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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Background:

Integrated gastric and oesophageal acidity can be calculated from measurements of gastric and oesophageal pH and used to quantify gastric and oesophageal acidity over time. Rabeprazole is a new proton pump inhibitor that is effective in treating gastro-oesophageal reflux disease (GERD).

Aim:

To use measurement of integrated gastric and oesophageal acidity to determine the onset, duration and overall effect of rabeprazole in subjects with GERD.

Methods:

Subjects with GERD were required to have oesophageal pH ≤ 4 for at least 10% of a 24-h recording. Effects of 20 mg rabeprazole on 24-h gastric and oesophageal pH were measured on days 1 and 7 of dosing. Integrated gastric and oesophageal acidity were calculated from time-weighted average hydrogen ion concentrations at each second of the 24-h record.

Results:

At steady-state, 20 mg rabeprazole inhibited gastric acidity by 89% and oesophageal acidity by 95%. The first dose of rabeprazole inhibited gastric and oesophageal acidity by at least 70% of the steady-state effect. Oesophageal acidity could be divided into monophasic and biphasic patterns, and rabeprazole had different effects on oesophageal and gastric acidity in these two GERD subpopulations. The onset of action of the first dose of rabeprazole on gastric acidity was 4 h and on oesophageal acidity was 4 h in monophasic subjects and 7 h in biphasic subjects. Integrated acidity was more sensitive than time pH ≤ 4 in measuring the inhibitory actions of rabeprazole.

Conclusions:

Integrated gastric and oesophageal acidity are quantitative measurements that provide useful and novel information regarding the pathophysiology of GERD as well as the impact of antisecretory agents such as rabeprazole.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Use of continuous pH recordings has become the cornerstone for assessment of gastro-oesophageal reflux disease (GERD) and its treatment with antisecretory agents.1–9 Despite the fact that pH recordings involve about 900 measurements per hour, these data are frequently collapsed to a single value, such as the percentage of the recording period that pH < 4 or median pH for a particular recording period. It seems likely that fuller use of all available data from pH recordings should provide better definition of acidity and the differential effects of specific pharmacologic agents.

Previously,10 we calculated values for integrated gastric and oesophageal acidity from 24-h pH recordings performed in the conventional manner. Values that resulted from these calculations fully quantified oesophageal and gastric acidity, in contrast to conventional measurements of the percentage of time that the pH is below a particular value, which only partially quantified oesophageal or gastric acidity. As a result, values for integrated acidity were used to examine quantitative relationships between oesophageal acidity and gastric acidity. In addition, calculating integrated acidity made it possible to assess changes in acidity over time in a simple, straight-forward manner. These changes were then used to distinguish different pathophysiologic types of GERD based on patterns for integrated oesophageal acidity. We have also found that integrated acidity can be useful in determining the onset and duration of action of antacids and histamine H2-receptor antagonists on gastric and oesophageal acidity in subjects with recurrent heartburn.11

In the present study, we used measures of integrated acidity to characterize effects of rabeprazole, a new proton pump inhibitor, on oesophageal and gastric acidity in subjects with GERD and to compare assessments based on integrated acidity with those that utilize the conventional measure of percentage time pH ≤ 4 or some other cutoff value.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

This study was approved by and conducted in compliance with good clinical practices as supervised by the Western Institutional Review Board, Olympia, WA. All subjects enrolled in this study gave written informed consent.

Subjects

Subjects were 15 males and five females, aged 24–61 years, with clinical GERD, and oesophageal pH ≤ 4 for at least 10% of a 24-h recording period during baseline screening. Subjects were not tested for Helicobacter pylori infection. Subjects could not have been treated with a histamine H2-receptor antagonist, sucralfate or a prostaglandin analogue within 3 days, with omeprazole or bismuth subsalicylate within 7 days, or with an investigational drug within 30 days prior to study entry. Subjects were also excluded if they had deep oesophageal ulcers, oesophageal stricture, gastric ulcers or duodenal ulcers within 6 months prior to study entry, previous gastric or oesophageal surgery, pyloric stenosis or been treated for cancer other than basal cell skin cancer. Analyses of baseline recordings from these subjects have been reported previously.10

