Comparison of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of active gastric ulcerða European multicentre study

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1 Aliment Pharmacol Ther 1998; 12: 789±795. Comparison of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of active gastric ulcerða European multicentre study C. P. M. DEKKERS 1,J.A.BEKER 2, B. THJODLEIFSSON 3,A.GABRYELEWICZ 4,N.E.BELL 5, T. J. HUMPHRIES 5 AND THE EUROPEAN RABEPRAZOLE STUDY GROUP 1 Ignatius Hospital, Breda, the Netherlands; 2 St. Antoniushove Hospital, Leidschendam, the Netherlands; 3 The National Hospital of Iceland, Reykjavik, Iceland; 4 Medical Academy of Bialystok, Poland; 5 Eisai Ltd, London, UK Accepted for publication 21 April 1998 SUMMARY Background: Rabeprazole sodium is the newest member of a class of substituted benzimidazole molecules known as proton pump inhibitors. Other proton pump inhibitors have been shown to be effective in healing active, benign gastric ulcers. Methods: In this randomized, double-blind, multicentre study, conducted at 25 European sites, rabeprazole and omeprazole were compared in patients with active gastric ulcers. Two hundred and twenty-seven patients with active benign gastric ulcer were randomized to receive either rabeprazole 20 mg (n ˆ 113) or omeprazole 20 mg (n ˆ 114) once daily for 3 or 6 weeks, with healing monitored by endoscopy. Results: After 3 weeks, complete healing (ITT analysis) was documented in 58% of patients given rabeprazole and 61% in patients given omeprazole (N.S.). After 6 weeks the healing rates were identical in both groups at 91%. Rabeprazole-treated patients had numerically greater symptom relief at all 12 points of comparison. The differences signi cantly favoured rabeprazole at week 3 for daytime pain improvement (P = 0.023) and at week 6 for pain frequency (P = 0.006) and complete resolution of night pain (P = 0.022). Both drugs were well-tolerated over the 6-week treatment course. Mean changes from baseline to end-point in fasting serum gastrin were comparable. No signi cant differences in laboratory parameters were seen. Conclusion: In this study, rabeprazole produced healing rates comparable to omeprazole at weeks 3 and 6, but provided more consistent and occasionally signi cantly superior symptom improvement. Both treatments were well-tolerated. INTRODUCTION Rabeprazole sodium is the newest member of a class of substituted benzimidazole molecules known as proton pump inhibitors. As with other members of the proton pump inhibitor class, rabeprazole inhibits H + /K + -AT- Pase, the proton pump responsible for the terminal step in gastric acid secretion. There are several unique aspects of the biological activity of proton pump inhibitors which lead not only to increasing bioavailability during the rst few days of dosing, but also to a Correspondence to: Dr. T. J. Humphries, Eisai Limited, Hammersmith International Centre, 3 Shortlands, 2nd Floor, London W6 8EE, UK. tom_humphries@rocky.eisai.com. prolonged antisecretory effect, lasting 24 h or longer, despite a short plasma half life (approximately 1 h). In the parietal cell, proton pump inhibitors act in four stagesðabsorption, concentration, activation and nally covalent binding and inactivation of the H + /K + - ATPase. 1 H + /K + -ATPase is vulnerable to proton pump inhibitors only when the parietal cell has actively secreting canaliculi. It is in this acidic space that the proton pump inhibitors are concentrated in their activated form. With each additional dose of a proton pump inhibitor, additional parietal cells that have become active are available for blocking. A steady state of acid inhibition on once-a-day dosage is reached when there is balance between inhibition of active acid secreting parietal cells and de novo synthesis of new Ó 1998 Blackwell Science Ltd 789

2 790 C. P. M. DEKKERS et al. pumps and/or removal of a proton pump inhibitor from inhibited pumps. 1 Rabeprazole has been demonstrated to be a potent antisecretory agent, suppressing both basal and stimulated gastric acid secretion in a dose-dependent manner. 2±4 The antisecretory effect reaches a plateau for basal acid output with a 10 mg dose. With respect to stimulated acid output and decreased 24-h intragastric acidity the plateau is reached with a 20 mg dose. 2, 3 After multiple days of dosing, rabeprazole 20 mg produces an 86% decrease in basal acid output, a 95% decrease in stimulated acid output and 80±87% decreases in 24-h intragastric acidity. 2±4 In a placebocontrolled dose- nding study in patients with active benign gastric ulcer, rabeprazole 20 mg healed 90% of patients at week 6 vs. 86% healed with rabeprazole 40 mg (N.S.). 5 Similar studies in active duodenal ulcer and erosive gastro-oesophageal re ux disease have also failed to demonstrate incremental bene t in endoscopic healing with doses greater than 20 mg of rabeprazole. 6 Therefore, 20 mg was selected for further study in acidrelated disease. In clinical studies to-date, rabeprazole has been well-tolerated, and in speci c drug interaction studies, no interaction was seen with diazepam, theophylline, phenytoin or warfarin, distinguishing rabeprazole from various other members of the proton pump inhibitor class. 