and 2 Negma-Lerads, Toussus-le-Noble, Magny-Les-Hameaux Cedex, France INTRODUCTION

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1 American Journal of Gastroenterology ISSN C 2005 by Am. Coll. of Gastroenterology doi: /j x Published by Blackwell Publishing Effect on Intragastric ph of a PPI with a Prolonged Plasma Half-Life: Comparison between Tenatoprazole and Esomeprazole on the Duration of Acid Suppression in Healthy Male Volunteers Richard H. Hunt, F.R.C.P., F.R.C.P.C., F.A.C.G., 1 David Armstrong, M.A., M.B. B. Chir., F.R.C.P. (UK), F.R.C.P.C., 1 Cindy James, R.N., BScN., 1 Sadat K. Chowdhury, M.B.B.S., 1 Yuhong Yuan, M.D., M.Sc., Ph.D., 1 Paola Fiorentini, M.D., Ph.D., 2 Alain Taccoen, M.D., 2 and Patrick Cohen, M.D. 2 1 Division of Gastroenterology, McMaster University Medical Centre, Hamilton, Ontario, Canada; and 2 Negma-Lerads, Toussus-le-Noble, Magny-Les-Hameaux Cedex, France OBJECTIVE: METHODS: RESULTS: CONCLUSION: To compare the inhibitory effect of a novel proton pump inhibitor (PPI), tenatoprazole 40 mg once daily, with esomeprazole 40 mg once daily on intragastric acidity. A randomized, investigator-blind, two-way, crossover study was conducted in 30 healthy Helicobacter pylori negative male volunteers. Tenatoprazole 40 mg or esomeprazole 40 mg was administered once daily for 7 consecutive days with a 4-wk washout period between treatments. Ambulatory 24-h intragastric ph was recorded at baseline, after 7 days treatment, and 3 and 5 days after treatment was stopped. At presumed steady-state (day 7), median 24-h ph values were 5.02 and 4.79 for tenatoprazole and esomeprazole, respectively. There was a significant difference between tenatoprazole and esomeprazole during the nocturnal period when mean ph was 4.64 ± 0.67 versus 3.61 ± 0.90, respectively (p < ), as well as a significantly higher mean percentage of time with ph >4 on tenatoprazole (72.5 ± 14.9 vs 62.2 ± 13.6, p < ). The effect of tenatoprazole was still present 5 days after treatment withdrawal especially during the night-time. The mean area under the plasma concentration time curve and elimination half-time was significantly higher in the tenatoprazole group as compared with the esomeprazole group. Tenatoprazole 40 mg daily provides a prolonged duration of acid suppression and a shorter nocturnal acid breakthrough in healthy volunteers, even after stopping the drug. Thus, tenatoprazole may provide greater clinical efficacy for patients in whom a once daily PPI is ineffective. Further studies are indicated. (Am J Gastroenterol 2005;100: ) INTRODUCTION Proton pump inhibitors (PPIs) are very effective for the treatment of symptoms and the healing of erosive and ulcerative disease in the spectrum of acid-related disorders (duodenal and gastric ulcer disease and erosive esophagitis). PPIs produce significantly more effective and prolonged acid suppression than H 2 -receptor antagonists (H 2 -RAs) and maintain a ph >4 for up to h/day. It has been demonstrated that healing in acid-related disorders is directly related to the degree and duration of acid suppression and the length of treatment (1 4). The mean intragastric ph threshold achieved with a once daily dose of a PPI therapy given in the morning is much higher than that achieved by H 2 -RAs (5) and the increased clinical efficacy seen within the PPI class is correlated with more prolonged acid suppression (6, 7). However, the pharmacological properties of the currently available PPIs are such that they are not ideal for producing prolonged acid suppression. While usually given as a single morning dose one-half to 1 h before breakfast, up to 15 20% patients require b.i.d. dosing to achieve a satisfactory clinical response, maintenance of remission such as in patients with gastroesophageal reflux disease (GERD) (8). This is largely because of the short plasma half lives of these drugs which range from 1 to 1.5 h. It is only during this period when the drug is available in the plasma that proton pumps can be blocked. Moreover, in order for pumps to be blocked by the PPI, they must be inserted into the secretory canalicular membrane of the parietal cell, and for this to occur the pumps must be actively secreting acid (9). Pumps that are covalently bound by available PPI will remain so and will no longer be active. 1949