Study design

The study was conducted at the Oklahoma Foundation for Digestive Research on the campus of the University of Oklahoma Health Sciences Center and was a randomized, double-blind, two-way crossover evaluation of the effects of 20 mg and 40 mg rabeprazole on 24-h gastric and oesophageal pH. Data for 24-h gastric and oesophageal pH were acquired at baseline and then on days 1, 7 and 8 of dosing with either 20 mg or 40 mg rabeprazole for 7 days and again, at baseline and then on days 1, 7 and 8 of dosing with the alternate dose of rabeprazole. Three to 5 days elapsed between the baseline evaluation and the first dose of rabeprazole. The recordings on day 8 represented measurements from hours 24 through 48 following the last dose of rabeprazole on day 7. Subjects then underwent a 7–10 day washout period, a second baseline 24-h pH recording, and 3–5 days later, 7 days of dosing with the alternate dose of rabeprazole with 24-h pH recordings on days 1, 7 and 8.

Subjects fasted from approximately 22:00 hours the evening before until the beginning of pH recording the following morning, usually at 8:00 hours. Study medication was taken in the morning before breakfast at approximately 8:00 hours. Subjects remained in the study centre for the 24-h recording sessions and were given three defined meals during the pH recording periods. Breakfast was provided at 9:00–9:30 hours, lunch at 13:00–14:00 hours and dinner at 18:00–19:00 hours during the baseline period and on days 1, 7 and 8. Subjects spent the night supine in bed. Smoking and eating or drinking between meals were prohibited during pH recording periods. Gastric antisecretory medications other than study medication were prohibited for the duration of the study. Antacids were permitted as needed for relief of symptoms throughout the study, except during the pH recording periods.

Gastric and oesophageal pH data were collected using an ambulatory, disposable, dual channel pH recording system (Medtronic Synectics, Shoreview, MN, USA) with antimony electrodes. One electrode was placed in the stomach 10 cm below and the second was placed in the oesophagus 5 cm above the manometrically defined upper border of the lower oesophageal sphincter. Electrodes were calibrated to pH 1 and 7 using solutions composed of pH 1.07, 59 mM KNO3, 27 mM KCl and pH 7.01, 16.5 mM Tris buffer, 40 mM KNO3, 96 mM KCl. Data were collected using a portable data storage unit (Digitrapper, Medtronic Synectics). Recordings usually began at 8:00 hours and continued for 24 h. Values for intragastric and intraesophageal pH were recorded every 4 s. Data were transferred from the portable data storage unit and processed in DOS mode using software designed for pH recordings (Polygram for Windows, Version 2.04, Medtronic Synectics). The software adjusts all pH values for the difference between the temperature at which the electrodes were calibrated (25 °C) and the recording temperature (37 °C).

Although we refer to the current measurements as acid `concentration', the pH electrode actually measures hydrogen ion `activity'. Others have documented the extent to which hydrogen ion concentration can differ from hydrogen ion activity, particularly in the presence of other ions, and have developed methods to adjust hydrogen ion activity to hydrogen ion concentration.12, 13 We calibrated the electrodes to pH 1 and 7 using polyelectrolyte solutions provided by the manufacturer, which results in measured hydrogen ion activity more closely approximating the hydrogen ion concentration. We have not adjusted the measured hydrogen ion activity.

Analytical procedures

Polygram software calculates values for conventional indices of oesophageal and gastric pH recordings, e.g. number of oesophageal reflux episodes, number of reflux episodes > 5 min, percentage of the recording period that the oesophageal pH was < 4, and percentage of the recording period that the gastric pH was < 4. Polygram software also takes the individual pH values that are recorded every 4 s and fills in the same value for the other 3 s resulting in one value for every second of the recording period for each electrode. These pH data for one-second intervals were used to calculate integrated acidity.

Data from subjects treated with 40 mg rabeprazole were not analysed for the present report, because results with 20 mg rabeprazole illustrate the major findings from this study. Dual-channel recordings from both baseline periods, and day 1 and day 7 of dosing with 20 mg rabeprazole were analysed from each of 20 subjects (80 records). Recordings from day 8 were not analysed, because we wanted to focus on the onset of action and steady-state effects of rabeprazole instead of its actions that occur on the day after dosing is stopped. One subject had technically unsatisfactory baseline recordings resulting from a malfunctioning gastric electrode, and data from this subject were omitted from the analyses.

