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1 Science for Organizations, Inc., Chatham, New Jersey 07928; 2 Pfizer, Morris Plains, New Jersey 07950; and 3 Oklahoma Foundation for Digestive Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Measurement of meal- stimulated gastric acid secretion using manual intragastric titration is demanding in terms of personnel and specialized equipment. In the present study, we used a new method, in vivo gastric autotitration, to determine meal-stimulated gastric acid secretion. Gastric pH was measured every 4 s before, during, and after ingestion of a standard meal in 24 healthy subjects. Placebo, ranitidine (150 mg), ranitidine (75 mg), or famotidine (10 mg) was given 1 h after the beginning of the meal. Meal-stimulated gastric acid secretion was calculated from the amount of HCl required to titrate the homogenized standard meal to pH 2 in vitro (119 mmol) and the time required for the pH of the ingested meal to decrease to pH 2 in vivo. Values for pH were also converted to acid concentration (mM), and integrated acidity was calculated from the cumulative, time-weighted means of the acid concentrations for every fourth second of the postprandial recording period. Control meal-stimulated gastric acid secretion was 60 (40-71) mmol/h (median; interquartile range), and each histamine H2-receptor antagonist significantly decreased secretion by ~50%. Meal-stimulated acid secretion correlated directly with postprandial integrated gastric acidity (r = 0.72; P = 0.0001). Thus intragastric autotitration is a convenient, reproducible method for measuring gastric acid secretion after ingestion of a solid meal and offers several advantages over manual intragastric titration.
manual intragastric titration; gastric pH
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PREVIOUS MEASUREMENTS OF meal-stimulated gastric acid secretion have used manual intragastric titration, whereby after a meal NaHCO3 or NaOH is repeatedly infused into the stomach in amounts sufficient to maintain gastric pH at a predetermined, constant value (2-9, 13, 16-18, 20-23). The principle that underlies this technique is that the amount of base infused to maintain a constant gastric pH during a given interval is equal to the amount of gastric acid secreted during that same interval. Initially, manual intragastric titration was performed after ingestion of a solid meal (8); however, all subsequent studies used liquid meals or homogenized mixed meals that were infused into the stomach through a nasogastric tube (2-7, 9, 13, 16-18, 20-23). This change meant that the cephalic phase of gastric acid secretion was bypassed (21). Measuring meal-stimulated gastric acid secretion using manual intragastric titration is uncomfortable for subjects. It also requires specialized equipment, that subjects remain at the study site, and that study personnel be present for the duration of the study. These constraints may explain why studies using this technique have only been reported from a few research centers. Moreover, as acknowledged in the initial as well as subsequent descriptions of manual intragastric titration (5, 8), the technique is nonphysiological in that the cephalic phase of gastric secretion is bypassed and that gastric pH is maintained at a fixed value instead of being allowed to rise and fall as normally occurs after ingestion of a meal.
When a meal is ingested, gastric pH increases due to the buffering effect of the meal and then returns to baseline due to secretion of gastric acid. We considered the possibility that, if one knows the amount of acid required to reduce the pH of the meal to a particular value plus the time for the pH to reach that value in vivo, one can calculate the gastric acid secretory rate. Such a technique would allow gastric pH to decrease in the usual fashion after ingestion of a typical solid meal and would include the cephalic phase of gastric secretion. Furthermore, because methods to measure gastric pH continuously in ambulatory subjects are commercially available and widely used, it seemed to be technically possible to determine meal-stimulated gastric acid secretion and circumvent some of the limitations of manual intragastric titration. The present paper describes how in vivo gastric autotitration can be used to measure meal-stimulated gastric acid secretion.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study was approved by and conducted in compliance with good clinical practices as supervised by the Medical Ethics Committee (Assen, The Netherlands). The study was conducted by Pharma Bio-Research International in Zuidlaren, The Netherlands, and all subjects enrolled in this study gave written, informed consent.
