Omeprazole for maintenance therapy of erosive esophagitis in children

A658 AGA ABSTRACTS

GASTROENTEROLOGY Vol. 118, No.4

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3609

DEVELOPMENT OF ESOPHAGITIS AFTER H.PYLORl ERADICATION: IMPACT OF CAGA STATUS. Theodore Rokkas, Spiros D. Ladas, Constantine Triandafyllou, Christos Liatsos, Evangelia Petridou, George Papatheodorou, Andreas Kararneris, Sotirios A. Raptis, 401 Army Gen Hosp, Athens. Greece; Med Sch, Athens Univ, Athens, Greece. There is increasing evidence that Helicobacterpylori (H.pylori) eradication might predispose to refux esophagitis(RE). However, the role of CagA status in the development of RE after H.pylori eradication has not been studied so far. The aim of this prospective study was to examine the impact of CagA status in relation to the appearance of RE after successful H.pylori treatment. Methods: 50 consecutive, successfully eradicated patients, without RE at the time of H.pylori treatment [25 duodenal ulcer(DU) and 25 non-ulcer (NU), 30M, 20F, median age 41.5 yrs, range 21-57] were followed up for 24 months. All patients underwent upper GI endoscopy before and at 0, 6,12,18 and 24 months after H.pylori eradication or when reflux symptoms occurred. During endoscopy gastric, antral and corpus biopsies were taken for gastritis evaluation. The sum of the scores for acute [0-3 (0= absent, 3= severe)] and chronic inflammation (0-3) comprised the total gastritis score. CagA was determined by immunoblotting the sera from patients against H.pylori antigens. The independent variables CagA status, age, sex, smoking, alcohol intake, gastritis scores of antrum and corpus gastritis before Hipylori eradication, were introduced in a multivariate logistic regression analysis (MLRA) with RE during follow up as a dependent variable. Results: Among the 50 Hpylori( +) patients before eradication there were 22 (44%) CagA(+) patients and 28(56%) CagA(-). During follow up 12/50(24%) patients developed RE and among them there were 11 CagA(+) and I CagA(-) patient (p=0.OOO2, odds ratio 27, 95% CI 3.1-235.1). In the MLRA except for CagA(+) status, the severity of corpus gastritis before eradication exerted a significant influence (0.045) on the development of RE after H.pylori eradication. Conclusion: CagA( + ) status and severity of corpus gastritis before H.pylori eradication significantly favor the development of RE after successful Htpylori treatment.

NEUROENDOCRINE CELL PROLIFERATION AND CHANGES IN PARIETAL CELLS DURING DRUG-INDUCED ACHLORHYDRIA. Jakob W. Hendel, Esther Hage, Lene Hendel, Jens Gustafsen, Dept of Gastroenterology, Herlev Hosp, Copenhagen, Denmark; Dept of Pathology, Rigshospitalet, Copenhagen, Denmark; Dept of Dermatology, BBH, Copenhagen, Denmark; Dept of Surg, Hilleroed Hosp, Hilleroed, Denmark. Treatment with proton pump inhibitors is suspected to induce changes in gastric oxyntic mucosa. Standard treatment has proven safe. Systemic Sclerosis(SS)causes esophageal dysmotility resulting in severe GERD. To abolish GERD it is often necessary to achieve functional achlorhydria. AIM: To assess changes in gastric oxyntic mucosa during drug-induced functional achlorhydria. PATIENTS AND METHODS: 25 SS patients had their treatment tailored by pH-metry and incremental increase of omeprazole dose. 11 patients (MIF IIIO,median age 58 y (50-79), median observation time lOy (8.5-12, median dose 100 mg/day(40-140); median sgastrin 116 pmollL(45-652») required functional achlorhydria (mean gastric pH >5.0)to abolish GERD. Every 12 months gastric biopsies were obtained. Serial sections were hematoxylin-eosin stained. Neuroendocrine cells were stained by Grimelius' argyrophilic silver impregnation technique and/or marked by chromegranin A in an immunohistochemical procedure. Endocrine cell proliferation was scored as normal (Oj.diffuse(1) linear- (2) and micronodular (3) hyperplasia. Parietal cell changes were scored as none (0), slight (I), moderate (2) or severe (3). Similar investigation were done in 16 patients with Zollinger-Ellison Syndrome (ZES) (MIF 12/4, median age 65 y (45-81),median duration of observation 10 y (6-13), median dose 60 mg/day (20-160». Neuroendocrine cell proliferation and changes in parietal cells were scored before and at end of observation period. RESULTS: Scores are shown in Table I For SS patients changes were not statistically significant when assessed by paired t-test(p>O.1), while changes within ZES were highly significant (p
3608