Integrated gastric and oesophageal acidity were calculated for each second of the recording period as follows:

1 Acid concentration (mM)=1000 × 10–pH.

2 Acidity (mmol.h/L) = (acid in mM at time `t' + acid in mM at time `t – 1')/2 × (t – t – 1).

3 Values for acidity were summed cumulatively for every second.

4 Integrated acidity is expressed as mM × time, i.e. mmol.h/L.

5 In the present study, values for integrated acidity were analysed for each hour of the 24-h recording period.

This calculation of integrated acidity has been referred to as `mean weighted acidity' by others.14

The values for integrated acidity at any given time indicate the cumulative integrated acidity up to that point in time, and the mean acid concentration up to that point in time can be calculated by dividing the value for integrated acidity by the corresponding recording time. For example, the mean gastric acid concentration for hours 8:00–24:00 can be calculated by dividing the value for integrated gastric acidity at 24:00 hours by 16.

Mean acid concentration for each hour was calculated as integrated acidity at time `t' minus integrated acidity at time `t – 1'. The resulting value represents the mean acid concentration for the hour indicated.

Values are displayed in relation to a 24-h clock with 8:00 hours as the beginning of the recording period.

Baseline values for integrated acidity for each subject were represented by the mean of values from the two baseline recordings. Similarly, baseline values for conventional indices for each subject were also represented by the mean of values from the two baseline recordings. Of the 38 technically satisfactory baseline records, 34 were for 24 h, three were for 23 h and one was for 22 h. Of the 38 technically satisfactory records with 20 mg rabeprazole, 36 were for 24 h, one was for 23 h and one was for 22 h. When a record was less than 24 h, the last calculated value was carried forward.

Statistical analyses were performed using Microsoft Excel 97 or GraphPad for InStat version 3.01 for Windows software. As will be shown later in Figure 1, values from different subjects for integrated gastric and oesophageal acidity as well as for time gastric and oesophageal pH ≤ 4 were not normally distributed, therefore median values are presented. Results were analysed using the Mann–Whitney test or the Wilcoxon matched pairs test.

image

Figure 1. . Distribution of values for time oesophageal and gastric pH ≤ 4 (left panel) and for integrated oesophageal and gastric acidity (right panel). Observed values for the 24-h recording period are given on the vertical axis, and values calculated for the normal distribution are given on the horizontal axis. The diagonal line is the identity line for the normal distribution. If the distribution of observed values is normal, all points will lie on the diagonal line. Values given are from 19 subjects.

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RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

Determining the time that gastric or oesophageal pH is ≤ 4 is used frequently to assess gastric and oesophageal acidity.1–9Figure 1 left panel illustrates the distributions of values for times that oesophageal and gastric pH were ≤ 4. Compared to the normal Gaussian distribution, both distributions were skewed.15 With oesophageal pH time, the distribution was skewed toward high values, whereas with gastric pH time, the distribution was skewed toward both low and high values. Figure 1 right panel illustrates that that the distributions for integrated gastric and oesophageal acidity were both skewed toward high values and the oesophageal values were more skewed than the gastric values. Because of the distributions illustrated in Figure 1, we analysed results in the present study using nonparametric statistical tests. The results illustrated in Figure 1 can be calculated using the procedures described in Chapter 2 of reference 15 and the normal distribution function in Microsoft Excel.

Previously, we reported that subjects with GERD could be divided into two groups based on their pattern of integrated oesophageal acidity.10 This classification was consistent with the different patterns of oesophageal acidity that had been described previously.16–18 Subjects with a monophasic pattern reached 50% of maximal integrated oesophageal acidity at 17:00 hours, whereas those with a biphasic pattern reached 50% of maximal integrated oesophageal acidity at 1:00 hours. Figure 2 illustrates values for integrated gastric acidity after the first and seventh doses of 20 mg rabeprazole in monophasic and biphasic subjects. In both groups, the first dose of rabeprazole caused a significant decrease in integrated gastric acidity from 14:00 hours until the end of the recording period, and integrated gastric acidity was decreased further after the seventh dose of rabeprazole.

image

Figure 2. . Effect of 20 mg rabeprazole on integrated gastric acidity in monophasic (left panel) and biphasic (right panel) GERD after 1 and 7 days of dosing. Values given are medians from 12 subjects with a monophasic pattern for oesophageal acidity and seven subjects with a biphasic pattern for oesophageal acidity. The closed circles at the top of the panel indicate the times at which values on the first day of dosing are significantly different from corresponding baseline values (P < 0.05).

