SUMMARY INTRODUCTION. Accepted for publication 14 January 2004

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1 Aliment Pharmacol Ther 2004; 19: doi: /j x, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric ph and comparison with esomeprazole in healthy volunteers J. P. GALMICHE, S. BRULEY DES VARANNES*, P. DUCROTTÉ*à, S. SACHER-HUVELIN, F. VAVASSEUR, A. TACCOEN, P. FIORENTINI & M. HOMERIN CIC-INSERM, CHU de Nantes, Nantes, France; àchu de Rouen, Rouen, France; Negma-GILD, Toussus-le-Noble, France Accepted for publication 14 January 2004 SUMMARY Background: Proton pump inhibitors control gastric acidity better during the day than at night, when nocturnal acid breakthrough can occur. is a novel proton pump inhibitor with a seven-fold longer plasma half-life. Aim: To compare the effects of tenatoprazole (T20), tenatoprazole (T40) and esomeprazole (E40) on intragastric acidity in healthy volunteers. Methods: This randomized, three-period, cross-over study enrolled 18 Helicobacter pylori-negative volunteers, who received E40, T20 and T40 once daily for 7 days with a 14-day washout between periods. Twenty-four-hour gastric ph monitoring was performed on day 7. Serum gastrin was assessed on day 8. Results: T40 induced a more potent acid inhibition than T20 (24-h median ph: 4.6 vs. 4.0, P < 0.01; daytime: 4.5 vs. 3.9, P < 0.01; night-time: 4.7 vs. 4.1, P < 0.05). T40 was more potent than E40 (24-h median ph: 4.6 vs. 4.2, P < 0.05; night-time: 4.7 vs. 3.6, P < 0.01); the ph > 4 holding time was higher during the night for T40 than for E40: 64.3% vs. 46.8%, P < 0.01; the nocturnal acid breakthrough duration was significantly shorter for T40 than for E40. No significant gastrin increase was observed and all drugs were well tolerated. Conclusion: T40 is significantly more potent than T20 and E40 during the night. The therapeutic relevance of this pharmacological advantage deserves further study. INTRODUCTION There is a strong relationship between the degree and duration of gastric acid inhibition, as measured by monitoring of the 24-h intragastric ph in pharmacodynamic studies, and the rate of healing and symptom relief reported in clinical trials of acid suppressors in both gastro-oesophageal reflux disease 1 and peptic ulcer disease. 2 Proton pump inhibitors represent the most Correspondence to: Professor J. P. Galmiche, Department of Gastroenterology and Hepatology, CIC INSERM, CHU de Nantes, Nantes, France. galmiche@easynet.fr *These authors contributed equally to this work. effective drug therapy for gastro-oesophageal reflux disease. 3 Of these, esomeprazole is the first proton pump inhibitor to be developed as an optical isomer. 4, 5 A once-daily dose of of esomeprazole is significantly more potent in terms of the control of gastric acidity than any other standard proton pump inhibitor regimen. 6, 7 However, despite the overall efficacy of proton pump inhibitors, 15 30% of patients with gastro-oesophageal reflux disease remain unhealed and/or have insufficient symptom relief after initial proton pump inhibitor therapy. Some patients are still refractory to the available proton pump inhibitors even when the doses or dosing frequency are increased. Some Ó 2004 Blackwell Publishing Ltd 655

2 656 J. P. GALMICHE et al. of these patients have a greater oesophageal acid exposure whilst on proton pump inhibitor therapy than the corresponding responders. 8 One cause of this more or less complete refractoriness to proton pump inhibitor therapy may be related to the persistent exposure of the oesophageal mucosa to acid reflux, especially during the night. This abnormal nocturnal oesophageal acid exposure may be itself related to the ineffectiveness of current proton pump inhibitors to adequately control gastric acidity during the night, a phenomenon referred to as nocturnal acid breakthrough Although the clinical relevance of nocturnal acid breakthrough is not yet fully established, several attempts have been made to decrease this phenomenon, in particular by combining an H 2 -receptor antagonist (H 2 RA) given at bedtime and a proton pump inhibitor given twice daily. Such a combination, although quite potent after a single administration, was found to be ineffective after only 1 week due to the rapid development of pharmacological tolerance to the H 2 RA. 13 These observations underscore the need for new antisecretory drugs able to achieve a better control of intragastric ph, not only during the day but also during the night. 