEN 1) have completed 36 months of treatment (7 men, 6 women, 11 white, 2 black). No patient has discontinued for lack of efficacy. No carcinoid tumor has developed. There were 5 deaths [sepsis (3), cardiac arrest (1), GI bleed (I; refusal of emergentT treatment; possible study drug noncomphance)}; none was considered by the investigator to be PANrelated. Nine (9) patients continue on treatment. AO was well controlled in the 13 patients wbo completed the 3-year treatment period. The majority (n = 8) achieved target AO levels with PAN 40 mg BID, without titration. Of the remaining 5, 1 was increased to 80 mg at momh 9, then to 120 mg BID at month 15. Two (2) were increased to 80 mg at month 6. One (1) alternated between 40 mg and 80 mg through month 36. One (1) took 40 mg through study completion, except 3 days at 80 mg in month 4. No undue safety, concerns emerged in this chronically ill population The most prevalent TEAEs considered by the investigator to be drug related were headache (n = 6), nausea (n = 5), back pain (n =4), and diarrhea (n=4). Patients withdrew due to TEAEs (n=8), patient or investigator request (n=3), and noncompliance (n= 1), Oral PAN 40 rag BiD successfully suppressed acid secretion in most (62%) ZES patients completing the study. Treatment for 3 years has not been associated with worsening control, worsening symptoms, neoplastic change or, in general, the need to increase dose. Five (5) patients required titration (3 in the first 6 months; 2 after > 12 months on a stable dose). Conclusion: Oral PAN in divided doses up to 240 mg daily effectively controls AO in patients with gastric acid hypersecretion.
Objective: To evaluate the effect on acid suppression of a single dose of rabeprazole (RAB) 10 mg versus omeprazole (OME) 20 rag in patients with confirmed duodenal ulcer. Methods: In this muhlcenter, randomized, parallel-group, double-blind, controlled clinical trial, 45 patients with duodenal ulcer received a single dose of' either RAB 10 rag (n = 23) or OME 20 mg (n = 22). Using 24-h pH monitoring, the percentage of time with intragastric pH > 3 and > 4 was calculated tot daytime (08:30-21:00), nighttime (21:00-8:30), and total 24-h periods. Minimal etlkacy was&fined as maintaining pH > 3 or > 4 for 30% of the time period indicated. Res~uhs: The percentage of time with pH > 3 and > 4 in the total 24-h and nighttime periods, and pH>4 for the daytime period were significantly higher with RAB than with OME (p<0,05) (table). However, there was no significant difierence in the percentage of time with pH>3 during the daytime between the treatment groups. The percentage of patients with intragastric pH>3 for at least 30% of daytime, nighttime, and total 2 4 h periods was significantly higher with RAB than with OME (p<0.05). Also, the percentage of patients with intragastric pH>4 for at least 30% of the total 24-h period was higher with RAB than with OME (p<0.05). However, there was no significant difference between the 2 treatment groups in maintaining intragastric pH>4 for 30% of the daytime or nighttime periods. The percentage of nonresponders to acid suppression with RAB (pH>3 for <30% of the 24-h period) ~vas significantly lower compared with OME (4.5% vs 34.8% respectively, p<0.05), Conclusion: Rabeprazole 10 mg provides superior acid suppression compared with omeprazole 20 mg in patients with duodenal ulcer, Research supported by Eisai Inc. Teaneck, NJ, USA and Xi'an-Janssen Pharmaceutical Ltd., Beijing, China
Intragastr~ pH>4 Daytime Nighttime
-30 12 2.4
Three-Year Treatment with Oral Pantoprazole Maintains Effective Long-Term Acid Control in Patients with Zollinger-Ellison Syndrome (ZES) and Idiopathic Hypersecretion David C. Metz, Elaine Softer, Kimberly Torrens, Michael Mack, Polly Eraga, Joseph Pisegna, Saunder
