SUMMARY INTRODUCTION. Accepted for publication 4 June 2004

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1 Aliment Pharmacol Ther 24; 2: doi: /j x Effect of low-dose rabeprazole and omeprazole on gastric acidity: results of a double blind, randomized, placebo-controlled, three-way crossover study in healthy subjects S. BRULEY DES VARANNES*, H. GHARIB*, V. BICHELER*, R. BOST, B. BONAZ, L. STANESCUà, J. C. DELCHIERà & S. BONNOT-MARLIER *CIC-INSERM, CHU Hôtel Dieu, Nantes, France; CHU Grenoble, Grenoble, France; àchu Henri Mondor, Creteil, France; Laboratoires Janssen-Cilag, Issy Les Moulineaux, France Accepted for publication 4 June 24 SUMMARY Background: The treatment of acid-related symptoms requires rapid and consistent acid suppression, especially with on-demand regimens. Aim: To compare the antisecretory activity of low-dose rabeprazole and omeprazole in healthy, Helicobacter pylori-negative subjects. Methods: In this randomized, double-blind, placebocontrolled, three-way crossover study, 27 volunteers were given rabeprazole 1 mg, omeprazole 1 mg, or placebo once daily for 7 days with a 1 14-day washout between treatments. Intragastric ph was monitored for 24-h on days 1 and 7 of each treatment. Results: Median gastric ph was significantly higher with rabeprazole than with omeprazole or placebo: day 1: 2.3, 1.4 and 1.3, respectively (P ¼.56, rabeprazole vs. omeprazole; P <.1, rabeprazole vs. placebo); day 7: 3.7, 2.2 and 1.3, respectively (P ¼.16 rabeprazole vs. omeprazole; P <.1, rabeprazole vs. placebo). Time with gastric ph above 4 was significantly higher with rabeprazole than with omeprazole: day 1, 5.8 h vs. 3.7 h, respectively (P <.2); day 7, 1.5 h vs. 4.6 h, respectively (P ¼.8). Conclusions: Rabeprazole 1 mg provides more rapid acid inhibition compared with omeprazole 1 mg. After 7 days, the time with ph above 4 is more than doubled with rabeprazole 1 mg vs. omeprazole 1 mg. INTRODUCTION The proton pump inhibitor rabeprazole is frequently classified as a next-generation proton pump inhibitor. 1, 2 As with other proton pump inhibitors, rabeprazole covalently binds with H + K + adenosine triphosphatase on the secretory membrane of the gastric parietal cell. However, rabeprazole shows potential pharmacological advantages over other agents in its class, such as a more powerful acid-suppressing effect and a more rapid onset of action. Studies by Williams et al. and Pantoflickova et al. Correspondence to: Dr S. Bruley des Varannes, CIC INSERM, Institut des Maladies de l Appareil Digestif CHU Hôtel Dieu, 4493 Nantes Cedex, France. bruley@easynet.fr have shown that, in comparison with omeprazole 2 mg, the time with intragastric ph above 4 is significantly increased with rabeprazole 2 mg. 3, 4 Both power and speed of onset of acid suppression are of pivotal importance in acid-related diseases. It has been well established by several trials that erosive oesophagitis healing rates are directly related to the duration of suppression of gastric acid secretion. 5, 6 Because of these pharmacological properties, it is possible that low doses of rabeprazole might be of clinical benefit for patients with moderate to severe symptoms. With other proton pump inhibitors, subject response to lower doses has been disappointing due to the variability of antisecretory response. 7, 8 This variability may be related partly to the metabolism of the agents in this class. Ó 24 Blackwell Publishing Ltd 899