Subjects. Subjects (12 men and 12 women) were healthy, nonsmoking adults aged 18-43 yr and weighing 58-97 kg with no symptoms of gastrointestinal or other disease. Subjects were not tested for Helicobacter pylori infection. All subjects had a normal physical examination, vital signs, electrocardiogram, and laboratory tests (blood chemistry, hematology, and urinalysis) pre- and poststudy. Negative pregnancy tests for females were obtained pre- and poststudy and before each study medication. Subjects had not been treated with a histamine H2-receptor antagonist, proton pump inhibitor, antacids, or any investigational drug within 3 mo before entry in the study.
Study design. The study was a randomized, open label, four-way crossover evaluation of the effects of placebo, 150 mg ranitidine, 75 mg ranitidine, and 10 mg famotidine on gastric pH. Gastric pH was measured for 2 h before, during, and at least 14 h after ingestion of a meal consisting of lean steak (125 g), boiled potatoes (200-250 g), fresh vegetables (200-250 g), salad (50 g), dessert (200 ml), and water (200 ml) over 30 min. Treatments were administered 1 h after the beginning of the meal. Subjects underwent a washout period of at least 72 h between each treatment.
Subjects ingested only liquids and then fasted from ~1300 on the day of the study until the beginning of pH recording at 1630. The standard meal was ingested at 1830 and treatments were given at 1930. Smoking and ingestion of food other than the test meal or liquids other than the water for medication were prohibited during the pH recording periods. Gastric antisecretory medications other than study medications were prohibited for the duration of the study. Gastric pH data were collected using an ambulatory, disposable, single-channel pH recording system (Medtronic Synectics) with antimony electrodes. The electrode was placed in the stomach 55 cm from the nares, and a pH value of <2.5 was recorded at least twice. Electrodes were calibrated to pH 1 and 7 using solutions composed of (pH 1.07) 59 mM KNO3 and 27 mM KCl and (pH 7.01) 16.5 mM Tris buffer, 40 mM KNO3, and 96 mM KCl. Data were collected using a portable data storage unit (Digitrapper, Medtronic Synectics). Recordings began at ~1630 and continued for 16.5 h. Values for intragastric pH were recorded every 4 s. 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 (15, 19). We calibrated the electrodes to pH 1 and 7 using polyelectrolyte solutions provided by the manufacturer, which resulted in measured hydrogen ion activity more closely approximating the hydrogen ion concentration. We have not adjusted hydrogen ion activity to hydrogen ion concentration.Analytical procedures. Recordings from each treatment period were analyzed for each of 24 subjects (96 records). All recordings were technically satisfactory.
To calculate meal-stimulated gastric acid secretion, each recording was divided into time intervals, and the percentage of time that gastric pH was less than a particular value was calculated for each interval. As described below, different time intervals and different pH endpoints were evaluated to determine the interval that was most useful for calculating gastric acid secretion. The components of the standard meal were combined and homogenized. The volume of the homogenate was 907 ml, weight was 961 g, osmolality was 449 mosmol/kgH2O, and pH was 5.9. Integrated gastric acidity was calculated for each 4 s of the recording period as follows: 1) acid concentration (mM) = 1,000 × 10
pH; 2) acidity
(mmol · h1 · l1) = [acid in mM at time (t) + acid in mM at
t1]/2 × (t 
t1); 3) values for acidity were
summed cumulatively; 4) integrated acidity was expressed as
mM × time (i.e.,
mmol · h1 · l1); and
5) values for integrated acidity were analyzed for each 0.5 h (30 min) of the 14-h period beginning with the start of the
meal. This calculation has been referred to as "mean weighted acidity" by others (11). Mean acid concentration for
each 0.5 h was calculated as 2 × (integrated acidity at
t integrated acidity at
t1).
Statistical analyses. Statistical analyses were performed using Microsoft Excel 97 or GraphPad for InStat version 3.01 for Windows software. Results for the four treatments were analyzed using nonparametric repeated measures ANOVA and Dunn's multiple comparisons test. Correlation was tested using the Spearman test (nonparametric).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Figure 1A illustrates
that, at baseline, median gastric pH was ~1, increased to pH 4.5 with
ingestion of the meal, and then returned to approximately pH 1 3-4
h after the start of the meal.