Efficacy of Rabeprazole versus Omeprazole for Acid Suppression in Patients with Duodenal Ulcer: a Muhicenter, Randomized, Double-Blind Clinical Trial Meiynn Ke, Zfiiieng Wang, JinTa Luo, Jun Zhang, Baoy-a Fu, Xiuying Xu, Yao-Zong Yuan, Jing Sun, Hong Fan, Yanmin Chen, Xinguang Liu, Huahong Wang
~ c pH>3 Daytime Nighttime
960 1,2 2.3
T901
T899
Percentageof Time ~
No.e PPI
T902
Comparison of Rabeprazole lOmg Twice Daily and 2Omg Twice Daily on Intragastric PH in Helicobacter Pylori-Negative Healthy Subjects in Three Different CYP2C19 Genotype Groups Tomohiko Shimatani, Susumu Tazuma, Tomoko Kuroiwa, Masaki Inoue
24.h 55.2*
35.3
Background: Treatment of severe gastroesophageal reflux disease and eradication therapy for Hdicobacter pylori require stronger gastric acid suppression. Aim: We compared the effects of rabeprazole 10 mg twice daily and 20 mg tvdce daily on intragastric acidity and the relative potency of each dosage regimen to prevent nocturnal gastric acid breakthrough
A-445
AGA
Abstracts
Tgo0
H2-recepter antagonist at night with proton pump inhibitor enhances gastric acid neutralization before and after phase llI activity Yukihiko Koizumi, Motoyasu Kusano, Masaki Maeda, Yasuyuki Shimoyama, Testuya Higuchi, Shikou Kuribayashi, Masatomo Mort
Correlation Indices (a ~,~mean+_SD) Electrode location
PEA
OMI
PC 1.206~0.057 1.2730.059 = DC 1 243~0.060 1.305~0.044b AN 1A03 fl.073 1.2080.069= (paired 24ai1~1,Student t-test ~;, a: p<0.02, b: p
Nocturnal gastric acid breakthrough (NAB) has been defined as a gastric pH<4 for more than one hour during sleep despite protom pump inhibitor (PH) therapy Administration of an H2-receptor antagonist (H2A) before sleep with a PH suppresses the onset of NAB, although the precise effect of H2A therapy on NAB is still unknown The aim of this study was to measure the gastric motor activity and pH simultaneously in order to investigate the mechanism of NAB and the effect of H2A on gastric motor activity, which is considered to have an important role in gastric acid regulation. METHODS: In eight healthy volunteers (mean age 24.6 y., 5 men and 3 women with negative IgG antibody, for H. pylori), gastric motility was measured with a 3-channel strain gauge transducer, and the pH at 5 cm above an d 10 cm below the LES was measured with a 2-channel antimony electrode. The stud)" was performed fi'om 17:00 p.m until 8:30 a.m with a standard dinner (788 Kcal) and breakfast (391 Kcal). NAB was defined as explain e d above, while sleep which was confirnled by a body position sensor. All vohmteers underwent the manometry study four times: without medicines, with PH alone (rabeprazole 20 rag, 2X a day'), with PPI + H2A (raintidine 150 mg before sleep), and with P H + s ele ctive 5-HT4 agonist (mosapride 15 rag, 3X a day'). The mean gastric pH tor each 30-rain period was calculated by computer software (Mull igram) before and after first gastric phase III activity. RESULTS: NAB was found in all subjects. Adding H2A to PPI the rapy abolished NAB in 6 out of 8 subjects. Changes of the gastric pH are shown in the table. The gastric pH was significantly (p<0.0 5) higher after the phase II1 activity than before. Gastric acid neutralization after phase llI was strongest and longest with PPI + H2A therapy. The antral motility index in phase lll was highest with PPI + H2A therapy, but there was no significant difference. CONCLUSIONS: Gastric phase III activity is closely related to changes of the gastric pH. It is considered that suppression of NAB by adding H2A therapy is due to enhancement of gastric acid neutralization after gastric phase lll activity.