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As illustrated in Figure 3, in both monophasic and biphasic subjects, the baseline mean gastric acid concentration had a triphasic pattern that correlated with ingestion of three meals during the 24-h baseline period. For example, after breakfast at 9:00 hours, mean acid concentration increased progressively until 13:00 hours when subjects ate lunch. After the beginning of lunch, mean acid concentration decreased over the next 2 h as a result of meal-related buffering effects on gastric acidity, and then increased to another peak when subjects ate dinner at 18:00 hours. After dinner, mean acid concentration again decreased to a nadir and then increased to a prominent third peak at 2:00–4:00 hours. Mean acid concentration then decreased progressively, in this case without ingestion of a meal. Figure 3 left panel illustrates that in subjects with monophasic GERD, the first dose of 20 mg rabeprazole decreased mean gastric acid concentrations over much of the recording period, and nearly abolished the triphasic pattern. Figure 3 right panel illustrates that in subjects with biphasic GERD, the first dose of 20 mg rabeprazole also decreased mean gastric acid concentrations over much of the recording period, but did not abolish the nocturnal increase. The results in Figure 3 also illustrate that calculating integrated gastric acidity makes it possible to distinguish a clear difference in the action of rabeprazole on gastric acidity in different types of GERD. The onset of action of the first dose of rabeprazole, defined as the earliest time that the mean gastric acid concentration was significantly less than the corresponding baseline concentration, was 4 h after dosing when results from all subjects combined were analysed. The duration of action of a single 20 mg dose of rabeprazole on gastric acidity was 24 h.

image

Figure 3. . Effect of 20 mg rabeprazole on mean gastric acid concentration in monophasic (left panel) and biphasic (right panel) GERD after 1 day of dosing. Values given are medians from 12 subjects with a monophasic pattern for oesophageal acidity and seven subjects with a biphasic pattern for oesophageal acidity. The closed circles at the top of the panel indicate the times at which values on the first day of dosing are significantly different from corresponding baseline values (P < 0.05).

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Figure 4 illustrates values for integrated oesophageal acidity after the first and seventh doses of 20 mg rabeprazole in monophasic and biphasic subjects. In monophasic subjects, the first dose of rabeprazole caused a significant decrease in integrated oesophageal acidity from 13:00 hours until the end of the recording period. In contrast, in biphasic subjects, the first dose of rabeprazole did not cause a significant decrease in integrated oesophageal acidity until 24:00 hours and this decrease persisted until the end of the recording period. In monophasic subjects, the seventh dose of rabeprazole produced a further decrease in integrated oesophageal acidity during the period 8:00–14:00 hours. In biphasic subjects, the seventh dose of rabeprazole produced a further decrease in integrated oesophageal acidity over the entire 24-h period.

image

Figure 4. . Effect of 20 mg rabeprazole on integrated oesophageal acidity in monophasic (left panel) and biphasic (right panel) GERD after 1 and 7 days of dosing. Values given are medians from 12 subjects with a monophasic pattern for oesophageal acidity and seven subjects with a biphasic pattern for oesophageal acidity. The closed circles at the top of the panel indicate the times at which values on the first day of dosing are significantly different from corresponding baseline values (P < 0.05).

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It is important to note that the vertical scale in the right panel in Figure 4 is five times greater than that in the left panel. Thus, the first dose of rabeprazole failed to produce a significant decrease in integrated oesophageal acidity in biphasic subjects during the times that their values were comparable to those in monophasic subjects that were significantly decreased by rabeprazole. This lack of effect of rabeprazole in biphasic subjects during hours 13:00–23:00 was not attributable to a lack of effect of rabeprazole on gastric acidity, because as illustrated in Figure 2, gastric acidity following the first dose of rabeprazole in biphasic subjects was lower than that in monophasic subjects.