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To determine meal-stimulated gastric acid secretion, we calculated the time required for the pH of the ingested meal (5.9) to decrease to below pH 2. Figure 1B illustrates the percentage of time that gastric pH was <2 during consecutive 10-min intervals for the first 8 h of the recording period in subjects treated with placebo or a histamine H2-receptor antagonist. We performed similar analyses using intervals as short as 5 min and as long as 30 min and pH endpoints from 4 to 1 in steps of 0.3 to decide on the interval to use to calculate the time required for gastric pH to decrease to below a particular value. We wanted to use the shortest interval possible to maximize precision but also to choose an interval that would minimize the normal fluctuations in gastric pH that occur when pH is recorded every 4 s following a meal. Of the time intervals and pH endpoints tested, a 10-min interval and pH 2 gave the smallest interquartile range of values. Titration of the homogenized meal to pH 2.0 in vitro required 119 mmol of 0.1 N HCl.
We first numbered each consecutive 10-min interval from the beginning
of the recording. We then determined the first of two consecutive
10-min intervals with gastric pH of <2 for less than 5% of the
interval and referred to this interval as P1. Only one subject had two
consecutive intervals with gastric pH 2 for less than 5% of the time
followed immediately by an interval that was not less than 5%. (Values
from this subject fluctuated to such an extent that we were unable to
determine a reliable value for P1, and this subject was excluded from
all analyses of meal-stimulated gastric acid secretion.) We next
determined the first of two consecutive intervals during which gastric
pH was <2 for more than 90% of the interval and referred to this
interval as P2. Gastric titration time was calculated as (P2 P1) × 10 min. Meal-stimulated gastric acid secretion (in mmol/h)
was then calculated as
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Figure 1B illustrates results for time gastric pH was <2 for control and after administration of a histamine H2-receptor antagonist. Each gastric antisecretory agent prolonged the time required for the curve to return to 100% (prolonged the titration time), an effect that is consistent with their abilities to inhibit gastric acid secretion. The curves were similar with ranitidine (75 mg) and famotidine (10 mg), and both curves returned toward 100% earlier than did the curve with 150 mg of ranitidine.
To decide what type of statistical analyses to perform using results
for meal-stimulated gastric acid secretion as well as those for
integrated gastric acidity, we examined the distribution of values for
these two measures with placebo during each treatment. As illustrated
in Fig. 2, compared with the normal
Gaussian distribution, the distributions were skewed toward high
values, producing a curvature to the distribution at higher values
(1). Because of the skewed distributions illustrated in
Fig. 2, we analyzed the present results with the use of nonparametric
statistical tests.
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Figure 3 illustrates modified box plots
(1) for gastric titration times and for meal-stimulated
gastric acid secretion. The skewness of the distributions of the values
can be seen by comparing the location of the median value to the
minimum and maximum values. With each gastric antisecretory agent,
gastric titration time was significantly longer and meal-stimulated
gastric acid secretion was significantly lower than corresponding
values with placebo. Findings that known gastric antisecretory agents significantly increase gastric titration time determined by in vivo
autotitration support the validity of this technique as a measure of
meal-stimulated gastric acid secretion.
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Figure 4 displays results for
meal-stimulated gastric acid secretion for each subject with each
histamine H2-receptor antagonist compared with placebo. In
Fig. 4, the solid diagonal line is not the least-squares regression
line; it is the identity line for placebo values. Each point on the
graph represents a pair of values from one subject, and the vertical or
horizontal distance from the solid line gives the magnitude of the
difference between the pair of values. Values below the solid line
indicate that acid secretion with histamine H2-receptor
antagonist is less than that with placebo, and values above the line
indicate the opposite. Figure 4 illustrates that, even though results
with each histamine H2-receptor antagonist are
significantly different from results with placebo, 150 mg of ranitidine
was more consistent than 75 mg of ranitidine or 10 mg of famotidine in
decreasing meal-stimulated gastric acid secretion, particularly in
subjects with higher placebo values for acid secretion. Notice, too,
that two subjects had high values for gastric acid secretion with
placebo (102 and 119 mmol/h). It may be that these high values resulted
from inhomogeneous mixing of the gastric contents, causing the gastric
electrode to record from a region of the stomach that reached pH 2 before the remaining contents.