OM2 1.266~0.047" 1.313-~0.053 b 1.25(] 0.040~
T898 Oral Cysteamine Bitartrate, an Ahernative to Pentagastrin for Gastric Acid Secretion Testing R~njan Dohil, Jerry A. ~hneider Previously, studies have demonstrated that cysteamine causes gastric acid-hy~0ersecretion in laboratory animals. Until recently" the efik'ct of cysteamine in human subjects had not been well documented. We have reported the effect of oral cysteamine bitartrate on children with cystinosis wbo are required to take cysteamine every 6 hours, eveD" day of their lives, and as a result frequently develop SyTnptoms such as vomiting, pain, anorexia and heartburn. Gastric acid output studies in these children demonstrated a mean 3 fold rise in peak acid production compared with baseline (PAO v's BAO 728.2 v's 256.5 uEqH +/kg/hr respectively, P < 0.001); children with cystinosis have a higher mean BAO than age-matched normal controls (40-67 uEqH +/kg/hr). Gastric acid stimulation following sub-cutaneous pentagastrin (6ug/kg), in normal children, resulted in a 5-8 fold increase in acid output. Children with cystinosis were show'n also to have a mean baseline serum gastrin level of 48.1 pg/ml (compared with 14.8 - 20.9 pg/ml in normal control children over 3 yrs of age) and a mean peak gastrin level of 73.9 pg/ral (P < 0.01) following a single oral dose of cysteamine bitartrate (mean dose 15 mg/kg). Cysteamine is such a powerful stimulant of acid secretion that when the output studies were repeated whilst receiving regular omeprazole therapy (mean dose 1.3 mg/kg~ a mean 1.8 fold increase in maximal acid production above baseline was still observed. Cysteamine, administered orally, appears therefore to cause a similar gastric acid output profile to that seen following subcutaneous pentagastrin administration. Pentagastrin-induced gastric acid output measurements have been useful in differentiating between appropriate and non-appropriate causes of fasting hyqpergastrinemia such as Zollinger-Efiisun syndrome Appropriate hypergastrinem/a is usually due to reduced acid production that might be seen in gastric atrophy ( e g , pemicions anemia or H.pylori infection) or with gasmc acid anti-secretory therapy. Pentagastrin is hOVeunavailable in the USA. Oral cysteamine may provide a sale alternative to pentagastrin; it is FDA approved for the treatment of cystinosis and is currently available by mail-ordan The dose of cysteamine for acid secretion testing in adults is yet to be established, but 3-5 mg/kg may be appropriate. *The study of GI disease in children with cystinosis was sponsored by"AstraZeneca, Wilmington, DE. and by NIH grant MO1RR00827.
Changes of gastrlc pH before and after phase m act~'ity
RAB 10 mg OME 20 m9 *p
62.0 51.0
Intragaslrlc pH >3 and >4 in DuodenalUlcer Patients
62.6" 39.4
2&h 62.5* 47.6
56.4* 39.1
40.6* 28.8
r 1.4 2.6
+60 1.7 3.9
+90 1,8 4.4
+120 1.8 4.9
§ 1.4 4.8
+180 mln 1.4 47
PPI~H2A
4.3
4.7
6.0
6.3
6.0
PPI~SHT4
3,3
2.8
2.8
3,7
3,7
6.0
6.3
6.6
4,2
4.t
3.5
Introduction: An ongoing study is evaluating the safety and efficacy of oral pantoprazole (PAN) in patients with ZES. We enrolled 35 patients aged 30 to 74 years (8 patients aged 65 or older; 63% were men; 91% were white) in a 36-month, opendabel, PAN-only, multicenter study to evaluate AO control; 26 had ZES (74%) and 9 had idiopathic hypersecretion (IH; 26%). Six had multiple endocrine neoplasia type 1 (MEN 1). Eleven had had acidreducing surgeD, (ARS). AO measurements and endoscopy were performed at 3 and 6 month intervals, respectively. Methods: The initial PAN dose was 40 or 80 rag twice daily (BID), at the investigator's discretion. Doses (all BID) at 36 months were 40 mg (n=25), 80 mg (n=8), and 120 mg (n=2), titrated to maintain AO at < 10 mEq/hr (< 5 mEq/hr in patients with prior ARS). Results: To date, 13 patients (ages 32-68; all with ZES, including the 6 with MEN 1) have completed 36 months of treatment (7 men, 6 women, 11 white, 2 black). No patient has discontinued for lack of efficacy. No carcinoid tumor has developed. There were 5 deaths [sepsis (3), cardiac arrest (1), GI bleed (I; refusal of emergentT treatment; possible study drug noncomphance)}; none was considered by the investigator to be PANrelated. Nine (9) patients continue on treatment. AO was well controlled in the 13 patients wbo completed the 3-year treatment period. The majority (n = 8) achieved target AO levels with PAN 40 mg BID, without titration. Of the remaining 5, 1 was increased to 80 mg at momh 9, then to 120 mg BID at month 15. Two (2) were increased to 80 mg at month 6. One (1) alternated between 40 mg and 80 mg through month 36. One (1) took 40 mg through study completion, except 3 days at 80 mg in month 4. No undue safety, concerns emerged in this chronically ill population The most prevalent TEAEs considered by the investigator to be drug related were headache (n = 6), nausea (n = 5), back pain (n =4), and diarrhea (n=4). Patients withdrew due to TEAEs (n=8), patient or investigator request (n=3), and noncompliance (n= 1), Oral PAN 40 rag BiD successfully suppressed acid secretion in most (62%) ZES patients completing the study. Treatment for 3 years has not been associated with worsening control, worsening symptoms, neoplastic change or, in general, the need to increase dose. Five (5) patients required titration (3 in the first 6 months; 2 after > 12 months on a stable dose). Conclusion: Oral PAN in divided doses up to 240 mg daily effectively controls AO in patients with gastric acid hypersecretion.