14 Such a goal may be difficult to reach with the currently available substituted benzimidazole proton pump inhibitors, as their plasma half-lives are quite short (about 1.5 h). (TU-199) is a novel compound that also belongs to the proton pump inhibitor class, but that has been designed as a new chemical entity with a substantially prolonged plasma half-life (7 h). Unlike other proton pump inhibitors, tenatoprazole is not a substituted benzimidazole, and is characterized by an imidazopyridine backbone. The drug inhibits parietal cell H +,K + -ATPase activity in isolated hog gastric vesicles to a similar extent to omeprazole. However, studies of the effect of tenatoprazole on acid secretion in in vivo animal models, such as pylorus-ligated rats and acute gastric fistula rats, demonstrated a 2 4-fold more potent inhibitory activity compared with omeprazole. A more potent inhibitory activity was also shown in several models of induced gastric lesions. 15 For histamine-induced acid output in Heidenhain pouch dogs, the inhibition from repeated administration of tenatoprazole was found to be greater and longer lasting than that obtained with omeprazole and lansoprazole. 16 In Asian as well as Caucasian healthy subjects, tenatoprazole exhibited a seven-fold longer half-life than the existing H +,K + -ATPase inhibitors. 17 We thus hypothesized that a longer half-life would result in a more prolonged inhibition of gastric acid secretion, especially during the night. The aim of the present pharmacodynamic randomized study was to compare the effects of a 7-day regimen of tenatoprazole or once daily with esomeprazole once daily on intragastric acidity in healthy volunteers. SUBJECTS AND METHODS Subjects The subjects were recruited in two academic centres (Nantes and Rouen, France). They were all healthy male Caucasian subjects, non-smokers or smokers who consumed no more than 10 cigarettes per day, aged years and with a body mass index of kg/m 2. A screening assessment was performed within 2 weeks prior to inclusion and included a medical history, physical examination, electrocardiogram, standard biochemistry and haematology tests and urinalysis. All subjects were negative for Helicobacter pylori (as proven by urea breath test; INFAI, Janssen- Cilag, Issy les Moulineaux, France), hepatitis B and C, and human immunodeficiency virus. None of the subjects had a history of gastrointestinal disorders or drug or alcohol abuse. Heavy smokers (more than 10 cigarettes smoked per day) were not included. The subjects included had not used any prescribed medication for at least 1 week prior to the study and had not received any enzyme inhibitor or inducer in the 3 months preceding the start of the trial. The study protocol was approved by the Ethics Committee of Pays de la Loire N 2 and all the subjects gave written informed consent. Study design The study had an open, randomized, three-period, crossover design. The subjects received the three following dosing regimens in a random order: esomeprazole once daily, tenatoprazole once daily and tenatoprazole once daily Accordingly, six subjects received tenatoprazole first, followed by tenatoprazole and esomeprazole ; six subjects received tenatoprazole, followed by esomeprazole and tenatoprazole ; the final six subjects received esomeprazole, followed by tenatoprazole and tenatoprazole. Each dosing period

3 TENATOPRAZOLE VS. ESOMEPRAZOLE ON GASTRIC ph 657 consisted of 7 days of proton pump inhibitor administration (given before breakfast) and ended with 24-h intragastric ph monitoring starting on the morning of day 7 until the morning of day 8. Each treatment period was separated from the next by a washout period of at least 14 days. Each treatment intake took place at the clinical centre under the supervision of the investigator, and subjects attended the clinical unit every day until the final visit. For practical reasons linked to the unavailability of esomeprazole placebo, the study was not double blind. However, the analysis of the ph data was conducted blind (see below). 24-h gastric ph monitoring The subjects were hospitalized the day before gastric ph monitoring and fasted overnight. Intragastric ph monitoring was performed according to a previously described technique, 18 using a combined glass electrode (440-M3/6/2.5m/FS00.250, Solal, Strasbourg, France) connected to a portable ph datalogger (UPS-2020/ ORION, MMS, Enschede, The Netherlands); the intragastric ph was sampled every 5 s. The ph recorder was first calibrated at ph 1 and then at ph 7. Thereafter, the electrode was positioned through the nose 10 cm below the oesophago-gastric junction, determined by the sudden rise in ph when withdrawing the electrode from the stomach. The correct position was checked fluoroscopically in case of doubt and the location was kept constant during the three ph monitoring periods. The ph recording began at h on the seventh day of dosing and ended at h on the following day. Meals were standardized for breakfast (at h), lunch (at h) and dinner (at h). The subjects were not allowed to drink any alcohol-containing beverages or to smoke whilst in the hospital and undergoing ph examination. At the end of the recording session, the Digitrapper data were downloaded onto a computer. All tracings were analysed blind and were crossvalidated by an investigator at each centre who was unaware of the treatment received by the subjects at