Table 1 summarizes values for percentage inhibition of 24-h integrated gastric and oesophageal acidity with the first and seventh doses of rabeprazole. Inhibition of gastric acidity with the first dose was 72% and 70%, and with the seventh dose was 93% and 84% in monophasic and biphasic subjects, respectively. Assuming that the inhibition with the seventh dose of rabeprazole represents steady-state inhibition, inhibition of gastric acidity with the first dose of rabeprazole was 83% and 86% of the steady-state inhibition in monophasic and biphasic subjects, respectively (Table 1). There were no significant differences between monophasic and biphasic subjects in terms of rabeprazole inhibition of 24-h integrated gastric acidity with the first dose, the seventh dose or at the steady-state (Table 1). In contrast to gastric acidity, inhibition of oesophageal acidity with both the first and seventh doses of rabeprazole was significantly higher in biphasic subjects than in monophasic subjects. Inhibition of oesophageal acidity with the first dose of rabeprazole as a percentage of the steady-state inhibition in monophasic subjects was not significantly different from that in biphasic subjects (Table 1). Also, there were no significant differences between inhibition of oesophageal and gastric acidity for either group for any dose.

Table 1.  . Inhibition of 24-h integrated acidity by the first and seventh doses of the 20 mg rabeprazole in subjects with monophasic and biphasic GERD Thumbnail image of

As illustrated in Figure 5, in both monophasic and biphasic subjects, the baseline mean oesophageal acid concentration had a triphasic pattern that correlated with the pattern for mean gastric acid concentration. As might be expected from the episodic nature of oesophageal acid exposure, there was substantial variation among subjects for mean oesophageal acid concentration at any particular time. Biphasic, but not monophasic subjects had a prominent nocturnal increase in mean oesophageal acid concentrations that correlated with the prominent nocturnal increase in mean gastric acid concentrations. Figure 5 left panel illustrates that in subjects with monophasic GERD, the first dose of 20 mg rabeprazole decreased mean oesophageal acid concentrations from 12:00 to 1:00 hours. Figure 5 right panel illustrates that in subjects with biphasic GERD, the first dose of 20 mg rabeprazole decreased mean oesophageal acid concentrations from 15:00 to 3:00 hours. Interestingly, the first dose of rabeprazole abolished the nocturnal increase in the mean oesophageal acid concentration in biphasic subjects even though there was a persistent increase in mean gastric acid concentration. The results in Figures 3 and 5 illustrate that calculating integrated acidity makes it possible to distinguish a clear difference between the action of rabeprazole on gastric acidity and oesophageal acidity in biphasic subjects. The onset of action of the first dose of rabeprazole, defined as the earliest time that the mean oesophageal acid concentration was significantly less than the corresponding baseline concentration, was 4 h after dosing for monophasic subjects and 7 h after dosing for biphasic subjects (Figure 5).

image

Figure 5. . Effect of 20 mg rabeprazole on mean oesophageal acid concentration in monophasic (left panel) and biphasic (right panel) GERD after 1 day of dosing. Values given are medians from 12 subjects with a monophasic pattern for oesophageal acidity and seven subjects with a biphasic pattern for oesophageal acidity. The closed circles at the top of the panel indicate the times at which values on the first day of dosing are significantly different from corresponding baseline values (P < 0.05).

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Determining the time that gastric or oesophageal pH ≤ 4 is used frequently to assess gastric and oesophageal acidity,1–9 therefore we compared these parameters to values for 24-h integrated acidity in terms of measuring the inhibitory action of the first dose of rabeprazole. Figure 6 left panel plots inhibition of gastric acidity determined from values for 24-h integrated gastric acidity vs. corresponding values determined from time gastric pH ≤ 4. In 16 of 18 subjects, the magnitude of inhibition assessed by integrated acidity was higher than that assessed by time pH ≤ 4. Thus, 24-h integrated gastric acidity is significantly more sensitive than time gastric pH ≤ 4 in assessing the effect of rabeprazole on gastric acidity. Figure 6 right panel displays modified box plots15 of values for inhibition of integrated gastric acidity and corresponding values obtained using different pH cutoff values for time gastric pH was less than a particular value. Median values using pH cutoffs of 2, 3 and 4, but not 1, were lower than the median value for integrated gastric acidity.

image

Figure 6. . Comparison of the inhibitory effect of 20 mg rabeprazole on gastric acidity assessed by different parameters. The left panel compares values for inhibition of integrated gastric acidity with corresponding values for inhibition of time gastric pH ≤ 4. Each point represents two values from a single subject. The diagonal line is the identity line for values on the horizontal axis. The difference between the two values is given by the vertical or horizontal distance from the diagonal line. Values above the diagonal line indicate that inhibition is greater with integrated acidity than with time pH ≤ 4, and values below the line indicate the opposite. Values with integrated acidity were significantly greater than those with time pH ≤ 4 (P=0.0116). The right panel is a modified box plot of inhibition with different pH cutoffs and integrated acidity. Solid symbols give medians; asterisks give minimum and maximum values; and horizontal bars give the 1st and 3rd quartiles. Values given are from 18 subjects for the 24-h recording period. Results from one subject were omitted because of very large negative values with pH time.