ESOMEPRAZOLE 40MG AND 20MG IS EFFICACIOUS IN THE LONG-TERM MANAGEMENT OF PATIENTS WITH ENDOSCOPY·NEGATIVE GERD: A PLACEBO·CONTROLLED TRIAL OF ON-DEMAND THERAPY FOR 6 MONTHS. Nicholas 1. Talley, Thomas L. Venables, Jonathan R. Green, David Armstrong, Kevin P. 0' Kane, Mustafa H. Giaffer, Kama D. Bardhan, Rolf Carlsson, Samuel Chen, Goran Hasselgren, The Nepean Hosp, Penrith, Australia; Calverton Practice, Nottingham, United Kingdom; North Staffordshire Hosp Ctr, Stoke-on Trent, United Kingdom; McMaster Univ, Hamilton, Canada; Cowglen Hosp, Glasgow, United Kingdom; Hull Royal Infirmary, Hull, United Kingdom; Rotherham Gen Hosp, Rotherham, United Kingdom; AstraZeneca R&D, Molndal, Sweden. Objectives: Esomeprazole, an optical isomer of omeprazole, produces longer-lasting gastric acid suppression and more effective pH control than omeprazole. The present study investigated the use of esomeprazole for on-demand treatment of GERD. Methods: This multicenter, double-blind, parallel-group study compared the efficacies of esomeprazole and placebo in maintaining symptom control in endoscopy-negative GERD. Patients who had achieved complete resolution of heartburn after 4 weeks of double-blind treatment with esomeprazole 40rng (E40), 20mg (E20) or omeprazole 20mg once daily were randomised to receive E40 (n=293), E20 (n=282) or placebo (n= 146) on demand (maximum I dose per day) for the following 6 months. Antacids were permitted as rescue medication. Primary and secondary efficacy variables were times to study discontinuation due to unwillingness to continue I) for any reason, and 2) for inadequate heartburn control. Dosing patterns were assessed by electronic monitoring of drug container openings. Results: A total of 721 patients (328 males) aged 18-80 (mean 48.2) years entered the study and were included in the intent-to-treat analysis. The log-rank test showed significant differences in favour of E40 and E20 over placebo for both primary and secondary endpoints (p2-fold higher in the placebo group. On-demand treatment with esomeprazole was well tolerated: laboratory and adverse event data were similar across the 3 treatment groups. Conclusion: E20 was superior to placebo; a higher dose did not increase the clinical benefit. More than 90% of patients were willing to continue on-demand treatment with esomeprazole over a 6-month period, taking an average of I capsule every third day.

Score

ECL scoring SS patients before I after

0 1

8/5 112 214 0/0

2 3

Parietal scoring SS ECL scoring ZES patients before I patients before I after after 3/4 8/5 0/2 0/0