7 Modest and predictable interactions have been seen with drugs whose absorption is dependent upon intragastric ph, such as ketoconazole and digoxin. 7 The proton pump inhibitors omeprazole, lansoprazole and pantoprazole have been shown to be of bene t in the healing of active benign gastric ulcer. 8±14 In this study, we compared rabeprazole 20 mg given once daily with the European recommended dose of omeprazole (20 mg once daily) in the treatment of active benign gastric ulcer. MATERIALS AND METHODS Patients This study was designed as a randomized, balanced, double-blind, multicentre, parallel-group comparison. The study protocol was conducted in accordance with the recommendations of the Declaration of Helsinki [as amended in Tokyo (1975), Venice (1983) and Hong Kong (1989)], the EEC guidelines for good clinical practice for trials of medicinal products in the European community (1990), and was in compliance with Section 33(6) of the UK Data Protection Act of This study was conducted by 25 members of the European Rabeprazole Study Group in 10 European countries. Men and women aged 18 years or older were included in the study if they had one active gastric ulcer with a diameter of ³ 0.03 cm to 2.5 cm, a location ³ 2 cm from the pyloric channel when measured by open biopsy forceps, and if four quadrant biopsies taken at the ulcer margins revealed no evidence of malignant disease. Women were included in the study if they were not of child bearing potential or were using an approved method of contraception. In one country (Sweden), concurrent use of oral contraceptives was not permitted because of a perceived risk, by the regulatory authority of that country, of a potential interaction with proton pump inhibitors. Major exclusion criteria included: a history of de nitive acid lowering surgery or previous oesophageal or gastric surgery (except for simple close of perforations); oesophageal and/or gastric varices; pyloric stenosis; treatment with full therapeutic doses of an H 2 receptor antagonist; prostaglandin analogue or sucralfate for more than 5 consecutive days within 2 weeks prior to enrolment in the study; treatment with therapeutic doses of a proton pump inhibitor for 3 consecutive days within 2 weeks prior to enrolment and any treatment with therapeutic doses of a proton pump inhibitor within 5 days prior to enrolment; concurrent treatment with high doses of corticosteroids, anticoagulants, antidepressants or motility agents. Other exclusion criteria included: concurrent renal insuf ciency, hepatic insuf ciency, treatment for cancer within the previous year and any conditions associated with potential poor patient compliance as judged by the principal investigator. Patients were also excluded if they had received treatment with any investigational drug within 30 days prior to enrolment. Patients were permitted to use acetaminophen for pain relief and an antacid containing a balanced formulation of magnesium and aluminium hydroxides as needed for relief of ulcer symptoms. In addition, low-dose aspirin therapy ( 165 mg/day) for prevention of cardiovascular disease was permitted. Treatment Patients were randomized to receive either 20 mg rabeprazole plus a placebo matching omeprazole once

3 RABEPRAZOLE VS. OMEPRAZOLE FOR GASTRIC ULCER 791 daily in the morning (n ˆ 113) or 20 mg of omeprazole plus a placebo matching rabeprazole once daily in the morning (n ˆ 114). Study medication was started within 3 days of the base line endoscopy, and endoscopic examinations were repeated at weeks 3 and 6. Patients healed at week 3 exited the study at that point. The primary ef cacy criterion was ulcer healing, de ned as complete regeneration of the mucosa (re-epithelialization) with no visible mucosal breaks. Patient evaluation In addition to the endoscopic monitoring of ulcer healing at weeks 3 and 6 of the study, the frequency and severity of daytime and night-time ulcer pain, the number of antacid doses taken during the study and the patients' ratings of overall physical well-being were recorded at baseline and at the endoscopy visits. The scoring of severity and frequency of symptoms was based on a ve-point scale and was recorded by the patients on diary cards. At each visit, adverse events and their potential relationship to the study medications were also recorded. Safety monitoring at each visit included haematology, blood chemistry, urinalysis, fasting serum gastrin and electrocardiograms (ECG). The sample size in this study was designed to provide at least 80% power to rule out a difference of at least 10% between rabeprazole and omeprazole, assuming 6-week healing response rates of 93% for both drugs. The sample size was computed using the approximation described by Donner et al and the approximation of Casagrande et al. 1978, 16 assuming a two-sided hypothesis test performed at the 5% signi cance level. Statistical analysis The primary response variable was endoscopic healing; healing rates were evaluated using two difference approaches. The rst approach examined the intention-to-treat (ITT) or last-observation-carried-forward population of patients and was considered to be the primary method for