Integrated acidity and rabeprazole pharmacology

Integrated acidity and rabeprazole pharmacology

J . D. GARDNER*, C. PERDOMO , S. SLOANà , W. F. HAHNE , J . A. BARTH ,

S. RODRIGUEZ-STANLEY§ & M. ROBINSON§

*Science for Organizations Inc., Chatham, NJ; Eisai Inc., Teaneck, NJ; àJanssen Pharmaceutica Inc., Titusville, NJ;

§Oklahoma Foundation for Digestive Research, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Accepted for publication 8 August 2001

INTRODUCTION

Use of continuous pH recordings has become the

cornerstone for assessment of gastro-oesophageal re¯ux

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 de®nition of acidity and

the differential effects of speci®c pharmacologic agents.

Previously,10 we calculated values for integrated

gastric and oesophageal acidity from 24-h pH record-

ings performed in the conventional manner. Values that

resulted from these calculations fully quanti®ed oeso-

phageal and gastric acidity, in contrast to conventional

measurements of the percentage of time that the pH is

below a particular value, which only partially quanti®ed

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

SUMMARY

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 re¯ux 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 ®rst dose of rabeprazole inhibited gastric and

oesophageal acidity by at least 70% of the steady-state

effect. Oesophageal acidity could be divided into mono-

phasic and biphasic patterns, and rabeprazole had

different effects on oesophageal and gastric acidity in

these two GERD subpopulations. The onset of action of

the ®rst 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.

Correspondence to: Dr J. D. Gardner, Science for Organizations Inc., 156

Terrace Drive, Chatham, NJ 07928, USA.E-mail: [email protected]

Aliment Pharmacol Ther 2002; 16: 455±464.

Ó 2002 Blackwell Science Ltd 455

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 antag-

onists 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 assess-

ments based on integrated acidity with those that utilize

the conventional measure of percentage time pH £ 4 or

some other cutoff value.

METHODS

This study was approved by and conducted in compli-

ance 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 ®ve 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 Helicob-

acter 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 evalu-

ation 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 ®rst 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 break-

fast at approximately 8:00 hours. Subjects remained

in the study centre for the 24-h recording sessions

and were given three de®ned 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 de®ned

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

456 J. D. GARDNER et al.

Ó 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 455±464

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 concentra-

tion.12, 13 We calibrated the electrodes to pH 1 and 7

using polyelectrolyte solutions provided by the manu-

facturer, 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 re¯ux episodes, number of re¯ux

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 ®lls 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 ®ndings 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 cal-

culated 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 repre-

sented 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.

INTEGRATED ACIDITY AND RABEPRAZOLE PHARMACOLOGY 457


RESULTS

Determining the time that gastric or oesophageal pH is

£ 4 is used frequently to assess gastric and oesophageal

acidity.1±9 Figure 1 left panel illustrates the distribu-

tions of values for times that oesophageal and gastric pH

were £ 4. Compared to the normal Gaussian distribu-

tion, both distributions were skewed.15 With oesopha-

geal 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 classi®cation was

consistent with the different patterns of oesophageal

acidity that had been described previously.16±18 Sub-

jects with a monophasic pattern reached 50% of maxi-

mal 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 ®rst and seventh doses of 20 mg rabeprazole in

monophasic and biphasic subjects. In both groups, the

®rst dose of rabeprazole caused a signi®cant decrease in

integrated gastric acidity from 14:00 hours until the

end of the recording period, and integrated gastric

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 ®rst day of dosing are

signi®cantly different from corresponding

baseline values (P < 0.05).

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 hori-

zontal axis. The diagonal line is the identity

line for the normal distribution. If the dis-

tribution of observed values is normal, all

points will lie on the diagonal line. Values

given are from 19 subjects.



acidity was decreased further after the seventh dose of

rabeprazole.

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

®rst 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 ®rst 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 ®rst dose of

rabeprazole, de®ned as the earliest time that the mean

gastric acid concentration was signi®cantly 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.

Figure 4 illustrates values for integrated oesophageal

acidity after the ®rst and seventh doses of 20 mg

rabeprazole in monophasic and biphasic subjects. In

monophasic subjects, the ®rst dose of rabeprazole

caused a signi®cant decrease in integrated oesophageal

acidity from 13:00 hours until the end of the recording

period. In contrast, in biphasic subjects, the ®rst dose of

rabeprazole did not cause a signi®cant 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.

It is important to note that the vertical scale in the

right panel in Figure 4 is ®ve times greater than that in

the left panel. Thus, the ®rst dose of rabeprazole failed

to produce a signi®cant decrease in integrated oeso-

phageal acidity in biphasic subjects during the times

that their values were comparable to those in mono-

phasic subjects that were signi®cantly decreased by

rabeprazole. This lack of effect of rabeprazole in biphasic

subjects during hours 13:00±23:00 was not attribut-

able to a lack of effect of rabeprazole on gastric acidity,

because as illustrated in Figure 2, gastric acidity

following the ®rst dose of rabeprazole in biphasic

subjects was lower than that in monophasic subjects.


mean gastric acid concentration in mono-

phasic (left panel) and biphasic (right

panel) GERD after 1 day of dosing. Values

given are medians from 12 subjects with a










Table 1 summarizes values for percentage inhibition of

24-h integrated gastric and oesophageal acidity with

the ®rst and seventh doses of rabeprazole. Inhibition of

gastric acidity with the ®rst dose was 72% and 70%,

and with the seventh dose was 93% and 84% in

monophasic and biphasic subjects, respectively. Assu-

ming that the inhibition with the seventh dose of

rabeprazole represents steady-state inhibition, inhibition

of gastric acidity with the ®rst dose of rabeprazole was

83% and 86% of the steady-state inhibition in mono-

phasic and biphasic subjects, respectively (Table 1).

