Aliment Pharmacol Ther 2002; 16: 435–443.
`
`Effects of antacid formulation on postprandial oesophageal acidity
`in patients with a history of episodic heartburn
`
`M. ROB INSON *, S. RODR IGUEZ-STANLEY*, P . B . MINER*, A. J. M CGUIR E(cid:160),
`K. FU NG(cid:160) & A. A. CI O CIO LA(cid:160)
`*Oklahoma Foundation for Digestive Research, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;
`(cid:160)Pfizer Consumer Healthcare, Morris Plains, NJ, USA
`
`Accepted for publication 28 September 2001
`
`S U MM ARY
`
`Background: Heartburn self-treatment with antacids is
`extremely common. If the oesophagus is the primary site
`of antacid action, chewable antacids might raise the
`oesophageal pH more effectively than swallowable tablets.
`Aim: To establish a model to assess postprandial acid
`reflux and to compare the onset and duration of action
`on oesophageal pH of different antacid formulations.
`Methods: Twenty subjects with a history of episodic
`heartburn underwent eight pH monitoring sessions
`each for 5.5 h postprandially. One hour after con-
`suming a meal consisting of chilli, cheese, raw onions
`and cola, subjects received 750 mg, 1500 mg and
`3000 mg of either chewable or swallowable CaCO3
`tablets, an effervescent bicarbonate solution or placebo.
`Oesophageal and gastric pH data were collected.
`
`Results: Mean intra-oesophageal pH remained lower
`than baseline for more than 1 h (pH range 5–5.5)
`postprandially,
`indicating reflux of somewhat acidic
`intragastric contents into the oesophagus. The onset of
`action on oesophageal pH was similar for all antacids
`(30–35 min). The duration of action on pH varied:
`chewable tablets and effervescent bicarbonate had
`relatively long durations of action (oesophagus, 40–
`45 min; stomach, 100–180 min); swallowable tablets
`had little effect.
`Conclusions: The meal model used in this study depend-
`ably produced acidic gastro-oesophageal reflux. Ant-
`acids increased oesophageal pH independent of gastric
`pH, demonstrating that chewing antacids controls
`oesophageal acidity more effectively than swallowing
`antacid tablets.
`
`I N T R O DU C T IO N
`
`Heartburn occurs intermittently in more than 30% of
`otherwise healthy individuals and is almost always
`associated with acidic gastro-oesophageal reflux.1–3 In
`addition, heartburn and related symptoms can be
`foods1, 4, 5 or by
`produced by certain ‘provocative’
`overindulgence in food and drink.6
`
`Correspondence to: Dr S. Rodriguez-Stanley, GI Laboratory Director,
`Oklahoma Foundation for Digestive Research, University of Oklahoma
`Health Sciences Center, 711 Stanton L. Young Boulevard, Suite 624,
`Oklahoma City, OK 73104, USA.
`E-mail: sheila-stanley@ouhsc.edu
`
`Antacids are popular ‘over-the-counter’ preparations
`for the relief of episodic heartburn, and have been assu-
`med to assuage heartburn by neutralizing gastric acid,
`thus preventing subsequent acidic gastro-oesophageal
`reflux.7, 8 With large antacid doses (e.g. 156 mmol), fed
`subjects demonstrate significantly elevated gastric pH.2
`However, more recent studies have indicated that usual
`doses of antacids are primarily active in the distal
`oesophageal lumen9, 10 rather than by neutralization of
`intragastric contents. If this is indeed the case, chewable
`antacids should rapidly increase and sustain the elevated
`intra-oesophageal pH better than swallowable antacids.
`The use of standardized meals eliminates a significant
`variable in reflux and heartburn studies. In a previous
`
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`435
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`436 M . RO BI N SO N et al.
`
`comparative study of three meals (hamburger, chilli and
`sausage-biscuit),11 the chilli meal induced more reflux
`episodes and more severe heartburn over the initial
`45 min postprandially, as measured on a 100-point
`visual analogue scale, compared to the other meals.