2 9 S. BRULEY DES VARANNES et al. Most are metabolized via the cytochrome P45 (CYP45) pathway, which is affected by variations that result in some patients being slow and fast metabolizers. However, because rabeprazole has a non-enzymatic metabolic pathway consisting of a reduction to its thioether, rabeprazole metabolism causes less interaction with CYP45 isoenzymes Thus rabeprazole could provide a more homogenous pharmacological response, even at lower doses. Such pharmacokinetics and pharmacological properties may be clinically relevant, and justify testing new therapeutic approaches. For example, treatment with proton pump inhibitors on demand in gastrooesophageal reflux disease (GERD) could be relevant, but only if the proton pump inhibitor exhibits a rapid onset of antisecretory action. The present study was designed to examine the 24-h intragastric acidity of Helicobacter pylori-negative, healthy subjects in response to a single dose of rabeprazole 1 mg, omeprazole 1 mg or placebo, and after a 7-day administration period. MATERIALS AND METHODS Subjects Three centres recruited 27 healthy, H. pylori-negative (determined by serology testing) volunteers. All had baseline normal physical examination as well as normal haematological and biochemical profiles. Subjects were within the normal range for body weight as determined by the Metropolitan Life Insurance Tables and had no clinically significant disease as determined by medical history. Subjects with clinically relevant diseases such as cardiac, renal or hepatic impairment; digestive symptoms suggestive of reflux disease or dyspepsia; and/or a previous history of GERD or ulcers were excluded. In addition, subjects were excluded if they had hypersensitivity to a proton pump inhibitor, received acid-suppressing medications or a medication likely to interact with acid secretion in the previous month, or were felt unlikely to comply with the trial medication or investigation procedures. During the study, concomitant therapies were not allowed except paracetamol and oral contraceptives. Study design This was a randomized, double-blind, placebo-controlled, three-way crossover trial. Subjects received before breakfast each of the following study medication/placebo combinations for 7 days on three separate periods: rabeprazole 1 mg (tablet) and placebo omeprazole 1 mg (capsule); omeprazole 1 mg and placebo rabeprazole 1 mg; placebo rabeprazole 1 mg and placebo omeprazole 1 mg. The three periods were separated by a washout period of between 1 and 14 days. The trial was performed according to the Good Clinical Practice guidelines and in accordance with the principles for experimentation as defined in the Declaration of Helsinki. Each centre was qualified to conduct clinical trials in healthy volunteers without individual direct benefit. The study protocol received approval from the Ethics committee Pays de Loire No. 2. All subjects were informed about the trial and signed an informed consent form. Study procedure The ph monitoring procedure was identical in the three study centres and during the 6 ph-monitoring days. Subjects were instructed to fast from 1: pm the night prior their visits until their arrival at the centre at 7:3 am on each ph-monitoring day. The ph electrode (glass combined ph electrode, Ingold Ref.M3.) connected to a portable data logger (UPS_22/Onion, MMS, Enschede, The Netherlands) was calibrated before insertion for each subject using standard buffer solutions of ph 1. and 7. at room temperature. A recording was taken every 5 s. After checking blood pressure and heart rate, volunteers were given the allocated study medications with a glass of water at 8: am. Following light local anaesthesia (xylocaine spray 2%) of the nostril, the ph probe was inserted via the nostril and placed 1 cm below the oesophagogastric junction as determined by the ph step-up method. If needed, the position of the probe was checked by fluoroscopy at the start of the study. Twenty-four-hour ambulatory ph monitoring was conducted from 8: am to 8. am on the following day. Subjects were given three daily meals prepared in the pharmacological department, which were standardized for timing (breakfast at 8:3 am, lunch at 1: pm and dinner at 7: pm) as well as caloric composition. Only still mineral water and tea were allowed ad libitum. Smoking was not allowed. Subjects were required to go to bed and to remain in a recumbent position from 1: pm to 7: am.