11/1 2/4 3/8 0/3

Parietal scoring ZES patients before I after 5/1

6/2 3/4 2/9

3610 OMEPRAZOLE FOR MAINTENANCE THERAPY OF EROSIVE ESOPHAGITIS IN CHILDREN. Eric Hassall, and the International Pediatric Omeprazole Study Group, British Columbia Children's Hosp, Vancouver, BC, Canada; Canada" Australia" Germany" Denmark" England" Sweden. Aim: To prospectively determine the doses of omeprazole [omep] required to maintain remission of erosive esophagitis, and the safety and tolerability of lonyterm omep use in children Methods: In the healing part [A] of this study, the healing dose of omep was that on which 24hr-intraesophageal pH study normalized; on this dose for 3 months, erosive esophagitis healed in 54 patients [pts], of whom 46 entered the maintenance part [B] of 21 months duration. For part B, the dose of omep was halved [maint dose], and increased if relapse occurred. Results: Of 46 pts on the halved dose, 32 completed the 21 month maintenance phase; reasons for drop out included loss to follow-up, and referral for surgery. Of the 32, 41% had neurologic impairment or repaired esophageal atresia; 10 were <7yr age, 10 were 7-12yr, and 12 were 12-16yr. Relapse occurred in 15 [47%] of 32 pts; it was only symptomatic in 7, only endoscopic in 4, and both in 4; 9 first relapsed within 3 months of halving the dose, and 7 pts [22%] had> I relapse. Seventeen [53%] remained on maint dose, 4 [13%] returned to healing dose, but ended the study on maint dose, 8 [25%] remained on the healing dose, and 3 [9%] ended on a higher dose than the healing dose. Final doses were 1O-7Orng, median 25 mg. Of the 32 completers, 26 [81%] were healed at the study end, 3 had no final endoscopy but were asymptomatic, and 3 [9%] left the study unhealed. Even in the 14 pts who did not complete the maintenance part, significant improvement or resolution of symptoms was maintained. No clinically significant changes occurred in liver enzymes or other lab values. Median fasting gastrin levels remained normal during the 2yr study. No pt had gastric atrophy during the study. At the final visit, 2 pts had linear hyperplasia of ECL-like cells, and 2 had simple hyperplasia; 3 of these pts were Hp + at some time during the study. Conclusions: Of children with erosive esophagitis treated per protocol with omeprazole, 90% will heal and remain asymptomatic and/or endoscopically healed after treatment for 2 years. After healing, some 50% can be maintained for at least 21 months on half the dose of omeprazole required for healing [when adequacy of that dose had been determined by 24hr-intraesophageal pH study]; 40% will require full healing dose for maintenance, and 10% may require a higher dose. Omeprazole, even when used in doses larger on a rug/kg basis than those used in adults, is safe for

April 2000

AGAA659

use in children, and well tolerated for a duration of at least 2 years. I. Hassall E et al. Gastroenterology 1997;112:AI43.

3611 NG LANSOPRAZOLE OR IV PANTOPRAZOLE: WHICH PRO· VIDES BETTER PH CONTROL? James Freston, Jorg Taubel, Nancy Lukasik, Wei-Jian Pan, Vi-Lin Chiu, Univ of Connecticut Health Ctr, Farmington, CT; Charterhouse Clin Research Unit, London, United Kingdom; TAP Holdings, Inc, Deerfield, IL; Abbott Lab, Abbott Park, IL. Introduction: PPIs are highly effective in treating acid related disorders. Alternative methods of administration are often needed for hospitalized patients or patients unable to swallow oral medications. Therefore, a study was designed to compare the gastric acid inhibitory ability of lansoprazole (LAN) NG with that of pantoprazole (PAN) IV. Methods: This crossover study (5 days of once daily doses of LAN NG and PAN IV) evaluated 24-hour intragastric pH in 33 healthy subjects on Days I and 5 of each crossover period. Percent of time intragastric pH > 3, 4, and 5 for the total 24-hour time period was determined. Results: The mean pH and the percent of time pH > 3, 4 and 5 for 0-10 hours after dosing and the total 24-hour period on Days 1 and 5 are shown. Conclusions: LAN 30 mg NG is more effective in elevating intragastric pH above 3, 4 and 5 than PAN 40 mg IV 0-10 hours after dosing and throughout the 24-hour dosing period on Day I. In addition, LAN was more effective than PAN in raising mean 24-hour intragastric pH on Days 1 and 5. Therefore, these data suggest that the NG administration of LAN would be a more effective means of suppressing acid in patients who cannot take oral medications. Research funded by TAP Holdings Inc., Deerfield, IL.