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The results in Fig. 4 also illustrate that the present technique is able to distinguish quantitative differences between effects of gastric antisecretory agents on gastric acid secretion. Furthermore, Fig. 4 illustrates that, even though each histamine H2-receptor antagonist significantly decreased median values for meal-stimulated gastric acid secretion for the group, there were instances when a subject failed to respond to the antisecretory agent (points on or above the solid line). By comparing the placebo values for the points that are above the diagonal line, one can see that these nonresponses do not represent subjects who fail to respond to any histamine H2-receptor antagonist. Instead, they represent instances when a particular subject failed to respond to a particular histamine H2-receptor antagonist.
We were interested in possible relationships between values for
meal-stimulated gastric acid secretion and other measures of gastric
acidity in the same subjects. Figure
5A illustrates values for mean
gastric acid concentration over consecutive 30-min intervals during the
entire recording period. As was evident from the results illustrated in
Fig. 1, ingestion of the meal caused a prompt decrease in gastric acid
concentration due to the buffering effect of the meal. After a nadir
was reached, gastric acid concentration increased progressively to a
maximum at hour 10 (2:30 AM) and then decreased during the
subsequent early morning hours. Figure 5A illustrates
that the curves for mean gastric acid concentration with histamine
H2-receptor antagonists were below the curve for placebo.
Figure 5B gives values for integrated gastric acidity beginning at the start of the meal. Integrated gastric acidity with
placebo increased progressively over the course of the recording period. The curve with 75 mg ranitidine was similar to that with 10 mg
famotidine, and both curves were below the curve with placebo and above
the curve with 150 mg ranitidine.
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Figure 6A displays values for
the correlation coefficient from analyses of the correlation between
meal-stimulated gastric acid secretion and corresponding values for
integrated gastric acidity at different times after ingestion of the
meal. There was a significant correlation between gastric acid
secretion and integrated gastric acidity from the beginning of the meal
through hours 3-5.5, with the highest correlation
coefficient occurring at 0-3.5 h (Fig. 6A).
Thus integrated gastric acidity during the 3- to 5.5-h postprandial
period correlates directly with meal-stimulated gastric acid secretion.
Figure 6B illustrates that, in subjects who received
placebo, there was a significant correlation between values for
integrated gastric acidity over the initial 3.5-h postprandial period
and corresponding values for meal-stimulated gastric acid secretion.
Figure 6C, however, illustrates that there was no
significant correlation between values for integrated gastric acidity
over the baseline period from 5.5-14 h after the meal and
corresponding values for meal-stimulated gastric acid secretion.
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The results in Fig. 6 indicate that meal-stimulated gastric acid
secretion correlates directly with postprandial integrated gastric
acidity but not with baseline integrated gastric acidity. To examine
effects of histamine H2-receptor antagonists on integrated gastric acidity during these two periods, we examined values for integrated gastric acidity over the entire 14-h period as well as over
hours 0-3.5 (postprandial) and over hours
5.5-14 (basal). Figure 7
illustrates that, with each histamine H2-receptor
antagonist, median values over the interval of 5.5-14 h were
approximately eightfold greater than corresponding values over the 0- to 3.5-h interval. Except for the 75-mg ranitidine dose over
hours 0-3.5, values for each histamine
H2-receptor antagonist were significantly lower
(P < 0.01) than corresponding values with placebo over
each of the three different intervals examined. Thus the gastric
antisecretory agents decreased integrated gastric acidity during the
postprandial as well as during the basal period, and the postprandial
decrease reflects the drug-induced decrease in meal-stimulated gastric acid secretion.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we measured gastric pH every 4 s for 2 h before, during, and 14 h after ingestion of a standard meal in healthy subjects who were given placebo or a histamine H2-receptor antagonist 1 h after the beginning of the meal. We have demonstrated that meal-stimulated gastric acid secretion can be calculated from the amount of HCl necessary to titrate the homogenized meal to pH 2 in vitro and the time required for gastric pH to decrease to pH 2 in vivo after ingestion of the meal. Ranitidine and famotidine, which are known inhibitors of human gastric acid secretion (10, 14), significantly increased the time required for gastric pH to decrease to 2, therefore significantly decreasing meal-stimulated gastric secretion. In addition, in vivo gastric autotitration could detect quantitative differences in meal-stimulated gastric acid secretion under different conditions in the same subject. These findings with gastric antisecretory agents support the validity of using in vivo gastric autotitration to measure meal-stimulated gastric acid secretion.