2 1950 Hunt et al. However, any pumps that are newly synthesized in the period after plasma levels of the PPI fall will not be bound and they will therefore be able to secrete at full capacity (10). A PPI with a longer half-life should therefore produce more prolonged blockade of proton pumps with the potential for greater acid suppression and, hence, greater clinical effect, particularly for patients with postprandial evening and/or nocturnal symptoms. Tenatoprazole is a new PPI that has a prolonged plasma half-life in comparison with other current PPIs (11). Thus, this long acting PPI might be expected to provide effective acid suppression throughout the 24-h period and, in contrast to existing PPIs, be much more effective in the later part of the day and through the night. Moreover, such a drug might have a prolonged effect on acid secretion measurable more than 24 h after cessation of therapy. We therefore undertook a study to compare tenatoprazole with esomeprazole in healthy Helicobacter pylori negative volunteers. We compared intragastric ph after 7 days treatment, and 3 and 5 days after treatment was stopped. We also studied the serum gastrin level and pharmacokinetic parameters of tenatoprazole and esomeprazole. METHODS Subjects Thirty-one healthy male volunteers aged yr and with a body mass index of kg/m 2 were recruited for the study. Eligible subjects were H. pylori negative, based on a negative 13 C urea breath test ( 13 C UBT; Isodiagnostika, Edmonton, AB, Canada) and analyzed using an isotope ratio mass spectrometer (BreathMat, FinniganMat, Bremen, Germany), and all were in good health as determined by medical history, physical examination, laboratory profile, and electrocardiogram. No subject had taken any medication within the preceding 2 wk or participated in another drug study within the preceding 2 months, and none was a smoker or had a history of drug or alcohol abuse or drug allergies. Genotyping for cytochrome 2C19 was done in the screening period (DxS Limited, Manchester, UK), poor metabolizers were excluded. Each subject gave informed and signed consent prior to participation in the study. The study protocol was approved by the Institutional Research Ethics Board of McMaster University and Hamilton Health Sciences, Hamilton, Canada. Study Design This was an investigator-blind, randomized, two-way, crossover study. Following a screening period of 4 days 2 wk prior to study initiation, subjects were assigned randomly by computer to one of two treatment groups, defined by the sequence of administration of the two drugs. All subjects received each of two 7-day dosing regimens according to their treatment group assignment. During each sequence, subjects were given tenatoprazole 40 mg (Negma-Lerads, Toussus-le- Noble, France; four 10-mg tablets of enteric coated granules) once daily or esomeprazole 40 mg (Nexium R MUPS 40 mg, AstraZeneca Inc., Mississauga, Ontario, Canada) once daily, 30 min before breakfast with approximately 180 ml of water (at 07:30 h). A washout period of 4 wk separated the two dosing regimens. The administration of medication was supervised on day 1 and day 7 to ensure compliance. During day 7 of each treatment period, subjects remained in the clinical investigation unit for 12 h postdosing and returned at designated time for blood sampling. All meals were standardized and were served at the same times (08:00 a.m., 01:00 p.m., 06:00 p.m.) on each ph study day. Other food and drink, smoking, and alcohol consumption were prohibited during the entire study periods. Pharmacodynamic Evaluation Each participant underwent eight ambulatory 24-h intragastric ph-metry measurements