3 LOW-DOSE RABEPRAZOLE AND OMEPRAZOLE ON GASTRIC ACIDITY 91 For the safety evaluation, pulse and blood pressure measurements were performed at each visit. All adverse events occurring during the trial were recorded. Data processing and statistical analysis At the end of ph monitoring, experimental data were downloaded from the digital data logger to a personal computer and were analysed using dedicated MMS phmetric software (UPS_22/Onion, MMS, Enschede, 1 The Netherlands). Analysis was performed on the 24-h recording time, the diurnal period from 8: am to 1: pm, and the nocturnal period from 1: pm to 8: am. The primary efficacy criterion was the percentage of time spent above ph 3 measured on day 1. The secondary criteria, measured on day 1 and 7, were the percentage of time spent above ph 4, median ph, acid concentration and area under the plasma concentration time curve. An additional analysis was performed concerning the characteristics of nocturnal acid breakthrough (NAB). Nocturnal acid breakthrough was defined as the occurrence during the nocturnal 12, 13 period of intragastric ph <4 for more than 1 h. For all criteria analyses, the descriptive statistics were analysed per period, order and group of treatment. An analysis of variance (anova) including centres, subjects, treatment, period, and carryover effect was performed. In the cases where the distribution was not normal, a non-parametric analysis was considered. The comparison of treatment groups was carried out using the Student t-test or Wilcoxon test according to implementation conditions of the Student test. If there was no carryover effect using the threshold of 1%, the interaction was eliminated to reduce the model, and the result of this analysis was retained. When the treatment effect was significant, 2 2 comparisons were carried out using the Bonferroni test. Statistical analysis was carried out using the software 2 SAS version 8 (PC; Sas Institute, Cary, NC, USA). The risk of first species a was fixed at 5% for all tests. All the statistical tests were carried out using bilateral analysis. RESULTS Overall, 27 subjects (18 male) completed the trial and were analysed. One subject, wrongly included, withdrew at the end of the first period and was replaced by another according to the randomization replacement list. Mean age was 26 years (range, 2 42); mean weight and height were 69 kg (range, 47 9) and 176 cm (range, ), respectively. The anova showed no significant difference between centres, periods, and subjects, and there was no carryover effect. Antisecretory effect at day 1 On day 1, the 24-h median percentage of time spent above ph 3 was 4.5% (9.7 h) with rabeprazole, 24.1% (5.8 h) with omeprazole and 16.9% (4.1 h) with placebo. The differences between rabeprazole and omeprazole, and rabeprazole and placebo were statistically significant (P ¼.73 and P <.1, respectively), but there was no significant difference between omeprazole and placebo. The percentage of time spent above ph 4 over the 24-h period was 24.3% (5.8 h) with rabeprazole, 15.3% (3.7 h) with omeprazole and 7.9% (1.9 h) with placebo. Again, the differences between rabeprazole vs. omeprazole (P.2) and placebo (P.2) were significant, but with omeprazole vs. placebo, there was no significant difference. The 24-h median ph was significantly higher with rabeprazole (2.3) than with omeprazole (1.4) and placebo (1.3). As with the time spent above ph 3 and 4, there was no significant difference between omeprazole and placebo, but the differences were significant with rabeprazole vs. omeprazole (P ¼.56) and rabeprazole vs. placebo (P <.1) (Figure 1). The 24-h median acid concentration was significantly lower with rabeprazole than with omeprazole and placebo: 28, 58 and 69 mmoles [H + ]/L, respectively (P ¼.27, rabeprazole vs. omeprazole; P <.1, rabeprazole vs. placebo). No significant difference was found between omeprazole and placebo (Figure 2). Individual values of subjects for the 24-h percentage of time spent above ph 3 as well as the 24-h acid concentration are illustrated on Figure 3. Diurnal and nocturnal percentages of time above ph 3 and 4, median ph, and median acid 2concentrations are shown in Table 1. The occurrence and duration of NAB were not significantly different among treatments. However, the median ph of NAB was significantly higher with rabeprazole than with omeprazole and placebo (P <.1) (Table 2). Antisecretory effect at day 7 The 24-h median percentage of time spent at ph >3 on day 7 was 59.4% (14.2 h) with rabeprazole, 37.8%

4 92 S. BRULEY DES VARANNES et al. Day 1 7 Breakfast Lunch Dinner Rabeprazole 1 mg Omeprazole 1 mg Placebo 6 5 ph a.m. 12. a.m. 4. p.m. 8. p.m. 12. p.m. 4. a.m. 8. a.m. Time Figure 1. Median intragastric ph over 24 h after a single dose (1 mg) of rabeprazole, omeprazole or placebo at 8: am in 27 healthy subjects. Mmoles [H+]/L Day 1 Breakfast Lunch Dinner 8. a.m. 12. a.m. 4. p.m. 8. p.m. 12. p.m. 4. a.m. 8. a.m. Time Rabeprazole 1 mg Omeprazole 1 mg Placebo Figure 2. Median acid concentrations over 24 h after a single dose (1 mg) of rabeprazole, omeprazole or placebo at 8: am in 27 healthy subjects. Day 1 Percentage of time spent at ph> % 41% 52% 48% 19% 47% 5 24-h median ph Ome 1 mg Placebo Rabe 1 mg Ome 1 mg Placebo Rabe 1 mg Figure 3. Individual values of percentage of time spent above ph3 and individual median acid concentrations over 24 h in 27 healthy subjects after a single dose (1 mg) of rabeprazole, omeprazole or placebo. The coefficients of variations (standard deviation/mean) are indicated above each treatment group.