`In order to verify the site(s) of action of antacids and to
`determine the effects of various antacids on oesophageal
`and gastric pH, increasing doses of swallowable and
`chewable calcium carbonate tablets were studied using
`a refluxogenic chilli meal previously demonstrated to
`produce consistent effects on intragastric and intra-
`oesophageal pH.11
`
`METHODS
`
`This study had two goals: (i) to validate the consistency
`of a model designed to assess postprandial acid reflux;
`and (ii) to use this model to compare the onset and
`duration of action of acid neutralization of various
`antacid formulations.
`
`Subjects
`
`Twenty otherwise healthy subjects, 18 years or older,
`with a history of episodic heartburn on three or more
`days per week of at least 2 months’ duration, were
`recruited.
`
`Study design
`
`The protocol was approved by the independent national
`Western Institutional Review Board of Olympia,
`Washington, and all subjects signed informed consents
`prior to the study. Subjects taking antisecretory or
`motility drugs within 1 week prior to study entry were
`excluded. Normal physical examinations and laboratory
`screening tests were required,
`including a negative
`pregnancy test in women of childbearing potential. The
`study was a single-centre, randomized, crossover, pla-
`
`cebo-controlled study with each subject acting as his/her
`own control. Subjects randomly received the following
`eight study treatments, with study periods separated by
`at least 24 h:
`
`(a) Calcium carbonate (CaCO3) 750 mg chewable
`tablets (Tums E-X tablets, GlaxoSmithKline, UK);
`acid neutralizing capacity (ANC), 16 mmol;
`(b) CaCO3 1500 mg chewable tablets as above; ANC,
`32 mmol;
`(c) CaCO3 3000 mg chewable tablets as above; ANC,
`64 mmol;
`(d) CaCO3
`swallowable
`750 mg
`SmithKline, UK); ANC, 16 mmol;
`(e) CaCO3 1500 mg swallowable tablets as above;
`ANC, 32 mmol;
`(f) CaCO3 3000 mg swallowable tablets as above;
`ANC, 64 mmol;
`(g) Na+/K+ bicarbonate effervescent
`solution with
`32 mmol ANC (the effervescent bicarbonate solu-
`tion) as Alka-Seltzer Gold tablets (Bayer Corpora-
`tion, Consumer Care Division, USA);
`(h) placebo tablets identical to the swallowable tablets.
`
`(Glaxo-
`
`tablets
`
`is shown in
`the study protocol
`A description of
`Figure 1. Each subject
`remained confined to the
`research unit
`throughout each study day. Subjects
`consumed breakfast by 08.00 h. From 08.00 h to
`12.00 h, only water was permitted. Subjects fasted
`from 12.00 h until the refluxogenic meal at approxi-
`mately 18.00 h. At approximately 17.00 h, subjects
`were intubated transnasally with a dual antimony pH
`electrode catheter (15 cm spacing between electrodes)
`(Medtronics Synectics, Shoreview, MN, USA), placed to
`position the proximal electrode 5 cm above the upper
`margin of the manometrically identified lower oeso-
`phageal sphincter. All pH data were stored every 4 s for
`approximately 5.5 h using a portable digital recorder
`(Mark III Gold, Medtronic Synectics, Shoreview, MN,
`USA). Electrodes were calibrated to pH 1.07 and 7.01
`
`Figure 1. Diagrammatic example of the
`protocol for the study.
`
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`
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`ANTAC ID FORMULATION AND OESOPHAGEAL A CIDITY
`
`437
`
`with solutions composed of 59 mM KNO3, 27 mM KCl
`(pH 1.07) and 16.5 mM Tris buffer, 40 mM KNO3,
`(pH 7.01). Stored data were processed
`96 mM KCl
`in DOS mode using temperature-compensating pH
`recording software (Polygram for Windows, Version
`2.0, Medtronic Synectics, Shoreview, MN, USA).