during the study: at baseline (day 0), after a 7-day repeated dosing (day 7, the presumed steady-state), after 3-day discontinuation of the treatment (day 10, the early posttreatment), and after 5 day of discontinuation (day 12, the last posttreatment) of each crossover period. Briefly, a combination glass electrode, incorporating both ph and reference electrodes (Ingold Biopolar Electrode, MUI Scientific, Mississauga, ON, Canada) was inserted transnasally and positioned 10 cm below the lower esophageal sphincter, which was located manometrically and connected to a Medtronic Digitrapper data recorder (Medtronic, Mississauga, ON, Canada) to digitize and store the ph data. Electrodes were calibrated at 20 C using standard buffers to ph 4 and 7 (VWR, WestChester, PA) before each use; recorded ph values were corrected automatically to body temperature (37 C). Intragastric ph values were recorded every 4 s by the data recorder for 24 h and then downloaded to a native format Medtronic ph data file before conversion to an ASCII file for analysis by an investigator who remained blinded to the treatment schedule. Each intragastric ph recording was further validated by the investigator and values within the range 1 7 were considered as biologically accurate and values exceeding ph 7 or lower than ph 1 were excluded from analysis. Diurnal and nocturnal periods were defined as 7:00 a.m. to 7:00 p.m. and 7:00 p.m. to 7:00 a.m., respectively. For ph-metry analysis, 24-h periods with at least 20 h, diurnal periods with at least 10 h, and nocturnal periods with at least 10 h of accurate data were considered in the statistical analysis. Repeated ph recordings were analyzed only descriptively to confirm the ITT and per-protocol analyses. All valid recordings were then analyzed blindly, using standard, commercially available software (Polygram.Net; Medtronic Digitrapper, Mississauga, Ontario, Canada). The median ph and percentages of time spent above ph 3 and 4 were determined at baseline (day 0), at day 7, day 10, and day 12 for the 24-h period as well as for the diurnal and nocturnal periods. The proportion of subjects who had nocturnal acid breakthrough (NAB) episode, defined as the occurrence of intragastric ph <4 for at least1hduring the night-time, and total duration of NAB were also assessed.

3 Effect on Intragastric ph of a PPI with a Prolonged Plasma Half-Life 1951 Gastrin Response Serum gastrin levels were measured under fasting conditions at baseline, after a 7-day dosing period (day 7), and 3 and 6 days after discontinuation of the treatment (day 10 and 13, respectively) of each crossover period. Blood samples were separated and frozen to 20 C and shipped to the laboratory for serum gastrin concentrations evaluation (LDS laboratories, Quebec, Canada). All serum gastrin values were measured in a single assay by a sensitive and specific radioimmunoassay. Normal range of serum gastrin for this laboratory is ng/l. Pharmacokinetic Evaluation Blood samples for pharmacokinetic assessment of the study drugs were collected before dosing (day 0), and at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h (on day 8), 36 h, 48 h (on day 9), 72 h (on day 10), 96 h (on day 11), and 120 h (on day 12) after the last study treatment intake (7:30 a.m. on day 7). Samples were spun in a refrigerated centrifuge 4 C, separated and frozen at 20 C. All specimens were batched and sent on dry ice for analysis (ADME Bioanalyses, Vergeze, France). Two different analytical methods were used and validated, the first one for tenatoprazole and the second one for esomeprazole. Both methods consisted of a protein precipitation using for tenatoprazole sodium carbonate buffer Na 2 CO 3 5mMpH 9 or acetonitrile for esomeprazole. Esomeprazole SCR was used as an internal standard for tenatoprazole and tenatoprazole was used as an internal standard for esomeprazole. Analyses were performed using liquid chromatography and mass spectrometry (LC/MS) method. Pharmacokinetic