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Figure 7 left panel plots inhibition of oesophageal acidity determined from values for 24-h integrated oesophageal acidity vs. corresponding values determined from time oesophageal pH ≤ 4, and illustrates that 24-h integrated oesophageal acidity is significantly more sensitive than time oesophageal pH ≤ 4 in assessing the effect of rabeprazole on oesophageal acidity. Figure 6 right panel displays modified box plots of values for inhibition of integrated oesophageal acidity and corresponding values obtained using different pH cutoff values for time oesophageal pH was less than a particular value. Median values using pH cutoffs of 3, 4, 5 and 6 were lower than the median value for integrated oesophageal acidity.

image

Figure 7. . Comparison of the inhibitory effect of 20 mg rabeprazole on oesophageal acidity assessed by different parameters. The left panel compares values for inhibition of integrated oesophageal acidity with corresponding values for inhibition of time oesophageal pH ≤ 4. Each point represents two values from a single subject. The diagonal line is the identity line for values on the horizontal axis. The difference between the two values is given by the vertical or horizontal distance from the diagonal line. Values above the diagonal line indicate that inhibition is greater with integrated acidity than with time pH ≤ 4, and values below the line indicate the opposite. Values with integrated acidity were significantly greater than those with time pH ≤ 4 (P=0.018). The right panel is a modified box plot of inhibition with different pH cutoffs and integrated acidity. Solid symbols give medians; asterisks give minimum and maximum values; and horizontal bars give the 1st and 3rd quartiles. Values given are from 17 subjects for the 24-h recording period. Results from two subjects were omitted because of very large negative values with pH time.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

The present results illustrate that measurements of integrated acidity can provide particularly useful information regarding the actions of gastric antisecretory agents. These measurements can be used to assess the onset, duration, and overall effects of a drug on gastric and oesophageal acidity. In the present study, we found that the onset of action of rabeprazole on gastric acidity was 4 h, and on oesophageal acidity was 4 h in monophasic subjects and 7 h in biphasic subjects. The duration of action on gastric acidity was 24 h. In addition, the effect of the first dose of 20 mg rabeprazole on integrated gastric acidity was 83% (biphasic subjects) and 86% (monophasic subjects) of the corresponding effect on day 7 of dosing. There was also a substantial effect of the first dose of 20 mg rabeprazole on oesophageal acidity in that the effect of rabeprazole on integrated oesophageal acidity was 76% of the corresponding effect on day 7 of dosing in monophasic subjects and 100% in biphasic subjects. The finding that the first dose of rabeprazole produced full steady-state inhibition of integrated oesophageal acidity in subjects with biphasic GERD was not anticipated, because biphasic subjects had significantly higher baseline oesophageal acid exposure than monophasic subjects. These findings probably reflect differences between subjects with monophasic GERD and those with biphasic GERD with respect to their responses to proton pump inhibitors.

Other studies have used measurements of gastric pH determined with a pH electrode1, 5, 8 or by aspirating a sample of gastric contents19 to assess effects of gastric antisecretory agents on gastric acidity. The results have usually been expressed in terms of percentage of the recording time that gastric pH was above a particular value or median (or mean) gastric pH over different periods during the 24-h study. Onset of action has frequently been reported as the earliest period during which values with active treatment were significantly different from placebo (e.g. 8). The studies that have measured pH on samples of aspirated gastric fluid have also reported values for the area under the time–gastric acid concentration curve (e.g. 19), and our calculations of integrated acidity are conceptually the same as these measurements. The main difference between integrated acidity as determined in the present study and the AUC gastric acid concentration is the duration of the integration interval.