determining ef cacy. This technique incorporated data from all randomized patients who had at least one post-dose measurement of any ef cacy variable. Endoscopy results were carried forward to the next scheduled time point, if data for that time point were missing. This method tends to underestimate the true healing response rate. The second approach used was based on completed visits or endoscopies performed (the ENDO method). With this method, if endoscopy results were not available for a time point, the missing value was not lled in with the result of the previous endoscopic for evaluation, unless the previous result indicating healing. This method tends to overestimate true healing rates. The signi cance of differences in overall healing rates between the two treatment groups was assessed using the strati ed Cochran±Mantel±Haemszel (CMH) statistic. Differences in response rates between the two treatment groups with respect to the secondary response variables of frequency and severity of pain, and ratings of overall well-being were assessed using the strati ed CMH statistic with the investigator's site as the stratum. Only patients with gastric ulcer symptoms at baseline were included in the analysis of improvement for that symptom. The differences between the two treatment groups with respect to antacid use were assessed using an ANCOVA model with the effects for the respective baseline value, investigator and treatment. With respect to laboratory evaluation of safety, differences between the two treatment groups in incidences of laboratory values outside, below and above, the normal ranges were compared using the Pearson's high-square statistic. For each continuous laboratory value, scatter points of end-point values versus baseline values were evaluated for the two treatment groups. The differences between the two treatment groups for fasting serum gastrin values were assessed using an ANCOVA model. RESULTS Study population Of the 227 patients enrolled in the study, 113 received rabeprazole and 114 omeprazole. 96% of patients completed the study. Nine patients (4%) discontinued from the study, four in the rabeprazole group and ve in the omeprazole group. There were three patients who were protocol violators, one in the rabeprazole group and two in the omeprazole group. Table 1 lists demographic and baseline characteristics of interest for the patients in this study. There were no signi cant differences between the groups for any of the characteristics listed. As can be seen from Table 1, there was a slight preponderance of male subjects and the mean age was approximately 55 years in both

4 792 C. P. M. DEKKERS et al. Table 1. Summary of demographic and baseline characteristics Characteristic groups. Approximately half of the patients smoked and relatively few took antacids prior to the study. Most (96%) patients in both groups had a baseline ulcer size of ³ 0.5 cm in diameter. Although not listed in Table 1, IgA and IgG antibodies to H. pylori were positive for 40% and 57% of the patients, respectively. These H. pylori serology results were comparable for both treatment groups. Ef cacy Rabeprazole (n ˆ 113) Omeprazole (n ˆ 114) Sex Male Female Total (n ˆ 227) Age (years) Mean s.d Minimum Maximum Tobacco use No Yes Antacid use No Yes Missing data Baseline ulcer size ³ 0.3±< 0.50 cm 5 (4%) 5 (4%) 10 (4%) ³ 0.50 cm 108 (96%) 109 (96%) 217 (96%) For the ITT population, the gastric ulcer healing rates observed at weeks 3 and 6 were similar in the two Figure 1. Gastric ulcer healing after 3 and 6 weeks of administration of rabeprazole 20 mg or omeprazole 20 mg once daily (ITT analysis). There was no signi cant difference at either time point. treatment groups (Figure 1). At week 3, the healing rate was 58% in the rabeprazole group compared to 61% in the omeprazole group. At week 6, the healing rate was 91% for both groups (N.S.). The ndings were similar in the ENDO analysis, 58% and 63% for rabeprazole and omeprazole, respectively, at week 3 and 93% in both groups at week 6. A total of 12 comparisons of the effect of rabeprazole versus omeprazole on the relief of gastric ulcer symptoms were made in this study (Table 2). These summary data points comprised the percentage of patients with improvement or resolution at weeks 3 and 6 with respect to gastric ulcer pain frequency, day pain severity and night pain severity. Rabeprazole was numerically Table 2. Effect of rabeprazole 20 mg versus omeprazole 20 mg on relief of gastric ulcer symptoms. A summary of improvement or resolution of frequency and severity grades Gastric ulcer pain frequency grades improvement* resolution Week Rabeprazole 20 mg 3 73/108 (71%) 6 89/108 (82%) 3 37/108 (34%) 6 56/108 (52%) Day pain severity grades improvement 3 94/107 (88%) 6 96/107 (90%) 3 64/107 resolution (60%) 6 80/107 (75%) Night pain severity grades improvement resolution 3 65/79 (82%) 6 70/79 (89%) 3 54/79 (68%) 6 66/79 (84%) Omeprazole 20 mg P-value 68/112 (61%) 73/112 (65%) 32/112 (29%) 49/112 (44%) 82/109 (75%) 91/109 (83%) 64/109 (59%) 73/109 (67%) 60/76 (79%) 61/76 (80%) 46/76 (61%) 52/76 (68%) *Frequency or severity grade lower than baseline evaluation; frequency or severity grade of 0 (none).