There were no signi®cant differences between mono-

phasic and biphasic subjects in terms of rabeprazole

inhibition of 24-h integrated gastric acidity with the

®rst dose, the seventh dose or at the steady-state

(Table 1). In contrast to gastric acidity, inhibition of

oesophageal acidity with both the ®rst and seventh

doses of rabeprazole was signi®cantly higher in biphasic

subjects than in monophasic subjects. Inhibition of

oesophageal acidity with the ®rst dose of rabeprazole as

a percentage of the steady-state inhibition in monopha-

sic subjects was not signi®cantly different from that in

biphasic subjects (Table 1). Also, there were no signi-

®cant differences between inhibition of oesophageal and

gastric acidity for either group for any dose.

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 oesopha-

geal acid exposure, there was substantial variation

among subjects for mean oesophageal acid concen-

tration 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

Inhibition of integrated acidity (%)

First dose Seventh dose

First dose as percentage

of seventh dose

Monophasic GERD (n � 12)

Gastric 72 93 83

Oesophageal 74 89 76

Biphasic GERD (n � 7)

Gastric 70 84 86

Oesophageal 95a 99a 100

All (n � 19)

Gastric 70 89 85

Oesophageal 80 95 93

Values are medians from the number of subjects indicated. A ± signi®cantly different from

corresponding value for monophasic subjects P < 0.05 by Mann±Whitney test.

Table 1. Inhibition of 24-h integrated

acidity by the ®rst and seventh doses of

20 mg rabeprazole in subjects with

monophasic and biphasic GERD


integrated oesophageal acidity in mono-

phasic (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 ®rst day of

dosing are signi®cantly different from

corresponding baseline values (P < 0.05).



mean gastric acid concentrations. Figure 5 left panel

illustrates that in subjects with monophasic GERD, the

®rst dose of 20 mg rabeprazole decreased mean oeso-

phageal acid concentrations from 12:00 to 1:00 hours.

Figure 5 right panel illustrates that in subjects with

biphasic GERD, the ®rst dose of 20 mg rabeprazole

decreased mean oesophageal acid concentrations from

15:00 to 3:00 hours. Interestingly, the ®rst 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 ®rst dose of rabeprazole, de®ned as the

earliest time that the mean oesophageal acid concen-

tration was signi®cantly less than the corresponding

baseline concentration, was 4 h after dosing for mono-

phasic subjects and 7 h after dosing for biphasic

subjects (Figure 5).

Determining the time that gastric or oesophageal

pH £ 4 is used frequently to assess gastric and oeso-

phageal acidity,1±9 therefore we compared these param-

eters to values for 24-h integrated acidity in terms of

measuring the inhibitory action of the ®rst 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 signi®cantly more

sensitive than time gastric pH £ 4 in assessing the effect

of rabeprazole on gastric acidity. Figure 6 right panel

displays modi®ed 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.

Figure 7 left panel plots inhibition of oesophageal

acidity determined from values for 24-h integrated

oesophageal acidity vs. corresponding values deter-

mined from time oesophageal pH £ 4, and illustrates

that 24-h integrated oesophageal acidity is signi®cantly

more sensitive than time oesophageal pH £ 4 in asses-

sing the effect of rabeprazole on oesophageal acidity.

Figure 6 right panel displays modi®ed 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.

DISCUSSION

The present results illustrate that measurements

of integrated acidity can provide particularly useful

information regarding the actions of gastric antisecre-

tory 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


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










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 ®rst 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 ®rst dose of 20 mg

rabeprazole on oesophageal acidity in that the effect of

rabeprazole on integrated oesophageal acidity was 76%

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 signi®cantly greater than those with time pH £ 4 (P � 0.0116). The right panel is a modi®ed 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.

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 signi®cantly greater than those with time pH £ 4 (P � 0.018). The right panel is a modi®ed 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.



of the corresponding effect on day 7 of dosing in

monophasic subjects and 100% in biphasic subjects.

The ®nding that the ®rst dose of rabeprazole produced

full steady-state inhibition of integrated oesophageal

acidity in subjects with biphasic GERD was not antici-

pated, because biphasic subjects had signi®cantly higher

baseline oesophageal acid exposure than monophasic

subjects. These ®ndings probably re¯ect 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 signi®cantly

different from placebo (e.g. 8). The studies that have

measured pH on samples of aspirated gastric ¯uid 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 signi®cant

antisecretory effect of either agent assessed at 4, 10,

16 and 24 h after the ®rst dose.20 In contrast,

assessments of the gastric antisecretory actions of

lansoprazole and omeprazole measuring gastric pH

have demonstrated signi®cant effects within several

hours after the ®rst 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

quanti®es 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 signi®cant

correlation between the values for baseline integrated

acidity and corresponding values for conventional indi-

ces, 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 signi®cantly

lower than those determined using integrated oesopha-

geal and gastric acidity, respectively. These ®ndings

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 signi®cance 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, how-

ever, the ®rst 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 ®rst 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

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 Organiza-

tions Inc. and Eisai Inc., and Science for Organizations

Inc. and Janssen Pharmaceutica Research Foundation.

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Integrated acidity and rabeprazole pharmacology

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