parameters included individual and mean plasma concentrations, peak concentration (C max ), time to peak concentration (T max ), area under the plasma concentration time curve from zero to infinity (AUC ), and elimination half-time (t 1/2 ). Safety Evaluation Safety evaluation included a physical examination, monitoring of vital signs, and a one time screening ECG. Routine laboratory analyses included hematology, biochemistry, and urinalysis. Subjects kept daily diaries to monitor any adverse event including severity and investigator closely assessed the possible relationship of each adverse event to the study drug. Study Endpoints The primary endpoint of this study was to assess the sustained anti-secretory effects of 7-day dosing of tenatoprazole (40 mg daily) and esomeprazole (40 mg daily) on 24-h intragastric ph, 3 days and 5 days after discontinuation of the treatment. Second endpoints were to assess the anti-secretory effects of two therapy regimens on 24-h intragastric ph after 7-day of repeating dosing; the gastrin response and the pharmacokinetics profile of the two therapy regimens after 7-day repeating dosing; and the clinical and biological safety and tolerability of tenatoprazole 40 mg daily. Statistical Analysis Sample size calculation was based on the previous comparable published studies; 30 subjects were needed to detect an effect size of 0.5 at 0.05 level of significant with 80% power. Any possible order effect of the treatment regimen was first excluded and a General Linear Model (GLM) analysis was performed with three factors (regimen, period, and subject). If a statistical difference was found for the treatment effect, a two-by-two comparison was done between tenatoprazole and esomeprazole using the LSD (least significant difference) test. The relationship between pharmacokinetic parameters and pharmacodynamic parameters was analyzed using a linear model of regression. Data from all subjects who received at least one dose of study medication were included in the safety analyses. Paired t-test was used to compare the difference within subject of the ph data between two groups. All statistical tests were 2-tailed and analyses were performed using SAS software version 8. Statistical significance was considered when the p value was less than RESULTS Thirty healthy male volunteers (27 Caucasian, 1 Black, and 2 Asian; mean age 22.7 ± 3.4 yr, range yr) completed the study. One subject was excluded due to major protocol violation (excessive alcohol consumption). Nine subjects were heterozygous extensive metabolizers and 21 were homozygous extensive metabolizers. There is no demographic difference at baseline in two study sequence groups. For each studied parameter, the study sequence did not have an impact on the results (data not shown). Intragastric ph In the 30 subjects, 16 recordings out of 240 were considered invalid for analysis and were repeated. Baseline 24-h intragastric ph is summarized in Table 1. Mean ± SD 24-h intragastric ph values for each of the two crossover periods (30 subjects) for the tenatoprazole and esomeprazole periods were 1.58 ± 0.19 and 1.59 ± 0.25 (p = 0.48), respectively. Baseline median 24-h intragastric ph values were comparable in the two treatment periods (1.53 and 1.51 for tenatoprazole and esomeprazole, respectively) and the mean percentage of time ± SD of gastric ph exceeding 3.0 and 4.0 in 24 hwere ± 7.66 and ± 5.58 for tenatoprazole, and ± 7.73 and ± 6.57 for esomeprazole, p = 0.26 and p = 0.38 for tenatoprazole versus esomeprazole, respectively. Median percentage of periods during which gastric ph exceeded 3.0 and 4.0 were and for tenatoprazole, and 9.23 for esomeprazole, respectively. At presumed steady-state (day 7), median 24-h ph was 5.02 and 4.79 for tenatoprazole and esomeprazole, respectively. Mean 24-h ph with tenatoprazole was not significantly higher than with esomeprazole (4.86 ± 0.68 vs 4.65 ± 0.72, p = 0.14) (Table 2). There was a significant difference between tenatoprazole and esomeprazole during the nocturnal