5 RABEPRAZOLE VS. OMEPRAZOLE FOR GASTRIC ULCER 793 superior to omeprazole in all 12 points of comparison and signi cantly better in three; percentage improvement of ulcer pain frequency at week 6, percentage improvement in day pain at week 3 and percentage complete resolution of night pain at the end-point, week 6. The proportions of patients with improvement or normalization in overall well-being at weeks 3 and 6 were comparable for both treatment groups. At week 6, 44% of rabeprazole-treated patients reported normalization versus 39% of omeprazole-treated patients. Patients in both treatment groups tended to use fewer doses of antacid during treatment. The difference between the two treatment groups in the mean reduction in antacid consumption was not signi cant. Both rabeprazole and omeprazole administered at a daily dose of 20 mg given once daily in the morning, for up to 6 weeks in patients in this study, were welltolerated as assessed by adverse event recording, laboratory evaluations, vital signs and ECGs. Serious adverse events were reported for one patient in the rabeprazole group and ve patients in the omeprazole group. None of these serious adverse events were felt to be related to study medication. The events themselves led to the discontinuation of three omeprazole-treated patients, two of whom had serious adverse events Table 3. Number of patients with treatment-emergent signs and symptoms (TESS) reported by at least 2% of patients in either treatment group Event classi cation term Rabeprazole (n ˆ 113) Omeprazole (n ˆ 114) P-value* 25 (22%) 35 (31%) at least one event Headache 3 (3%) 7 (6%) Infection 3 (3%) 4 (4%) Rash 3 (3%) 0 (0%) Asthenia 3 (3%) 0 (0%) Diarrhoea 2 (2%) 3 (3%) Laboratory test 2 (2%) 2 (2%) abnormal Bronchitis 2 (2%) 0 (0%) Pain 1 (1%) 3 (3%) Nausea 1 (1%) 2 (2%) Abdominal pain 0 (1%) 2 (2%) Flu syndrome 0 (0%) 2 (2%) Overdose 1 (1%) 2 (2%) Constipation 0 (0%) 2 (2%) Rhinitis 0 (0%) 2 (2%) *Treatment P-value is obtained using Pearson's chi-squared statistic. Note: treatment comparison performed only if there were more than two patients in more than one treatment group. Figure 2. Fasting serum gastrin levels for rabeprazole and omeprazole treated patients at baseline and at end-point (normal range: 0±149 pg/ml). For each time point, the 10%, 25%, 50%, 75% and 90% values are given and all data outside the 10th and 90th percentiles. related to pre-existing conditions that violated the entry criteria of the protocol. Table 3 lists the number and percentage of patients with treatment emergent signs and symptoms (TESS) reported by patients in either treatment group. No TESS occurred in a signi cantly higher percentage of patients in either treatment group. Analysis by sex, age and race failed to discriminate any statistical differences between the two treatment groups. Speci cally, there was no signi cant difference in the incidence of TESS among the 68 patients in this study ³ 65 years of age versus younger patients. With respect to haematology, chemistry and urinanalysis monitoring, minor changes, occasionally statistically signi cant, occurred between the groups, but none were clinically meaningful. Creatine phosphokinase values were outside the normal range at end-point in six omeprazole-treated patients who had normal values at baseline versus none in the rabeprazole-treated group. In general, these elevations were only slightly above the upper limit of normal for the test and no speci c explanation for these changes could be found.