Measuring meal-stimulated gastric acid secretion using in vivo gastric autotitration, as described in the present report, offers several advantages over manual intragastric titration. With in vivo gastric autotitration, measurements can be performed under conditions that more closely approximate those of normal living (including ingestion of solid meals), do not require that subjects remain at the study site, are not labor intensive, and employ commercially available equipment that is used widely for clinical diagnostic as well as for research studies. As illustrated in the present study, measurements can be performed after ingestion of a typical meal and allow gastric pH to decrease physiologically. Although not illustrated in the present study, measurements can also be performed after different meals are consumed in the usual fashion during a typical day and can assess the physiological response of gastric acid secretion to ingestion of different nutrients. Moreover, in vivo gastric autotitration can be performed at the same time that esophageal pH is recorded.
There are also some limitations to in vivo autotitration. First, this technique can never give a value of zero for gastric secretion, regardless of the time taken to reach pH 2 or when the recording is stopped, because the titration time (denominator) is always divided into a fixed value for the buffer capacity of the meal in vitro (numerator). Second, after ingestion of a mixed meal, the intragastric contents are not homogeneous, particularly during the early postprandial period. If the gastric electrode samples a region of the intragastric contents that has a different pH-time profile from the remainder of the contents, the value calculated for gastric secretion will differ from the true gastric secretory rate. This may account for the high values obtained from two subjects during placebo treatment. Repeat measurements in the same subject may be able to address this issue.
Several reports that have used manual intragastric titration have also measured gastric emptying (4, 8, 16-18, 20, 22, 23). In some instances, particularly when liquid meals were infused, the half time of emptying was less than 30 min (16, 18, 23). With manual intragastric titration, gastric emptying will cause the true rate of acid secretion to be underestimated, and the greater the emptying rate, the greater the magnitude of underestimation. The effect of gastric emptying on values determined with the use of manual intragastric titration is also magnified when liquid meals that are emptied faster than solid meals are used (12). In contrast, with in vivo gastric autotitration, gastric emptying causes the true rate of gastric acid secretion to be overestimated, and the greater the rate of gastric emptying, the greater the magnitude of overestimation. The magnitude of the overestimation with in vivo gastric autotitration is minimized by allowing gastric pH to fall normally after ingestion of the meal because the rate of gastric emptying decreases at lower gastric pH (18). In addition, performing studies with solid meals, which empty at a slower rate than liquid meals, can further minimize the effect of gastric emptying on values calculated for gastric secretion (12). These different effects of gastric emptying mean that values for acid secretion obtained with in vivo autotitration will be higher than those obtained with manual intragastric titration. In this regard, values in the present study for meal-stimulated gastric acid secretion in subjects who received placebo (60 mmol/h; interquartile range of 40-71) are higher than those for normal subjects reported using manual intragastric titration, which have been ~15-30 mmol/h (4-6, 8, 9, 13, 17, 18, 21, 22).