`One hour after intubation, at approximately 18.00 h,
`a refluxogenic meal was consumed over 30 min.11 The
`meal consisted of at least 227 g of Wendy’sTM chilli
`supplemented with half a cup of cheddar cheese and
`half a cup of chopped raw onions and 340 mL CokeTM
`Classic cola.
`Additional portions of chilli and cola were allowed (in
`half portions), but each subject was
`required to
`consume the same amount at each subsequent study
`session.
`The study medication was administered 1 h postpran-
`dially at 19.30 h. Tablets were chewed, swallowed
`whole with water or dissolved in water and the liquid
`swallowed, according to the randomization treatment
`code. Three hours after administration of the study
`medication (at 22.30 h), pH recording was terminated
`and the pH electrodes were removed. During the 5-h
`observation period, subjects did not recline at an angle
`of more than 30(cid:176) from upright.
`Untoward events were monitored for safety (none
`occurred).
`
`Study analyses
`
`Intragastric pH. Intragastric pH was recorded every 4 s.
`All data points between 0 and 5 min (75 values) were
`used to calculate the mean pH for this time point. For
`each treatment and each subject, 5-min average
`oesophageal and gastric pH values were calculated and
`the 5-min pH averages were computed over the entire
`study period. These mean pH values were then averaged
`for all subjects at the specified time points (every 5 min)
`and over the specific time periods as described below. For
`each subject, the difference was calculated between
`5-min averages for each active treatment and placebo.
`These differences were tested for normality using
`the Shapiro–Wilks procedure.12 The differences were
`then analysed using a paired t-test if the normality
`assumption was not rejected, or a Wilcoxon signed-rank
`test if the normality assumption was rejected.
`The onset of action, duration of action and mean
`intragastric pH over specific time periods were all
`computed as described below.
`
`(cid:211) 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 435–443
`
`Onset and duration of action. Analyses were carried out
`separately for intragastric and intra-oesophageal pH,
`producing estimates of the onset and duration of action
`for each active treatment in the stomach and in the
`oesophagus. The onset of action is the time from dosing
`to the first statistically significant difference vs. placebo
`(P < 0.05). The offset time is the time to the first non-
`significant difference following the onset
`time. The
`duration of action is defined as the offset time minus the
`onset time.
`
`Specific time periods before and after dosing. For each
`pre-treatment
`and
`post-treatment
`time
`interval,
`oesophageal and gastric pH averages were calculated.
`Mean pre-treatment pH was calculated for two time
`intubation (i.e. )145 to
`periods: 5–60 min after
`)90 min) and the 60 min before administration of the
`study medication (i.e. )60 to 0 min).
`Mean pH was calculated for four post-treatment time
`periods: 0–30, 0–60, 0–90 and 0–120 min post-dosing.
`Each mean pH was calculated for intra-oesophageal and
`intragastric pH. Mean pH values were compared using
`univariate analysis of variance (ANOVA) with the factors
`sequence, period and treatment. All pairwise treatment
`comparisons were then made using Fisher’s
`least
`significant difference procedure.
`
`RESULTS
`
`Demographics
`
`Twenty subjects (11 males, nine females) completed all
`eight treatments. The mean age was 44 years, with a
`range of 24–63 years. At the time of study initiation, 15
`of 20 subjects were using antacids for the treatment of
`heartburn. Ten were taking calcium-rich Rolaids and
`five were using the antacid Mylanta. These pre-study
`medications were deemed to have no significant effect
`on subsequent study results and all such medications
`were discontinued for the duration of the study period.
`
`Pharmacodynamic data: intra-oesophageal and intragastric
`pH profiles
`
`The mean 5-min oesophageal and gastric pH values
`over the 5.5-h study period are presented in Figures 2
`and 3, respectively. Statistical analyses showed that
`there were no significant differences within dosage
`forms (i.e. various chewable doses vs. the swallowable
`
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`

`438 M . RO BI N SO N et al.