6 794 C. P. M. DEKKERS et al. The mean changes from baseline to end-point in fasting serum gastrin were 12.7 pg/ml in the rabeprazole group and 10.0 pg/ml in the omeprazole group (N.S.). Figure 2 displays baseline and end-point fasting serum gastrin data for both treatment groups as box whisker plots. In both treatment groups at baseline there were patients whose fasting serum gastrin value was outside the normal range. As a rule, these patients still tended to be above the upper limit of normal at endpoint, although the value declined during the study. No patients had end-point gastrin values greater than twice the upper limit of normal. DISCUSSION A review of the treatment of gastric ulcer with various antisecretory drugs with a goal of de ning a relationship between pharmacological effects and healing rates, suggests that a relationship between antisecretory effect and healing is not as clearly de ned in gastric as has been noted in duodenal ulcer. 8 With duodenal ulcer, there is a clear mathematical relationship between the degree of acid suppression and percentage healing rates, whereas in gastric ulcer studies to-date this association has been a weak one, especially when placebo data are excluded. A weak correlation with effect on 24-h intragastric acidity remains, as does a stronger one with length of treatment. 8 The three marketed proton pump inhibitors, omeprazole, lansoprazole and pantoprazole, have been demonstrated to be effective in healing gastric ulcer, with 8- week healing rates approaching or exceeding 90%. 8±14 Eight-week healing rates of 84%, 89% and 95%, have been reported with omeprazole 20 mg given once daily. 8±10 Although gastric ulcer healing studies with a duration of 6 weeks were common with H 2 receptor antagonists, gastric ulcer studies with proton pump inhibitors have been of 8 weeks duration, until the present study. The present study is therefore unique with respect to its shorter duration and the fact that the demonstrated 6-week healing rates of 91% for both rabeprazole 20 mg and omeprazole 20 mg are in the range of what would be expected after 8 weeks of treatment with proton pump inhibitors. There were no obvious reasons for this higher than expected healing rate. In both groups, 96% of ulcers were ³ 0.5 cm in diameter, and there were no differences in other baseline characteristics. The antisecretory effect on 24-h intragastric acidity is similar for both drugs at the doses given. 3, 4, 8 An indirect re ection of antisecretory ef cacy can be seen in the fasting serum gastrin levels recorded in this study, which also show no difference between the agents. The only difference between rabeprazole and omeprazole seen in this study was with respect to drug effect on gastric ulcer pain frequency and severity. Even if one excludes the fact that there was a numerical difference favouring rabeprazole in all 12 of the symptomatic comparisons, there was still a signi cantly higher proportion of patients taking rabeprazole showing improvement in ulcer pain frequency, daytime pain severity and night-time pain severity than in the omeprazole-treated group. Whether or not this symptomatic difference is related to recently demonstrated differences in the proton pump inhibitors with respect to binding site interactions is unknown. Besancon et al. have shown that, of the four proton pump inhibitors in clinical use, rabeprazole is the most rapid in inhibiting ATPase activity and acid transport. 17 In summary, this study demonstrated that both rabeprazole 20 mg and omeprazole 20 mg result in similar healing rates after 3 and 6 weeks of therapy in patients with active benign gastric ulcer, and that both drugs were well-tolerated by patients in the setting of this study. The healing rates achieved by both compounds after 6 weeks of therapy were in the range of what one would expect with 8 weeks of therapy with proton pump inhibitors, based on published studies. In this study, rabeprazole demonstrated signi cant bene t over omeprazole in improvement of some of the pain parameters studied. ACKNOWLEDGEMENTS The following principal investigators and centres participated in this study as part of the European Rabeprazole Study Group: Dr Pierre Hoang, Brussels, Belgium; Dr Jean-Luc Van Laethem, Brussels, Belgium; Dr Janssens, Turnhout, Belgium; Dr B. Plucnar, Solred Strand, Denmark; Dr med. Christiane Klein, Kunzing, Germany; Dr med. Peter Krupp, Bad Zwischenhahn, Germany; Dr med. Dieter Raps, Schopfheim, Germany; Dr med. Axel Dettmer, Munchen, Germany; Dr med. R. Burle nger, Munchen, Germany; Dr Bjarni Thjodleifsson, Reykjavik, Iceland; Dr John Patrick Crowe, Dublin, Ireland; Dr Cornelius Dekkers, Breda, the Netherlands; Dr Johannes Beker, Leidschendam, the Netherlands; Prof. Antoni Gabryelewicz, Bialystok, Poland; Prof.