5 LOW-DOSE RABEPRAZOLE AND OMEPRAZOLE ON GASTRIC ACIDITY 93 Table 1. Percentages of time with gastric ph above 3 and 4, ph, and acid concentrations during 24-h gastric ph monitoring for the diurnal and nocturnal periods following a single dose of rabeprazole 1 mg (R), omeprazole 1 mg (O) or placebo (P) (Day 1) in 27 healthy subjects R O P R vs. O (P) R vs. P (P) O vs. P (P) Time >3 (%) 8: am 1: pm 39.5 ( ) 21.8 ( ) 19.2 ( ).56.2 NS 1: pm 8: am 34. ( ) 18.6 ( ) 9.7 ( ).2.2 NS Time >4 (%) 8: am 1: pm 24.7 ( ) 11.8 ( ) 9.9 ( ) : pm 8: am 17. ( ) 9.5 ( ) 5.5 ( ) NS ph 8: am 1: pm 2.3 ( ) 1.6 ( ) 1.3 ( ).2.1 NS 1: pm 8: am 2.1 ( ) 1.2 (.9 1.9) 1.2 (1. 1.3).6. 1 NS Acid concentration (mmoles/l) 8: am 1: pm 32 (9 57) 43 (21 67) 58 (45 79).49.3 NS 1: pm 8: am 48 (11 72) 78 (36 13) 82 (64 97).1 <.1 NS Values are medians and interquartiles. Table 2. Characteristics (median and interquartiles) of nocturnal acid breakthrough monitored using intragastric ph monitoring following a single dose of rabeprazole 1 mg, omeprazole 1 mg and placebo (Day 1) and after 7 days of treatment (Day 7) in 27 healthy subjects Rabeprazole Omeprazole Placebo Day 1 Number 2 (1 3) 2 (1 3) 2 (2 3) Duration (min) 19 (77 263) 124 (9 341) 163 (95 38) Median ph 1.4* (1. 1.8) 1.1 (.9 1.4) 1.1 (.8 1.4) Day 7 Number 2 (1 2) 2 (1 2) 2 (1 3) Duration (min) 12 (69 257) 178 (98 313) 129 (88 333) Median ph 1.5à ( ) 1.2 (.9 1.6) 1.1 (.8 1.3) * P <.1 vs. omeprazole and placebo. P <.5 vs. placebo. à P <.5 vs. omeprazole. 3 P <.1 vs. placebo. (9.1 h) with omeprazole and 16.3% (3.9 h) with placebo (P ¼.13 rabeprazole vs. omeprazole; P <.1 rabeprazole vs. placebo; P ¼.4 omeprazole vs. placebo). The 24-h median percentage of time spent above ph 4 was 43.7% (1.5 h) with rabeprazole, 19.1% (4.6 h) with omeprazole and 8.2% (2. h) with placebo (P ¼.8 rabeprazole vs. omeprazole; P <.2 rabeprazole vs. placebo; P ¼.2 omeprazole vs. placebo). The median ph over the 24-h period on day 7 was significantly higher with rabeprazole than with omeprazole and placebo: 3.7, 2.2 and 1.3, respectively (P ¼.16 rabeprazole vs. omeprazole; P <.1, rabeprazole vs. placebo). Median 24-h ph on day 7 was significantly higher with omeprazole than with placebo (P <.1) (Figure 4). The 24-h median acid concentration with rabeprazole, omeprazole and placebo was 19, 4 and 75 mmoles [H + ]/L, respectively. This was significantly lower with rabeprazole compared with omeprazole (P ¼.3) and placebo (P <.1), and also with omeprazole compared with placebo (P <.1) (Figure 5). Diurnal and nocturnal percentages of time above ph 3 and 4, median ph, and median acid concentrations are shown in Table 3. The occurrence of NAB after 7 days was significantly decreased with rabeprazole as compared with placebo. In addition, the median ph of NAB was significantly higher with rabeprazole than with omeprazole and placebo (Table 2). Tolerability No serious adverse events were reported during the study. The incidences of adverse events among treatment groups were not significantly different.