4 1952 Hunt et al. Table 1. Intragastric 24-h ph at Baseline Tenatoprazole Esomeprazole Overall p Value Mean ph ± SD 1.58 ± ± Median ph (min, max) 1.53 (1.31, 2.00) 1.51 (1.28, 2.21) Mean% time ph > ± ± Median% time ph >3 (min, max) (5.09, 33.50) (3.68, 36.50) Mean% time ph > ± ± Median% time ph >4 (min, max) (1.84, 23.60) 9.23 (1.20, 28.81) period (4.64 ± 0.67 vs 3.61 ± 0.90, p < ) (Fig. 1). As a consequence, the mean percentage of time with ph >3 and >4 was significantly higher with tenatoprazole than with esomeprazole (86.37 ± vs ± 11.54, ± vs ± 13.55, both p < ) especially during the nocturnal period (82.93 ± vs ± 15.34, ± vs ± 15.05, both p < , respectively) (Fig. 2A and B). The proportion of subjects with at last 12 h above ph 4 during a 24-h period was 92.6% for tenatoprazole and 89.7% for esomeprazole (p > 0.05) and the proportion of subjects with at least 16 h above ph 4 in the 24-h period was significantly higher with tenatoprazole than with esomeprazole (81.5% vs 34.5%, p < 0.001). Three days after treatment was discontinued (day 10), mean 24-h ph, percentage of time with ph >3 and >4 were significantly higher with tenatoprazole (2.20 ± 0.78 vs 1.83 ± 0.29, p = 0.01; ± vs ± 9.19, p = 0.005; and ± vs ± 7.29, p = , respectively), indicating a sustained control of intragastric acidity with tenatoprazole compared to esomeprazole. The effect of tenatoprazole was still present after treatment withdrawal (day 12) especially during the night-time, the mean percentage of time with nocturnal ph >4 was significantly higher with tenatoprazole (14.33 ± vs 7.25 ± 7.99, p = 0.04). The number of subjects in whom gastric ph <4 for more than 1 h during the nocturnal period was comparable during both of the baseline recordings. The proportion of subjects with NAB was lower at steady-state on tenatoprazole (n = 19) than on esomeprazole (n = 27) (73.1% vs 93.1%, p = 0.06), although the difference was not statistically significant. Mean duration of NAB was shorter on tenatoprazole than on esomeprazole (day 7, 4.3 vs 6.5 h, p < ; day 10, 9.3 vs 10.1 h, p = 0.05; and day 12, 10.1 vs 11.0 h, p = 0.03). Serum Gastrin Integrated mean baseline gastrin levels were 39.8 ± 9.5 pg/ml and 40.1 ± 10.1 pg/ml in the tenatoprazole and esomeprazole groups, respectively. After a transient increase at day 7 (70.1 ± 33.4 vs 60.0 ± 28.8 pg/ml, 76.0% with tenatoprazole and 50.0% with esomeprazole compared to baseline, respectively), mean serum gastrin values returned rapidly to baseline levels at day 10 (52.0 ± 29.6 pg/ml and 44.7 ± 9.7 pg/ml, respectively), then day 13 (43.5 ± 9.9 pg/ml and 43.9 ± 10.6 pg/ml, respectively). Pharmacokinetics After 7-days repeated dosing (Table 3, Fig. 3), mean plasma concentration of tenatoprazole was higher compared to esomeprazole (mean AUC t 102,887 ± 82,113 ng h/ml vs 3,374 ± 1,293 ng h/ml). As a consequence, the maximal concentration of tenatoprazole was almost six times higher than that of esomeprazole (7, ± 1, ng/ml vs 1, ± ng/ml). The mean concentrations of tenatoprazole were ± ng/ml at day 9, ± ng/ml at day 10, ± ng/ml at day 11, and ± ng/ml at day 12, whereas they were no longer detectable 12 h after esomeprazole. The presence of these sustained concentrations of tenatoprazole was explained by the longer half-life of tenatoprazole when compared to that of esomeprazole (t 1/2 = 9.28 ± 6.41 h vs 1.44 ± 0.29 h). A significant correlation with tenatoprazole between AUC and percentage of time intragastric ph >4 was Table 2. Intragastric 24-h ph at Day 7 Tenatoprazole Esomeprazole Overall p Value Mean ph ± SD 4.86 ± ± Daytime 5.05 ± ± Night-time 4.64 ± ± 0.90 < Median ph (min, max) 5.02 (2.34, 5.82) 4.79 (2.52, 5.84) Mean% time ph > ± ± < Daytime ± ± Night time ± ± < Median% time ph >3 (min, max) (38.20, 99.65) (39.87, 93.32) Mean% time ph > ± ± < Daytime ± ± Night-time ± ± < Median% time ph >4 (min, max) 71.63(26.00, 97.49) 64.04(22.43, 87.84) SD = standard deviation.