Objective: To evaluate the effect on acid suppression of a single dose of rabeprazole (RAB) 10 mg versus omeprazole (OME) 20 rag in patients with confirmed duodenal ulcer. Methods: In this muhlcenter, randomized, parallel-group, double-blind, controlled clinical trial, 45 patients with duodenal ulcer received a single dose of' either RAB 10 rag (n = 23) or OME 20 mg (n = 22). Using 24-h pH monitoring, the percentage of time with intragastric pH > 3 and > 4 was calculated tot daytime (08:30-21:00), nighttime (21:00-8:30), and total 24-h periods. Minimal etlkacy was&fined as maintaining pH > 3 or > 4 for 30% of the time period indicated. Res~uhs: The percentage of time with pH > 3 and > 4 in the total 24-h and nighttime periods, and pH>4 for the daytime period were significantly higher with RAB than with OME (p<0,05) (table). However, there was no significant difierence in the percentage of time with pH>3 during the daytime between the treatment groups. The percentage of patients with intragastric pH>3 for at least 30% of daytime, nighttime, and total 2 4 h periods was significantly higher with RAB than with OME (p<0.05). Also, the percentage of patients with intragastric pH>4 for at least 30% of the total 24-h period was higher with RAB than with OME (p<0.05). However, there was no significant difference between the 2 treatment groups in maintaining intragastric pH>4 for 30% of the daytime or nighttime periods. The percentage of nonresponders to acid suppression with RAB (pH>3 for <30% of the 24-h period) ~vas significantly lower compared with OME (4.5% vs 34.8% respectively, p<0.05), Conclusion: Rabeprazole 10 mg provides superior acid suppression compared with omeprazole 20 mg in patients with duodenal ulcer, Research supported by Eisai Inc. Teaneck, NJ, USA and Xi'an-Janssen Pharmaceutical Ltd., Beijing, China
Intragastr~ pH>4 Daytime Nighttime
-30 12 2.4
Three-Year Treatment with Oral Pantoprazole Maintains Effective Long-Term Acid Control in Patients with Zollinger-Ellison Syndrome (ZES) and Idiopathic Hypersecretion David C. Metz, Elaine Softer, Kimberly Torrens, Michael Mack, Polly Eraga, Joseph Pisegna, Saunder
Efficacy of Rabeprazole versus Omeprazole for Acid Suppression in Patients with Duodenal Ulcer: a Muhicenter, Randomized, Double-Blind Clinical Trial Meiynn Ke, Zfiiieng Wang, JinTa Luo, Jun Zhang, Baoy-a Fu, Xiuying Xu, Yao-Zong Yuan, Jing Sun, Hong Fan, Yanmin Chen, Xinguang Liu, Huahong Wang
~ c pH>3 Daytime Nighttime
960 1,2 2.3
T901
T899
Percentageof Time ~
No.e PPI
T902
Comparison of Rabeprazole lOmg Twice Daily and 2Omg Twice Daily on Intragastric PH in Helicobacter Pylori-Negative Healthy Subjects in Three Different CYP2C19 Genotype Groups Tomohiko Shimatani, Susumu Tazuma, Tomoko Kuroiwa, Masaki Inoue
24.h 55.2*
35.3
Background: Treatment of severe gastroesophageal reflux disease and eradication therapy for Hdicobacter pylori require stronger gastric acid suppression. Aim: We compared the effects of rabeprazole 10 mg twice daily and 20 mg tvdce daily on intragastric acidity and the relative potency of each dosage regimen to prevent nocturnal gastric acid breakthrough
A-445
AGA
Abstracts