`
`Figure 2. Plot of mean intra-oesophageal
`pH/5 min during the entire recording
`period. Subjects consumed the refluxogenic
`meal from 60 to 90 min after the start of
`the study (shown by the shaded area).
`Antacids or placebo were given at 150 min
`after the start of the study (Dose). Data for
`swallowable tablets and for chewable
`tablets have been combined.
`
`Figure 3. Plot of mean intragastric pH/
`5 min during the entire recording period.
`Subjects consumed the refluxogenic meal
`from 60 to 90 min after the start of the
`study (shown by the shaded area). Antacids
`or placebo were given at 150 min after the
`start of the study (Dose). Data for swal-
`lowable and for chewable tablets have been
`combined.
`
`dosage levels). Therefore, the data for chewable tablets
`and for swallowable tablets have been combined for
`display in these figures. The 5-min oesophageal and
`gastric pH averages for 1 h after dosing are presented
`for each dosage form in greater detail in Figures 4 and 5,
`respectively.
`Overall, effervescent bicarbonate rapidly elevated oeso-
`phageal pH compared with the other active treatments,
`and chewable CaCO3 formulations sustained pH eleva-
`tion vs. swallowable CaCO3 (Figures 2 and 4; Table 1).
`Chewable calcium carbonate tablets and the effer-
`vescent antacid solution more effectively raised oeso-
`phageal pH than any of the swallowable formulations.
`In the stomach, only the effervescent bicarbonate and
`higher doses of chewable CaCO3 appeared to reliably
`
`elevate pH compared with the other antacid treatments
`and placebo (Figures 3 and 5; Table 1).
`Figures 4 and 5 show the 5-min means for oeso-
`phageal and gastric pH during the first hour after
`dosing. Figure 4 shows that, within 5 min of dosing, the
`effervescent solution and chewable calcium carbonate
`tablets produced a rise in pH in the oesophagus to above
`6.5 that was sustained for up to 60 min. Swallowable
`calcium carbonate tablets produced a slower and less
`marked rise in pH that was not sustained over this
`period. Figure 5 shows a marked increase in intra-
`gastric pH only with the effervescent bicarbonate
`solution. There were less marked and inconsistent
`increases in intragastric pH with the swallowable and
`chewable forms of calcium carbonate.
`
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`
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`

`ANTAC ID FORMULATION AND OESOPHAGEAL A CIDITY
`
`439
`
`Figure 4. Mean intra-oesophageal pH
`during the first hour after dosing (at
`150 min). Symbols for each individual
`treatment are shown in the diagram; Chew,
`chewable tablets; Swallow, swallowable
`tablets; Effervescent, effervescent solution.
`
`Figure 5. Mean intragastric pH during the
`first hour after dosing (at 150 min).
`Symbols for each individual treatment are
`shown in the diagram; Chew, chewable
`tablets; Swallow, swallowable tablets;
`Effervescent, effervescent solution.
`
`Table 1. Mean intra-oesophageal and intragastric pH with calcium carbonate formulations, effervescent bicarbonate solution or placebo
`for the period 0–60 min after dosing (n (cid:136) 20)
`
`Chew
`
`Swallow
`
`Placebo
`
`Effervescent
`
`750 mg
`
`1500 mg
`
`3000 mg
`
`750 mg
`
`1500 mg
`
`3000 mg
`
`Oesophageal pH
`Gastric pH
`
`5.12
`2.58
`
`5.88*(cid:160)
`3.89*(cid:160)
`
`5.71*(cid:160)
`2.78
`
`5.76*(cid:160)
`2.93*
`
`5.89*(cid:160)
`3.01*
`
`5.42*
`3.01*
`
`5.38
`2.92
`
`5.56
`3.10*
`
`*P < 0.05 vs. placebo.
`(cid:160)P < 0.05 vs. swallowable 750, 1500 mg.