the other centre (i.e. SBdV for all tracings performed in Rouen and PD for those performed in Nantes). The median ph and percentages of time spent above ph 4 and ph 3 were determined. A descriptive analysis was performed to show the percentage of subjects with more than 12 h spent above ph 4. The number and mean duration of nocturnal acid breakthrough episodes, defined as the occurrence of an intragastric ph below 4 for at least 1 h during the night, were also assessed. Diurnal and nocturnal periods were defined as h to h and h to h, respectively. Gastrin response Serum gastrin response was assessed under fasting conditions on study entry (baseline measurement) and on day 8 of the three therapeutic periods. Blood samples were withdrawn from an indwelling catheter placed in a forearm vein. Following collection, gastrin specimens were immediately frozen and stored at ) 80 C. At the end of the study, the frozen samples were sent to the laboratory and serum gastrin concentrations were determined by radioimmunoassay (GASK-PR, CIS-Bio International, subsidiary of Schering S.A., Gif-sur- Yvette, France). The detection limit, as defined by the lowest detectable concentration with a 95% probability to be different from zero, was found to be 10.5 ng/l. The intra-assay variability of the test in the range of values for normal subjects was 8.9% and the inter-assay variability was 9.9%. Safety evaluation Safety evaluations involved the monitoring of all adverse events and vital signs. The investigator closely assessed each adverse experience for severity and possible relationship to the study drug. Laboratory analyses were performed at the end of each cross-over period and included haematology, chemistry and urinalysis. Statistical analysis The size of the samples and the number of subjects required for the statistical analysis were determined empirically based on the previous experience of the authors and on comparable studies published in the literature. The effect of treatment regimen and period interaction was first checked in the analysis. In the absence of such an interaction, a General Linear Model was applied including the effects of treatment, site, period and subject nested within treatment, site and period. In the case of a statistical treatment effect, a two by two comparison between the treatment groups was performed using the LSD (least significant difference) test. SAS software (version 6.04) was used for the analysis. Statistical significance was defined by a P value lower than 0.05.

4 658 J. P. GALMICHE et al. RESULTS Demography and baseline characteristics Twenty subjects were randomized in this study. Two volunteers withdrew before the ph monitoring of the first treatment period and were excluded from the efficacy analysis. Eighteen subjects completed the three cross-over periods. The baseline characteristics of these healthy volunteers are summarized in Table 1. For each studied parameter, the order of drug administration did not have any influence on the results (data not shown). (a) (b) Intragastric ph The time courses of intragastric ph are shown in Figure 1. Although there was no major difference during the day, a better control of nocturnal gastric acidity was clearly observed with the tenatoprazole dose (Figure 2). This is further confirmed by Tables 2 4, which show the median gastric ph Table 1. Demographic details of the subjects (no difference between the different sequences of administration) T20, T40, E40 regimen E40, T20, T40 regimen T40, E20, T20 regimen Total n Age (years) 24.7 ± ± ± ± 3.8 Weight (kg) 76.8 ± ± ± ± 7.8 Body mass 23.7 ± ± ± ± 2.1 index (kg/m 2 ) E40, esomeprazole ; T20, tenatoprazole ; T40, tenatoprazole. Median ph Treatments: T T E 0 8h 10h 12h 14h 16h 18h 20h 22h 24h 2h 4h 6h 8h Figure 1. Profiles of the mean ph curves for the three treatment groups. E, esomeprazole; T, tenatoprazole. 0 0 E 40 T 20 T 40 E 40 T 20 T 40 Figure 2. The ph > 4 holding time by day (A) and night (B) for the three treatment groups. E, esomeprazole; T, tenatoprazole. (Table 2) and the percentages of time spent above ph 4 (Table 3) and ph 3 (Table 4) during the total time, daytime and night-time. achieved better control of acidity than tenatoprazole. Indeed, a statistically significant difference between the two dosing regimens was observed for three parameters (median ph, percentages of time spent above ph 4 and ph 3) during the three periods (i.e. 24 h, daytime and night-time), except for the percentage of time spent above ph 4 during the nocturnal period. was superior to tenatoprazole during the diurnal period (Table 2). In contrast, a statistically significant difference in favour of tenatoprazole was found between tenatoprazole and esomeprazole for the 24-h and night-time median ph, the 24-h and night-time percentages of time spent above ph 3 and the night-time percentage of time spent above ph 4. The better control of gastric acidity during the night with tenatoprazole, compared with esomeprazole, also resulted in a significantly shorter duration of nocturnal acid breakthrough (Table 5), but the total number of nocturnal acid breakthrough episodes was not significantly different between the three proton pump inhibitor regimens. Finally, the proportion of subjects with more than 12 h spent above ph 4 during 24 h is shown in Figure 3. Serum gastrin The individual gastrin concentrations, according to the treatment groups, are given in Figure 4. An increase in