Table 1: Analysis of24-Hour Intragastnc pH Determinations PAN 40mglV

LAN 30 mgNG Day 1 Total 24Hrs Mean pH 3.05" % oftimepH>3 37.34'" % oftimepH>4 26.60'" % oftimepH>5 15.11'" Total 24Hrs Day 5 Mean pH 365' % oftimepH>3 54.18' % oftimepH>4 40.48 % oftimepH >5 21.76

Q..5 Hrs 2.81' 36.63' 19.54" 5.69 Q..5 Hrs 379 6769 4726 16.66

6-10Hrs 3.55'" 56.07" 41.65'" 19.65'" 6-10Hrs 4.00" 72.17'''

54.95" 24.34

Total 24Hrs 2.76 28.19 1896 9.77 Total 24Hrs 3.45 48.67 36.55 19.90

Q..5Hrs 2.64 28.17 14.20 357 Q..5Hrs 3.89 6924 5015 15.47

6-10 Hrs 302 41:06 26.04 9.95 6-10 Hrs 369 6029 43.70 22.78

" ". '" statistically significant atpvaiues of0.05, 0.01, 0.001, respectively

3612 LANSOPRAZOLE MAINTENANCE TREATMENT FOR GERD (5 YEARS). DO WE HAVE TO ERADICATE ALL HP-POSITIVE PATIENTS? W. Dekker, Cjj Mulder, K. Geboes, Kennemer Gasthuis, Haarlem, Netherlands; Rijnstate Hosp, Arnhem, Netherlands; Univ Hosp St Raphael, Leuven, Belgium. Long-term acid suppression is believed to induce a faster development of atrophic gastritis in the corpus in Hp+ patients with chronic gastritis. The influence of long-term therapy with lansoprazole on the gastric mucosa of Hp+ and Hp- patients has not been established yet. This Dutch multi centre trial studied the efficacy of lansoprazole 30 mg (LAN30) in the prevention of reflux esophagitis (RE), and the clinical and histological evolution during 5 years of therapy. 175 patients (pts) were included. 148 completed the first year, of which 132 were in remission. 97 pts continued the long-term therapy, of which 21 stopped prematurely (10 refused further co-operation, 6 had adverse events, 4 were lost follow-up, 1 had a 2nd relapse despite of treatment with LAN60). During the subsequent 4 years 78 pts had 1 or more intervening endoscopies, of which 12 relapses of RE were observed in 11 pts (7 RE grade I; 4 RE grade II; 1 RE grade III). After 5 years of therapy, a final endoscopy was performed in 75/76 pts, of which 74 pts were in remission and only 1 patient had a relapse of RE (grade I). Gastric biopsies were taken at start according to the Sydney classification (antrum & corpus) and at 5 years according to the updated Sydney classification (incl. angulus). Biopsies from 73 pts were taken at start and at 5 years, and for analysis the updated Sydney classification was used. At start, 34 of these were Hp- (24 normal histology; 6 mild atrophy; 4 antral gastritis) and 39 Hp+ (2 atrophy; 25 antral gastritis; 12 pangastritis). At 5 years, 31 Hp- pts had normal histology (n=23+5+3) and 3 pts developed pangastritis. In the Hp+ group, 2 pts with atrophy and 18/25 pts with antral gastritis developed pangastritis, of which 1 patient developed limited

intestinal metaplasia. 6/25 pts had normal histology and 1 patient kept antral gastritis. 10/12 pts with pangastritis had reduced antral activity, of which 2 pts developed limited intestinal metaplasia. 2/12 pts had normal gastric mucosa. Overall samples of antrum and angulus were not especially different. In conclusion, 5 years LAN30 therapy was well tolerated and highly effective. During the 2nd up to and including 5th year of therapy, the total relapse rate was 14,8% (13/78). Gastric mucosa of Hp- patients remained normal during the 5 years period of continuous therapy. Glandular atrophy did not increase in Hp+ patients. Our findings do not confirm the necessity of Hp eradication for all patients. This study was funded by Hoechst Marion Roussel NL.