6 94 S. BRULEY DES VARANNES et al. 7 Day 7 Breakfast Lunch Dinner Rabeprazole 1 mg Omeprazole 1 mg Placebo 6 5 ph a.m. 12. a.m. 4. p.m. 8. p.m. 12. p.m. 4. a.m. 8. a.m. Time Figure 4. Median intragastric ph over 24 h after 7 days of treatment with a daily dose (1 mg) of rabeprazole, omeprazole or placebo in 27 healthy subjects. Mmoles [H+]/L Day 7 Breakfast Lunch Dinner 8. a.m. 12. a.m. 4. p.m. 8. p.m. 12. p.m. 4. a.m. 8. a.m. Time Rabeprazole 1 mg Omeprazole 1 mg Placebo Figure 5. Median acid concentrations over 24 h after 7 days of treatment with a daily dose (1 mg) of rabeprazole, omeprazole or placebo in 27 healthy subjects. Table 3. Percentages of time with gastric ph above 3 and 4, ph, and acid concentrations during 24-h gastric ph monitoring for the diurnal and nocturnal periods following 7 days of treatment with rabeprazole 1 mg (R), omeprazole 1 mg (O) or placebo (P) in 27 healthy subjects (Day 7) R O P R vs. O (P) R vs. P (P) O vs. P (P) Time > 3 (%) 8: am 1: pm 69.9 ( ) 51.9 ( ) 15.2 ( ).7 <.1.2 1: pm 8: am 51. ( ) 24.7 ( ) 9. ( ).4 <.1 NS Time > 4 (%) 8: am 1: pm 5. ( ) 21.8 ( ) 8.7 ( ).1 <.1.1 1: pm 8: am 36.9 ( ) 13.3 ( ) 4.5 ( ).3 <.1.3 ph 8: am 1: pm 4.1 (3.4 5.) 3.2 ( ) 1.4 ( ).2 <.1 <.1 1: pm 8: am 3.1 ( ) 1.5 ( ) 1.2 (1. 1.3).14 <.1.8 Acid concentration (mmoles/l) 8: am 1: pm 6 (2 15) 22 (5 44) 58 (49 91).2 <.1 <.1 1: pm 8: am 34 (17 39) 59 (27 72) 95 (75 11).4 <.1 <.1 Values are medians and interquartiles.