5 TENATOPRAZOLE VS. ESOMEPRAZOLE ON GASTRIC ph 659 Table 2. Median gastric ph on day 7 according to the three dosing groups (mean and standard deviation) 24 h ( h) 4.2 ± ± ± 0.9 à Daytime ( h) 4.5 ± ± ± 0.9 Night-time ( h) 3.6 ± ± ± 1.1* vs. tenatoprazole : *P < 0.05; P < vs. esomeprazole : àp < 0.05; P < vs. tenatoprazole : P < Table 3. Percentage of time spent above ph 4 on day 7 according to the three dosing groups (mean and standard deviation) 24 h ( h) 56.2 ± ± ± 17.8* Daytime ( h) 65.6 ± 17.7à 47.2 ± ± 18.5* Night-time ( h) 46.8 ± ± ± 21.7 vs. tenatoprazole : *P < vs. esomeprazole : P <0.01. vs. tenatoprazole : àp < Table 4. Percentage of time spent above ph 3 on day 7 according to the three dosing groups (mean and standard deviation) 24 h ( h) 69.4 ± ± ± 13.9 à Daytime ( h) 80.3 ± ± ± 14.8 Night-time ( h) 58.5 ± ± ± 17.2*à vs. tenatoprazole : *P < 0.05; P < vs. esomeprazole : àp <0.01. Table 5. Incidence and duration of nocturnal acid breakthrough (NAB) according to the three dosing groups Number and (%) of patients with at least 1 NAB Mean duration ± s.d. of 1 NAB (min) 14 (74) 15 (83) 12 (66) 238 ± ± ± 131* vs. esomeprazole : *P < mean serum gastrin from baseline to day 8 was observed for each of the three treatment regimens: baseline, 42.2 ± 5.0 ng/l; esomeprazole, 45.3 ± 6.1 ng/l; tenatoprazole, 50.4 ± 11.2 ng/l; tenatoprazole, 48.1 ± 9.2 ng/l. These increases were not statistically significant. Safety All three drug regimens were well tolerated and few side-effects were reported (Table 6). No serious adverse events were reported during the study. No significant elevation or decrease was shown in chemistry or haematology assessments. DISCUSSION Our results showed that both esomeprazole and tenatoprazole were highly effective in terms of acid inhibition: after 1 week of daily administration, all three proton pump inhibitor regimens resulted in a median 24-h intragastric ph at least equal or superior to ph 4 (Table 2). The inhibition induced by tenatoprazole was dose dependent, as shown by the statistically

6 660 J. P. GALMICHE et al. Figure 3. Proportion of patients with ph > 4 for more than 12 h for the three treatment groups ng/l Baseline E 40 T 20 T 40 Figure 4. Individual values of serum gastrin at baseline and on day 8 for the three treatment groups. E, esomeprazole; T, tenatoprazole. significant differences between tenatoprazole 40 and for most ph parameters (Tables 2 4). Although tenatoprazole and esomeprazole were not significantly different during the daytime, the most striking difference was observed during the night, when tenatoprazole was significantly superior to the same dose of esomeprazole in maintaining intragastric ph above high thresholds and reducing the duration of nocturnal acid breakthrough. Indeed, there was virtually no variation in the intragastric ph values between day and night with both doses of tenatoprazole, whereas the gastric ph was much lower during the night with esomeprazole (Table 2). From a methodological point of view, the design of the study, although not double blind, allowed a headto-head comparison, in steady state conditions, of the effects of tenatoprazole with the currently most potent available proton pump inhibitor, i.e. esomeprazole, given at its recommended dose (). The three treatment regimens were assigned to the patients in a random order, separated by a washout period of at least 14 days, and analysis of the ph data was blind with respect to the order of the sequences received by a given subject. No carry-over effect of a treatment was detected and there was no interaction between any treatment and its order of administration. This is the first time that the pharmacodynamic properties of tenatoprazole have been evaluated in healthy Caucasian subjects. As already established by previous studies, 19 results of pharmacodynamic assessments using intragastric ph monitoring in healthy volunteers are fully relevant to patients with gastro-oesophageal reflux disease or peptic ulcer disease. Moreover, the study was performed in H. pylori-negative subjects, as infection by this bacterium can enhance the antisecretory effect induced by 12, 20 proton pump inhibitors. Table 6. List of adverse events (AEs) according to the three treatment groups Type of AE AEs patients AEs patients AEs patients Tendon disorder 1 1 Diarrhoea Vomiting 1 1 Abdominal pain 1 Hyperbilirubinaemia 1 1 Rhinitis Bronchospasm 1 Bronchitis 1 Total * * Same subject affected.