5 Effect on Intragastric ph of a PPI with a Prolonged Plasma Half-Life 1953 ph Tenatoprazole 40mg ph=4 Esomeprazole 40mg h 10h 12h 14h 16h 18h 20h 22h 24h 2h 4h 6h 8h Hours Figure 1. Time course of ph fluctuations [average (mean) of 30 subjects] on day 7. observed, not only at day 7 but also, and significantly, at day 10 and 12. A significant correlation between AUC and percentage of time with ph >4 was only observed for day 7 with esomeprazole. Safety Both drugs were well tolerated. No serious adverse events were reported during and after the study. A total of 18 minor adverse events were considered possibly related to treatment (10 with tenatoprazole vs 8 with esomeprazole). The most frequent adverse event was headache, which was reported in 7 patients (4 with tenatoprazole vs 3 with esomeprazole). No clinically significant mean changes from baseline were observed for physical examination, routine laboratory assessments, and ECG, which remained normal during the study period, nor were such changes significantly different between dosing groups. DISCUSSION Our study extends the initial observations of Galmiche and colleagues s 7-day study (12), in which tenatoprazole 40 mg produced similar acid suppression to esomeprazole 40 mg during the daytime period, but was more effective than esomeprazole 40 mg with a significantly greater increase in intragastric ph for the whole 24-h period and for the nocturnal period (12). These differences are attributable, to the significantly longer t 1/2 and AUC of tenatoprazole compared with esomeprazole, and may be clinically relevant as the antisecretory effect of PPIs is generally acknowledged to be proportional to the AUC (6). In our study, pharmacokinetic data indicate that tenatoprazole 40 mg produces much higher initial drug levels and a greater AUC than esomeprazole, with detectable drug up to 120 h after administration. For tenatoprazole, the high AUC led to a prolonged effect at night-time, despite the fact that the effect during the day was similar to that seen with esomeprazole. These differences in pharmacokinetics are probably also responsible for our finding of a difference between tenatoprazole 40 mg and esomeprazole 40 mg on day 3 and day 5 after stopping treatment. This suggests that there is a plateau effect for PPIs, with an apparently maximum achievable ph, and that differences are related more to a prolonged presence of drug to block new pumps as they are synthesized. Recent work indicates that the pka of PPIs differs for activation in the secretory canaliculus and for binding to the proton pump (9). The currently available PPIs are substituted imidazoles, which are prodrugs with a two-stage protonation occurring in the secretory canaliculus. The first traps the imidazole compound in the canaliculus of the parietal cell and the second transforms the drug to the active sulfenamide which binds covalently to the H + K + ATPase. Thus, it has been suggested that when the ATPase is blocked, the secretory canaliculus is no longer acidic enough to trap the PPI and effect of the PPI is reduced. It is likely that this is the case both for a PPI with a prolonged plasma half-life and for a PPI given in multiple daily doses or by intravenous infusion. Further studies are required to define the relationships between drug concentrations in the plasma and in the secretory canaliculus, the rate of new pump synthesis and blockade and subsequent effect on intragastric acidity. Tenatoprazole exhibited a 6.4-fold longer half-life than esomeprazole in this study, which is consistent with its 5 7-fold longer half-life than the other PPIs in healthy subjects (11). The different chemical structure of tenatoprazole, which consists of one imidazopyridine ring, compared with other PPIs, which are all substituted benzimidazoles, may result in different interactions with the H + /K + -ATPase binding site, and contribute to the potent and long-lasting effects. The prolonged effect of tenatoprazole suggests that it may provide control of nocturnal symptoms with a single dose. Thus, tenatoprazole may act as a once daily PPI in a high proportion of patients and produce, improved control of night-time symptoms. As we have shown, there are fewer