These different effects of gastric emptying on values obtained by the two methods may also obscure any correlation between the two techniques. For example, in two subjects with identical rates of meal-stimulated gastric acid secretion but different rates of gastric emptying, the subject with the higher rate of gastric emptying will have a lower value for secretion determined by manual titration and a higher value determined by in vivo autotitration. As mentioned above, this distorting effect of gastric emptying can be minimized by using meals that empty relatively slowly.
In the present study, we found that each of three different histamine H2-receptor antagonists that are known to inhibit gastric acid secretion measured by aspirating gastric contents (10, 14) also decreased gastric acid secretion assessed by intragastric autotitration. These results offer support for the validity of intragastric autotitration as a method to measure meal-stimulated gastric acid secretion.
We did not perform measurements of manual intragastric titration in the subjects who participated in the present study for several reasons. First, to our knowledge, manual intragastric titration as performed in all but the original report (8) employs liquid meals that bypass the cephalic phase of gastric secretion (21), and we wanted to measure gastric acid secretion under conditions when subjects ingest typical meals under circumstances that include the cephalic phase of gastric secretion. Second, we wanted to measure gastric secretion under circumstances when the intragastric pH changes in the usual manner after ingestion of a solid meal. Third, we wanted to develop a method that used readily available equipment and that could be easily performed in ambulatory subjects by a variety of investigators. We accept, however, that the present studies were done without any direct correlation with manual intragastric titration, which is far more difficult to perform.
To examine possible relationships between values for meal-stimulated gastric acid secretion and other measures of gastric acidity, we calculated integrated gastric acidity for different intervals after the start of the meal. Values for integrated acidity, like those for meal-stimulated gastric acid secretion, were skewed toward high values. In subjects who received placebo, there was a significant correlation between gastric acid secretion and integrated gastric acidity from the beginning of the meal through hours 3.0-5.5, with the highest correlation coefficient occurring for 0-3.5 h. On the other hand, there was no significant correlation between values for meal-stimulated gastric acid secretion and those for integrated gastric acidity from hours 5.5 to 14. Thus meal-stimulated gastric acid secretion correlates directly with postprandial integrated gastric acidity but not with baseline integrated gastric acidity. Gastric antisecretory agents decreased integrated gastric acidity during the postprandial as well as during the basal period, and the postprandial decrease could be accounted for by the drug-induced decrease in meal-stimulated gastric acid secretion.
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ACKNOWLEDGEMENTS |
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This work was supported by a grant from Warner-Lambert to the Oklahoma Foundation for Digestive Research and a consulting agreement between Science for Organizations, Inc., and Warner-Lambert.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. D. Gardner, Science for Organizations, Inc., 156 Terrace Drive, Chatham, NJ 07928 (E-mail: gardnerj{at}bellatlantic.net).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/japplphysiol.00956.2001
Received 17 September 2001; accepted in final form 26 September 2001.
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TOP
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RESULTS
DISCUSSION
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 A. Asai, M. Terasaki, and A. Nagao An Epoxide-Furanoid Rearrangement of Spinach Neoxanthin Occurs in the Gastrointestinal Tract of Mice and In Vitro: Formation and Cytostatic Activity of Neochrome Stereoisomers J. Nutr., September 1, 2004; 134(9): 2237 - 2243. [Abstract] [Full Text] [PDF]
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E. C. Huh, A. Hotchkiss, J. Brouillette, and R. P. Glahn Carbohydrate Fractions from Cooked Fish Promote Iron Uptake by Caco-2 Cells J. Nutr., July 1, 2004; 134(7): 1681 - 1689. [Abstract] [Full Text]
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Y. P. Papastamatiou and C. G. Lowe Postprandial response of gastric pH in leopard sharks (Triakis semifasciata) and its use to study foraging ecology J. Exp. Biol., January 15, 2004; 207(2): 225 - 232. [Abstract] [Full Text] [PDF]
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, Median
values. Horizontal bars represent the 1st and 3rd quartile values. For
meal-stimulated gastric acid secretion, values with active treatment
were significantly different from control (placebo): 75 mg ranitidine,
P < 0.01; 150 mg ranitidine, P < 0.001; 10 mg famotidine, P < 0.05.