7 RABEPRAZOLE VS. OMEPRAZOLE FOR GASTRIC ULCER 795 Eugeniusz Butruk, Warsaw, Poland; Prof. Tadeusz Popiela, Krakow, Poland; Prof. Krzysztof Marlicz, Szczecin, Poland; Prof. I. Szczepanski, Lublin, Poland; Dr Joaquin Berenguer, Valencia, Spain; Prof. Manuel Diaz-Rubio, Madrid, Spain; Dr Arnold Soderlind, Visby, Sweden; Dr D.-A. Hallback, Karlskoga, Sweden; Dr Hans Tanghoj, Eskilstuna, Sweden; Dr G. Edlund, Ostersund, Sweden; Dr Graeme D. Kerr, Shrewsbury, UK. The authors are indebted to the following individuals for their critical input into this study and manuscript: B. Lombardi and B. Sytnik (medical writing), J. Jaskir (statistical analysis), A. Schwendimann and S. Cuthbert (manuscript preparation). REFERENCES 1 Sachs G, Prinz CK, Hersey SJ. Acid-Related Disorders. Mystery to Mechanism: Mechanism to Management. Palm Beach, FL: Sushu Publishing Inc, 1995: 72±85. 2 Kovacs TOG, Sytnik B, Humphries TJ, Walsh JH. A low dose of a new proton pump inhibitor LY (E3810) effectively inhibits acid secretion in humans. Gastroenterology 1996; 110: A161(Abstract). 3 Blanshard C, Millson C, Sercombe J, Pounder RE. The effects of rabeprazole on 24-hour intragastric acidity and plasma gastrin concentration in healthy subjects. Gut 1996; 39(Suppl. 3): A47(Abstract). 4 Dammann HG, Burkhardt F, Bell NE, Bjaaland T. Rabeprazole effectively inhibits 24-hour H + activity and nocturnal acid secretion in healthy subjects. Gut 1996; 39(Suppl. 3): A47(Abstract). 5 Humphries TJ, Cloud ML, Enas N, Bassion S, McNamara M. & the US Rabeprazole Gastric Ulcer Study Group. Rabeprazole (E3810, LY307640) achieves high rates of healing in active gastric ulcer. Gastroenterology 1996; 110: A138(Abstract). 6 Cloud ML, Enas N, Humphries TJ, Bassion S and the Rabeprazole Study Group. Rabeprazole in treatment of acid peptic diseases. Results of three placebo-controlled dose±response clinical trials in duodenal ulcer, gastric ulcer, and gastro-oesophageal re ux disease (GERD). Dig Dis Sci 1998; 43: 993± Humphries TJ, Nardi RV, Lazar JD, Spanyers SA. Drug±drug interaction evaluation of rabeprazole sodium. A clean/expected slate? Gut 1996; 39(Suppl. 3): A47(Abstract). 8 Howden CW, Jones DB, Peace KE, Burget DW, Hunt RN. The treatment of gastric ulcer with antisecretory drugs. Relationship of pharmacological effort to healing rates. Dig Dis Sci 1988; 33: 619±24. 9 Bate CM, Wilkinson SP, Bradby GUH, Bateson MC, Hislop WS, Willoughby CP, et al. Randomized, double-blind comparison of omeprazole and cimetidine in the treatment of symptomatic gastric ulcer. Gut 1989; 30: 1323±8. 10 Walan A, Bader J-P, Classen M, Lamers CBHW, Piper DW, Rutgersson K, et al. Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer. N Engl J Med 1989; 320: 69± Schepp W, Rehner M, Witzel L. A review of treatment of duodenal and gastric ulcersðpantoprazole vs. omeprazole. Aliment Pharmacol Ther 1994; 8(Suppl.): 53±7. 12 Witzel L, Gutz H, Huttemann W, Schepp W. Pantoprazole versus omeprazole in the treatment of acute gastric ulcers. Aliment Pharmacol Ther 1995; 9: 19± Hahn EG, Erlangen Bosseckert H, Jena Dammann HG. Tolerability and safety pro le of pantoprazole based on 100,134 patients, results of German Post Marketing Surveillance (PMS) Program. Gastroenterology 1997; 112: A138(Abstract). 14 Avner DL, Movva R, Nelson KJ, McFarland M, Berry W, Er- ing W. Comparison of once daily doses of lansoprazole (15, 30, and 60 mg) and placebo in patients with gastric ulcer. Am J Gastroenterol 1995; 90: 1289± Besancon M, Simon A, Sachs G, Shin JM. Sites of reaction of the gastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem 1997; 36: 22438±46.