Assessing the onset of action of an antisecretory agent by measuring gastric acid secretion is limited by the need to allow absorption of the drug before beginning aspiration or intragastric titration and the relative insensitivity of measurements of acid secretion. For example, one study that measured the antisecretory actions of 15 mg and 30 mg of lansoprazole and 20 mg and 40 mg omeprazole in 10 healthy subjects using intragastric titration failed to detect a significant antisecretory effect of either agent assessed at 4, 10, 16 and 24 h after the first dose.20 In contrast, assessments of the gastric antisecretory actions of lansoprazole and omeprazole measuring gastric pH have demonstrated significant effects within several hours after the first dose.8, 19, 21, 22

Previously,10 we systematically compared values for integrated oesophageal and gastric acidity to values from conventional assessments of the same data using different pH cutoff values. These comparisons showed that integrated acidity has several advantages over the conventional indices in that integrated acidity fully quantifies acidity with a single value. In contrast, conventional indices only partially quantify acidity, require two numbers to estimate acidity, employ arbitrary pH cutoff values, and a result using one pH cutoff value cannot be transformed to a result obtained using another pH cutoff value. There was a significant correlation between the values for baseline integrated acidity and corresponding values for conventional indices, however the strength of the correlation increased with decreasing pH cutoff values.

In the present study, we found that values for rabeprazole inhibition of both oesophageal and gastric acidity obtained using time pH ≤ 4 were significantly lower than those determined using integrated oesophageal and gastric acidity, respectively. These findings indicate that results using these pH cutoff values underestimate the effects of antisecretory agents and that these conventional assessments are less sensitive in quantifying the decrease in oesophageal or gastric acidity produced by a gastric antisecretory agent. We compared results obtained with integrated acidity to those obtained using pH cutoff values other than 4 and found that these other cutoff values also underestimated the magnitude of the inhibition of oesophageal and gastric acidity.

The present results also illustrate that simultaneous measurements of integrated oesophageal and gastric acidity make it possible to relate effects of a gastric antisecretory agent on gastric acidity to effects on oesophageal acidity in the same subject at the same time. Others23–25 have described nocturnal gastric acid breakthrough (nocturnal gastric pH < 4 for at least 1 h) in patients with GERD treated b.d. with 20 mg omperazole or 30 mg lansoprazole and have speculated regarding the potential significance of this phenomenon for treatment. We have found, however, that subjects with monophasic GERD have little, if any, baseline nocturnal oesophageal acid exposure even though they have a substantial nocturnal increase in gastric acidity. We have also found that subjects with biphasic GERD have a baseline increase in nocturnal gastric acidity that is accompanied by a pronounced nocturnal increase in oesophageal acidity. In these biphasic subjects, however, the first dose of 20 mg rabeprazole abolished the nocturnal increase in oesophageal acidity even though it did not abolish the nocturnal increase in gastric acidity. These results illustrate that simultaneous measurements of oesophageal and gastric pH are necessary to assess the effects that changes in gastric acidity may have on oesophageal acidity.

In summary, integrated gastric and oesophageal acidity are quantitative measurements that are more sensitive than time pH ≤ 4 in assessing the inhibitory actions of gastric antisecretory agents. In the present study, integrated acidity provided an excellent index of the overall effect of rabeprazole as well as its onset and duration of action on both gastric and oesophageal acidity in patients with GERD. These measurements also made it possible to demonstrate that the first dose of rabeprazole provided near steady-state inhibition of gastric and oesophageal acidity, and that the pattern of inhibitory action of rabeprazole on oesophageal acidity cannot necessarily be predicted from its inhibitory effect on gastric acidity.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References

This work was supported by grants from Eli Lilly and Company, Eisai Inc., and Janssen Pharmaceutica Inc. to the Oklahoma Foundation for Digestive Research and consulting agreements between Science for Organizations Inc. and Eisai Inc., and Science for Organizations Inc. and Janssen Pharmaceutica Research Foundation.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. References
  • 1
    Merki HS, Witzel L, Walt RP, et al. Day-to-day variation of 24-hour intragastric acidity. Gastroenterology 1988; 94: 88791.
  • 2
    Jamieson JR, Stein HJ, DeMeester TR, Bonavina L, Schwizer W, Hinder RA, Albertucci M. Ambulatory 24-h esophageal pH monitoring: normal values, optimal thresholds, specificity, sensitivity, and reproducibility. Am J Gastroenterol 1992; 87: 110211.
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