3613 GASTRIC INJURY ACTIVATES ANGIOPOIETIN, TIE2 AND VEGF GENES IN MUCOSA BORDERING NECROSIS. A KEY TO ANGIOGENESIS? A. S. Tarnawski, R. Pai, M. K. Jones, I. L. Szabo, H. Kawanaka, I. Sarfeh, VA Medical Ctr, Long Beach, CA; Univ of CA, Irvine, CA. Previous studies demonstrated that gastric injury increases VEGF expression in mucosa bordering necrosis (Am. J. Physiol. 1999;279:Gl345-55). Neutralization of VEGF only partly reduced angiogenesis, indicating involvement of other angiogenic factors. Angiopoietins (Angl, Ang2) and their receptor, Tie2 are important for embryonic angiogenesis and maintenance of vascular integrity. Their expression in normal or injured gastric mucosa has not been explored. Our aims were: a) to determine expression of Angl, Ang2 and Tie2 in normal and injured gastric mucosa, their relationship to VEGF expression, and b) to further characterize ultrastructural features of angiogenesis during mucosal repair. METHODS: 60 rats received i.g. 8 mllkg of 50% ethanol or saline (placebo) and gastric samples were obtained 3, 6 and 24 hrs subsequent to injury. STUDIES: 1) Quantification of angiogenesis with videoimage analysis system. 2) Angl, Ang2, Tie2 and VEGF mRNAs by RTIPCR and proteins by immunohistochemistry and Western blotting; 3) transmission EM. RESULTS: 24 hrs after ethanol administration, 8± 1% of microvessels in the mucosa bordering necrosis demonstrated angiogenesis - endothelial sprouting, formation of microvascular tubes associated with fibroblasts and pericytes and ultimately microvessel reconstruction. Alcohol injury caused a significant over-expression Ang2 and Tie2 mRNAs and proteins in the mucosa bordering necrosis (Ang2: 220±30% increase at 3 hrs and 390±40% at 24 hrs; p
3614 ANTACID TALCID INDUCES HEAT SHOCK PROTEINS IN HUMAN GASTRIC EPITHELIAL CELLS. IMPLICATIONS FOR MUCOSAL PROTECTION AND HEALING. A. S. Tarnawski, R. Pai, I. L. Szabo, I. Sarfeh, VA Medical Ctr, Long Beach, CA; Univ of CA, Irvine, CA. Heat shock proteins (HSPs) represent an universal cellular defense system, crucial for maintaining cell and tissue integrity and protection against a variety of cytotoxic insults, such as thermal injury, ischemialreperfusion and oxidative stress. HSPs act as molecular chaperones involved in protein assembly, translocation, binding and stabilization of denatured proteins. Previous studies suggested that Talcid, an antacid may induce heat shock response in rats (Gastroenterology 1999; 116:A331) but human relevance of these findings is uncertain. To test the human relevance, we studied whether Talcid can activate HSP response in human gastric epithelial cells. METHODS: Human gastric Kato III cells were cultured in RPMI 1640 medium and incubated with either Talcid or Placebo (PLA) 10-100 mg/ml for 2, 6 and 24 hrs. STUDIES: 1) Cell viability with ethidium homodimer uptake, 2) RTIPCR with specific primers HSP-70 and HSC-70 and mRNA quantitation after normalization with j3-actinusing videoimage system and 3) Immunofluorescence staining and Western blotting using specific antibodies. RESULTS: Treatment of Kato III cells with Talcid caused significant increase in HSP-70: 117% and 121% at 6 and 24 hrs; p<0.03, increased fluorescence signal by 160% and induced its nuclear translocation. In contrast, expression of HSC-70 (constitutive form) was significantly reduced at 6 and 24 hrs. CONCLUSIONS: 1) Talcid activates expression of HSP-70 mRNA and protein in human gastric epithelial cells. 2) Since HSP-70 proteins constitute an important component of cell and tissue defense, their activation provides entirely new mechanism for the mucosal protective and healing action of antacid Talcid.