7 LOW-DOSE RABEPRAZOLE AND OMEPRAZOLE ON GASTRIC ACIDITY 95 DISCUSSION The present study shows that a low-dose of rabeprazole (1 mg) results in stronger and more rapid antisecretory activity compared with a low-dose of omeprazole (1 mg). These pharmacological characteristics could be of clinical relevance for therapeutic use especially when considering on-demand treatment for GERD. The therapeutic efficacy of proton pump inhibitors is largely established in the control of healing of oesophageal erosions as well as in the control of GERD symptoms. 14 In some patients with severe symptoms and/or frequent relapses, continuous treatment may be needed. 15 However, in clinical practice, for the majority of patients with intermittent symptoms, the main objective is symptom control. For these patients, several therapeutic strategies have been proposed recently consisting of short, intermittent treatment episodes or on-demand treatment Ideally, an on-demand approach requires an agent that combines (i) a fast onset of action, (ii) prolonged action and (iii) a good safety profile, one characterized especially by the lack of 1, 21 drug drug interactions. Previously, proton pump inhibitors were not considered good candidates for very short treatment episodes because of the lag time needed to achieve a therapeutically relevant antisecretory steady state. 2 In this aspect, weekend therapy using omeprazole 2 mg for three consecutive days a week has been shown ineffective at least in maintaining 16, 22 healing in patients with reflux oesophagitis. Rabeprazole is considered a next-generation proton pump inhibitor due to its improved pharmacologic profile. 1, 2 This profile could be related partly to rabeprazole s lower acid stability (high pka) compared with other agents in this class, as the acid stability of a proton pump inhibitor determines the rate of accumulation of the prodrug in the acidic secretory canaliculus of the parietal cell. 23 This rate of accumulation may in turn influence the rate of acid-activated formation of an active sulfenamide. Because of these pharmacological differences, using rabeprazole in very short intermittent treatment regimens (2 4 days) or on an on-demand basis may be clinically relevant. Consequently, this study was designed to compare the pharmacological responses of healthy volunteers to low doses of omeprazole, a reference proton pump inhibitor, and low-dose rabeprazole. Particularly, the objective was to document the speed of onset of antisecretory activity with these low doses. As illustrated in Figures 1 and 2, the data clearly show that antisecretory activity occurs early following a single dose of rabeprazole 1 mg. Indeed after the breakfast-induced peak, the ph falled in a lesser extent with rabeprazole than with omeprazole and placebo. During the first 24 h, gastric ph was significantly increased compared with omeprazole 1 mg (median 2.3 vs. 1.4), approaching a 1-fold decrease in gastric acidity (Figure 3). The greater acid suppression observed after a single dose of rabeprazole 1 mg is consistent with the results recently reported with a single dose of rabeprazole 2 mg when compared with other proton pump inhibitors at usual doses. 4 As indicated in Table 1, during the diurnal period following morning drug intake, the percentages of time above ph 3 and 4 were significantly higher with rabeprazole than with omeprazole (P ¼.56 and.15, respectively). Furthermore, the increase in gastric ph as well as the decrease of gastric acidity [H + ] occurred before lunch for rabeprazole (Figures 1 and 2). Likewise, the nocturnal period analysis shows an increased percentage of time above ph 3 and 4 with rabeprazole vs. omeprazole, although the difference fell short of significance for ph 4 (P ¼.2 and.74, respectively). After a 7-day treatment period, gastric acid inhibition was significantly more pronounced with rabeprazole than with omeprazole (P ¼.3). As illustrated in Figure 4, rabeprazole produced virtual anacidity during the day as well as during the second part of the night. The magnitude of the antisecretory effect is illustrated by the percentage of time with intragastric ph above 4, which was 5.% with rabeprazole, compared with 21.8% with omeprazole (P ¼.1). The relatively moderate antisecretory activity observed with omeprazole 1 mg may be linked to the greater interindividual variability in antisecretory effect that the present authors and others have previously observed following 5 days of treatment with omeprazole 1 mg. 7, 8 Conversely, a more homogenous antisecretory effect already has been suggested with rabeprazole 1 mg. 3 Interestingly, the reduction of gastric acidity appears to be relatively close between rabeprazole 1 mg and rabeprazole 2 mg in some studies. 24 In this study, NAB was also analysed, which may be of clinical relevance at least in the healing of severe erosive oesophagitis. These results confirm that the occurrence of NAB is difficult to control with proton pump inhibitors, 12 although a significantly lower decrease in ph during NAB