6 1954 Hunt et al. Mean ph A. Mean 24 hours ph, diurnal and nocturnal ph at day 7 for tenatopraozole and esomeprazole Tenatoprazole Esomeprazole P< '24hours Diurnal Nocturnal B. Percentage of time in 24 hours, diurnal and nocturnal time ph>4 at day 7 of tenatoprazole and esomeprazole. Percentage time of ph >4 (%) P< Tenatoprazole Esomeprazole P< '24hours Diurnal Nocturnal Figure 2. Intragastric ph at day 7 of tenatoprazole and esomeprazole. (A) Mean 24-h ph, diurnal and nocturnal ph at day 7 for tenatoprazole and esomeprazole. (B) Percentage of time in 24-hpH, diurnal and nocturnal time ph >4 at day 7 of tenatoprazole and esomeprazole. night-time episodes with potential for acid breakthrough. NAB is defined strictly as the occurrence of intragastric ph <4 for at least 1 h during the night-time in patients taking a PPI twice daily and its clinical significance is widely debated (13). Tenatoprazole was associated with fewer subjects with NAB than was esomeprazole and the duration of acid breakthrough was significantly shorter with tenatoprazole than esomeprazole on day 7 and day 12. The potential benefit for once daily tenatoprazole in patients with NAB, and the clinical relevance of this finding remains to be assessed in comparison with twice daily PPI therapy. Any failure in PPI effectiveness is usually related to the duration of effect. The clinical effect is related to the degree of Table 3. Pharmacokinetics of Tenatoprazole and Esomeprazole Tenatoprazole Esomeprazole Mean AUC t (ng h/ml) 102,887 ± 82,113 3,374 ± 1,293 AUC (ng h/ml) 110,618 ± 94,950 3,458 ± 1,305 C max (ng/ml) 7, ± 1, , ± T max (h) 1.7 ± ± 0.9 t 1/2 (h) 9.28 ± ± 0.29 acid suppression and time with ph >4 (1 4). The ph profiles observed in our study predict that a PPI with these characteristics would be very effective but the results of intragastric ph studies need to be confirmed in clinical trials. Integrated acidity correlates with the grade of esophagitis (14), and the ability to control acid effectively over the whole 24-h period offers the promise of better prevention of GERD complications, such as stricture and Barrett s esophagus (BE). PPIs are important in the management of BE (15 17) and reduce the rate of progression of dysplasia in BE (18, 19). In patients with endoscopy negative reflux disease, the increased acid suppression produced by esomeprazole 40 and 20 mg, compared with omeprazole 20 mg daily, did not produce any incremental benefit in symptom resolution (20), but PPIs producing greater or more prolonged acid suppression may still be beneficial for on demand and intermittent therapy because the prolonged t 1/2 and acid suppression effect after stopping therapy, and also, perhaps, for patients with poor compliance. Treatment with PPIs results in higher healing rates than H 2 -RAs for peptic ulcer (21) although there are few recent data on the use of PPIs for peptic ulcer disease. PPIs produce higher healing rates than H 2 -RAs in NSAID-associated gastric and duodenal ulcer (22, 23) and are likely to give more rapid healing although no studies have reported on this to date. In a pooled evidence-based analysis, compared to patients using NSAIDs who were given placebo, 12 fewer such patients out of every 100 treated with esomeprazole 20 and 40 mg developed an ulcer, for every 8 or 9 patients treated with esomeprazole, one ulcer per 6 months is avoided (24). However, there may also be a ceiling effect for acid suppression in the management of NSAID-related ulcers as there was no significant difference between the two doses of esomeprazole in this study (24) or between omeprazole 20 mg and omeprazole 40 mg daily in ulcer healing (22, 25). Moreover, because these studies were conducted with once daily PPIs, it is still possible that there may be incremental benefit from the use of a PPI, such as tenatoprazole, which has a more prolonged effect on acid suppression. There are several mechanisms whereby PPIs might enhance the efficacy of antibiotic therapy for the eradication of H. pylori infection. In addition to their inhibitory effect on acid secretion, PPIs exert direct anti-h. pylori activity in vitro (26, 27) although this has not been studied for tenatoprazole. However, the prolonged effect of tenatoprazole may augment those effects of PPIs which are related specifically to their anti-secretory actions. For example, PPIs stabilize acid labile antibiotics and increase their bioavailability in the stomach (28). Moreover, elevation of intragastric ph allows H. pylori to reach its growth phase and thus become more sensitive to antibiotics (29). Suppression of acid secretion by a PPI increases the concentration of an antibiotic such as amoxicillin in the stomach (30) and the plasma concentrations of both a PPI and clarithromycin are increased when they are co-administered, as a result of a cytochrome P450-mediated drug drug interaction and perhaps as a result of other unknown mechanisms (31 33).