7 TENATOPRAZOLE VS. ESOMEPRAZOLE ON GASTRIC ph 661 The main pharmacological difference between tenatoprazole and other proton pump inhibitors is its much longer plasma half-life. This characteristic is likely to explain, at least in part, the equivalent acid suppression observed during the daytime and night-time. In contrast, proton pump inhibitors with a shorter half-life, such as omeprazole (), lansoprazole (30 mg), pantoprazole () or rabeprazole (10 mg, and ), consistently result in lower ph values during the night. 18, It is important to underscore that the gastric acid suppression profile and results yielded by esomeprazole in this population of healthy 4, 25 subjects were in agreement with the literature, although in the lower range of previously reported results. Although a longer plasma half-life results in a more prolonged exposure of active proton pumps to the proton pump inhibitor and can delay the restoration of new pumps, other factors may also play a role. Indeed, it is noteworthy that current proton pump inhibitors usually fail to adequately control nocturnal acidity even when they are given twice daily The different chemical structure of tenatoprazole compared with that of the other proton pump inhibitors, which are all substituted benzimidazoles, and/or the resulting features of its interaction with the cysteine-binding site or sites of the H + /K + -ATPase may contribute to the better and longer lasting inhibitory effect observed with tenatoprazole. 26 However, it should be remembered that, even at the highest dose used in this study, tenatoprazole did not abolish nocturnal acid breakthrough completely, even though its duration was dramatically shortened. The therapeutic relevance of such a reduction is presently unknown and, to our knowledge, there are no data in the literature concerning a threshold of nocturnal acid breakthrough suppression to predict clinical efficacy (as is the case for the time spent above ph 3 and ph 4 in peptic ulcer disease and gastro-oesophageal reflux disease). Higher doses of tenatoprazole and other dosing schedules deserve further investigation in order to test whether or not nocturnal acid breakthrough can be abolished completely with this proton pump inhibitor. The tolerance to the three proton pump inhibitor regimens was excellent and only a few minor sideeffects were reported (Table 6). The increase in gastrin plasma levels was small, not statistically significant and even lower than that usually reported with potent acid inhibition. 27 The reason for this lack of increase in gastrin levels is not completely clear, but one probable explanation is that blood samples for gastrin measurement were drawn 24 h after the last drug intake (i.e. on day 8). As shown in Figure 2, the ph values were clearly decreasing after h, but were still relatively high at this end of the ph recording session. Finally, from a clinical standpoint, the ability of tenatoprazole to maintain high diurnal and nocturnal ph levels may translate into better clinical results in erosive oesophagitis or peptic ulcer disease (i.e. more patients healed and/or more rapid symptom relief and healing of lesions). Such a prolonged acid inhibition and the subsequent decrease of the duration of nocturnal acid breakthrough may also be beneficial in patients with gastro-oesophageal reflux disease refractory to the usual proton pump inhibitors, especially those with Barrett s oesophagus or with conditions such as upper gastrointestinal bleeding. Further clinical trials are warranted to confirm these hypotheses, some of which are already in progress. ACKNOWLEDGEMENTS This study was supported by Negma-GILD, Toussusle-Noble, France. REFERENCES 1 Bell NJ, Burget D, Howden CW, Wilkinson J, Hunt RH. Appropriate acid suppression for the management of gastrooesophageal reflux disease. Digestion 1992; 51(Suppl. 