8 96 S. BRULEY DES VARANNES et al. was observed with rabeprazole vs. omeprazole and placebo at day 1, and a small but significant reduction of NAB occurrence at day 7 with rabeprazole compared with placebo. The clinical relevance of such a change is still unknown, and further studies should establish the extent to which NAB must be controlled to improve clinical efficacy with a proton pump inhibitor. In addition our results were observed in healthy volunteers but they have to be confirmed in GERD patients. In fact controlling NAB could be a relevant objective in some patients as those with Barrett s oesophagus or with poor oesophageal motility. 25 Because the efficacy of antisecretory drugs in GERD healing correlates with the degree of acidity over 24 h, 5, 6, 26 the longer time above ph 4 observed with rabeprazole (5.8 and 1.5 h, respectively, at day 1 and day 7) vs. omeprazole (3.6 and 4.6 h, respectively, at days 1 and 7) may correspond with more consistent clinical results with rabeprazole. Several clinical studies confirm that low doses of rabeprazole are significantly better than placebo and sometimes equivalent to rabeprazole 2 mg 27 for the control reflux symptoms 28, 29 both with continuous and on-demand dosing. In conclusion, this study demonstrates the ability of a single, low-dose of rabeprazole (1 mg) to maintain statistically higher diurnal and nocturnal gastric ph compared with omeprazole 1 mg. Whether these data translate into more rapid and longer lasting symptom control when used on an on-demand basis has yet to be established, although preliminary results indicate a clinical benefit with low-dose rabeprazole for this 27, 28 use. ACKNOWLEDGEMENT This study was supported by a grant from Janssen Cilag, France. REFERENCES 1 Tytgat GN. Shortcomings of the first-generation of proton pump inhibitors. Eur J Gastroenterol Hepatol 21; 13(Suppl. 1): S Robinson M. New-generation proton pump inhibitors: overcoming the limitations of early-generation agents. Eur J Gastroenterol Hepatol 21; 13(Suppl. 1): S Williams MP, Sercombe J, Hamilton MI, Pounder RE. A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther 1998; 12: Pantoflickova D, Dorta G, Ravic M, Jornod P, Blum AL. Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors. Aliment Pharmacol Ther 23; 17: Bell NJV, Burget D, Howden CW, Wilkinson J, Hunt RJ. Appropriate acid suppression for the management of gastrooesophageal reflux disease. Digestion 1992; 51(Suppl. 1): Hunt RH. Importance of ph control in the management of GERD. Arch Intern Med 1999; 159: Hémery P, Galmiche JP, Rozé C, et al. Low dose of omeprazole on gastric acid secretion in normal man. Gastroenterol Clin Biol 1987; 11: Savarino V, Mela GS, Zentilin P, et al. Variability in individual response to various doses of omeprazole. Implications for antiulcer therapy. Dig Dis Sci 1994; 39: Yasuda S. Comparison of the kinetic disposition and metabolism of E381, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4 -hydoxylation status. Clin Pharm Ther 1995; 58: Vanden Branden M, Ring BJ, Binkley SN, Wrighton SA. Interaction of human liver cyto P45 in vitro with LY3764, a gastric proton pump inhibitor. Pharmacogenetics 1996; 6: Saitoh T, Fukushima Y, Otsuka H, et al. Effects of rabeprazole, lansoprazole and omeprazole on intragastric ph in CYP2C19 extensive metabolizers. Aliment Pharmacol Ther 22; 16; Katz PO, Hattlebakk JG, Castell DO. Gastric acidity and acid breakthrough with twice-daily omeprazole and lansoprazole. Aliment Pharmacol Ther 2; 14: Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H 2 RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 22; 122: Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997; 112: Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 2; 118: Isal JP, Zeitoun P, Barbier P, Cayphas JP, Carlsson R. Comparison of two dosage regimens of omeprazole 1 mg once daily and 2 mg weekends as prophylaxis against recurrence of reflux esophagitis. Gastroenterology 199; 98: A Bardhan KD. Intermittent and on-demand use of proton pump inhibitors in the management of symptomatic gastroesophageal reflux disease. Am J Gastroenterol 23; 98(Suppl.): S Lind T, Havelund T, Lundell L, et al. On-demand therapy with omeprazole for the long-term management of patients with heartburn without oesophagitis a placebo-controlled randomized trial. Aliment Pharmacol Ther 1999; 13:

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