7 Effect on Intragastric ph of a PPI with a Prolonged Plasma Half-Life MEAN AND SD PLASMA CONCENTRATION 1000 Log concentration Tenatoprazole Esomeprazole Time (h) Figure 3. Mean plasma concentrations of tenatoprazole and esomeprazole (logarithmical coordinates). The plasma t 1/2 of PPIs is considered important for management of upper GI bleeding, which has traditionally required IV infusions to maintain drug levels for prolonged periods. There are potential benefits for an oral PPI with a long plasma half-life for patients with upper GI bleeding since they have already been used for those with a clean ulcer base (no stigmata) (34). Acute use of PPIs may be associated with a reduction in rebleeding overall and even in patients with high-risk stigmata (35). An oral PPI effecting greater acid suppression can also produce greater acid suppression than a PPI given by intravenous infusion (36). Therefore, a drug such as tenatoprazole with superior anti-secretory effect and a long duration of action might become a drug of choice for patients and, if this proves to be the case in clinical practice, it might lead to a decreased length of hospital stay for patients with uncomplicated upper GI hemorrhage. All the available PPIs are extensively metabolized in the liver by the cytochrome P450 isoenzymes. Homozygous poor metabolizers and heterozygous extensive metabolizers show greater acid inhibition and higher H. pylori eradication rates compared to homozygous extensive metabolizers of PPIs (37). Genotyping for CYP2C19 was undertaken with a view to excluding homozygous poor metabolizers but no poor metabolizers were identified in our study and we are not, therefore, able to comment on the effect of metabolizer status. Gastrin levels after 7 days were numerically, but not statistically higher with tenatoprazole than with esomeprazole and all gastrin levels were within the normal range. This is not surprising given that the subjects were all H. pylori negative and that they received only short-term therapy. Both drugs were equally safe in this short-term study and no serious adverse events were observed. In conclusion, we have confirmed the prolonged effect of tenatoprazole, even after stopping treatment. No adverse events were seen. Tenatoprazole promises greater clinical efficacy, particularly for patients in whom once daily PPI is ineffective and in whom on-demand treatment is indicated. However, appropriate studies are needed to test these hypotheses in appropriate clinical settings. ACKNOWLEDGMENTS We thank Douglas Bair, M.D., F.R.C.P.C., for his assistance with this study. This research was funded and supported by Negma-Lerads, France. Reprint requests and correspondence: Richard Hunt, Division of Gastroenterology, Room HSC: 4W8A, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada, L8N 3Z5. Received December 14, 2004; accepted March 8, REFERENCES 1. Jones DB, Howden CW, Burget DW, et al. Acid suppression in duodenal ulcer: A meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987;28: Howden CW, Jones DB, Peace KE, et al. The treatment of gastric ulcer with antisecretory drugs. Relationship of pharmacological effect to healing rates. Dig Dis Sci 1988;33: 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: Bell NJ, Hunt RH. Role of gastric acid suppression in the treatment of gastro-oesophageal reflux disease. Gut 1992;33: Hunt RH, Cederberg C, Dent J, et al. Optimizing acid suppression for treatment of acid-related diseases. Dig Dis Sci 1995;40(2 suppl):24s 49S.

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