1): Burget DW, Chiverton SG, Hunt RH. Is there an optimal degree of acid suppression for healing of duodenal ulcers? A model of the relationship between ulcer healing and acid suppression. Gastroenterology 1990; 99: Chiba N, De Gara CJ, Wilkinson JM. Speed of healing and symptom relief in grade II to IV gastro-oesophageal reflux disease: a meta-analysis. Gastroenterology 1997; 112: Spencer CM, Faulds D.. Drugs 2000; 60: Andersson T, Röhss K, Bredberg E, Hassan-Alin M. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther 2001; 15: Hatlebakk JG. Review article: gastric acidity comparison of esomeprazole with other proton pump inhibitors. Aliment Pharmacol Ther 2003; 17: Dent J. Review article: initial therapy of reflux disease with esomeprazole. Aliment Pharmacol Ther 2003; 17(Suppl. 1):

8 662 J. P. GALMICHE et al. 8 Holloway RH, Dent J, Narielvala F, Mackinnon AM. Relation between oesophageal acid exposure and healing of oesophagitis with omeprazole in patients with severe reflux oesophagitis. Gut 1996; 38: Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998; 115: Peghini PL, Katz PO, Bracy NA, Castell DO. Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 1998; 93: Katz PO, Anderson C, Khoury R, Castell DO. Gastro-oesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther 1998; 12: Katsube T, Adachi K, Kawamura A, et al. Helicobacter pylori infection influences nocturnal gastric acid breakthrough. Aliment Pharmacol Ther 2000; 14: Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H 2 RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 2002; 122: Tytgat GNJ. Shortcomings of the first-generation proton pump inhibitors. Eur J Gastroenterol Hepatol 2001; 13(Suppl. 1): S Uchiyama K, Wakatsuki D, Kakinoki B, Takeuchi Y, Araki T, Morinaka Y. Effects of TU-199, a novel H +,K + -ATPase inhibitor, on gastric acid secretion and gastroduodenal ulcers in rats. Meth Find Exp Clin Pharmacol 1999; 24: Uchiyama K, Wakatsuki D, Kakinoki B, Takeuchi Y, Araki T, Morinaka Y. The long-lasting effect of TU-199, a novel H +,K + - ATPase inhibitor, in gastric acid secretion in dogs. J Pharm Pharmacol 1999; 51: Ficheux H, Domagala F. Pharmacokinetics of tenatoprazole, a novel proton pump inhibitor, in healthy male Caucasian volunteers. Gastroenterology 2003; 124: S Bruley des Varannes S, Levy P, Lartigue S, Dellatolas F, Lemaire M, Galmiche JP. Comparison of lansoprazole with omeprazole on 24-hour intragastric ph, acid secretion and serum gastrin in healthy volunteers. Aliment Pharmacol Ther 1994; 8: Galmiche JP, Bruley des Varannes S. Gastric ph-metry: clinical relevance. In: Scarpignato C, Bianchi Porro G, eds. Clinical Investigation of Gastric Function. Frontiers in Gastrointestinal Research, Vol. 17. Basel: Karger, 1990: Ohning GV, Barbuti RC, Kovacs TOG, Sytnik B, Humphries TJ, Walsh JH. Rabeprazole produces rapid, potent and long-acting inhibition of gastric acid secretion in subjects with Helicobacter pylori infection. Aliment Pharmacol Ther 2000; 14: Armstrong D, Bair D, James C, Tanser L, Escobedo S, Nevin K. Oral esomeprazole vs. intravenous pantoprazole: a comparison of the effect on intragastric ph in healthy subjects. Aliment Pharmacol Ther 2003; 18: Cheer SM, Prakash A, Faulds D, Lamb HM. Pantoprazole. An update of its pharmacological properties and therapeutic use in the management of acid-related disorders. Drugs 2003; 63: 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: Tolman KG, Sanders SW, Buchi KN, Karol MD, Jennings DE, Ringham GL. The effects of oral doses of lansoprazole and omeprazole on gastric ph. J Clin Gastroenterol 1997; 24: Scott LE, Dunn CJ, Mallarkey G, Sharpe M.. A review of its use in the management of acid-related disorders. Drugs 2002; 62: Stedman CAM, Barclay M. Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther 2000; 14: Freston JW. Clinical significance of hypergastrinaemia: relevance to gastrin monitoring during omeprazole therapy. Digestion 1992; 51(Suppl. 1):