`
`Effects of the refluxogenic meal
`
`A previous study demonstrated that a chilli meal
`reliably produces reflux and heartburn in this popula-
`tion.11 The present study verified the refluxogenic
`nature of a chilli meal. The analysis of
`intra-oeso-
`phageal and intragastric pH after meals is often difficult
`due to the inherent variability of pH: the ingested food
`buffers and dilutes gastric acid against a background of
`
`(cid:211) 2002 Blackwell Science Ltd, Aliment Pharmacol Ther 16, 435–443
`
`rapidly rising stimulated acidity as the stomach empties.
`However,
`the following generalities can be made
`regarding the effects of this meal on intra-oesophageal
`and intragastric pH.
`Before test meal ingestion, the intra-oesophageal pH
`remained stable with a value of approximately 6.7
`(mean values for all treatment groups were in the range
`6.68–6.88). This fell to a value of approximately pH 5
`during meal ingestion (see Figures 2 and 4, 0–60 min).
`
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`440 M . RO BI N SO N et al.
`
`The actual pH of the test meal was 5.5 (measured by
`homogenizing the constituents). The oesophageal pH
`remained low compared to baseline (mean values for
`the treatment groups were in the range 5.21–5.40) for
`the 60-min period following consumption of the test
`meal,
`indicating the reflux of gastric contents and
`substantiating the ability of the test meal to provoke
`acidic reflux.
`As expected, gastric pH was low before the test meal
`(mean pH for the groups was in the range 1.49–1.78)
`and rose to approximately pH 5 during the meal.
`Postprandially, this was followed by a gradual
`fall
`towards pre-meal pH values that did not reach pre-meal
`values before antacid dosing (see Figures 3 and 5).
`During the 60-min period after test meal consumption,
`and before antacid dosing, mean pH values for the
`treatment groups ranged from 3.98 to 4.31.
`
`Onset and duration of action
`
`The onset of action and duration of action were
`estimated separately for oesophageal and gastric pH.
`Calculated times to onset of a significant reduction in
`oesophageal and gastric acidity were similar for all
`doses and product forms, except that the low doses
`(750 mg) of chewable and swallowable antacid for-
`mulations had minimal effects on gastric pH. Swallow-
`able calcium carbonate 750 mg had no measurable
`onset time for gastric pH. The onset of a significant
`reduction in oesophageal and gastric acidity (increase
`in pH) for all other active treatments was between 30
`and 35 min.
`The duration of action varied widely between products
`(Figure 6). In general, chewable CaCO3 forms had a
`
`substantially longer duration of action (up to four times
`longer) than the same dose of swallowable CaCO3 for
`the neutralization of oesophageal acid. For example,
`chewable CaCO3 3000 mg and effervescent Na+/K+
`bicarbonate had relatively persistent effects (ranges:
`40 min in the oesophagus and 100–180 min in the
`stomach), while swallowable 750 mg and 1500 mg
`CaCO3 only transiently altered pH (ranges: 10–15 min
`in the oesophagus and 5–35 min in the stomach).
`
`Specific time intervals for post-treatment pH
`
`For the period 0–30 min after dosing, the mean intra-
`oesophageal pH ranged from 4.88 to 5.14. From
`Figure 4,
`the maximum mean pH appeared to be
`highest for the effervescent solution at around pH 7;
`for the chewable tablets, this value was pH 6.5 and, for
`the swallowable tablets, it was pH 6–6.5. The mean
`intragastric pH ranged from 2.85 to 3.36. Effervescent
`solutions produced the highest rise in mean intragastric
`pH (pH 4.7; Figure 5). Statistical analyses of pH for this
`period did not show any significant differences in mean
`oesophageal or gastric values.
`The analysis of the three post-treatment periods (0–60,
`0–90 and 0–120 min) produced similar results, and
`only those for the period 0–60 min are presented in
`Table 1. During the first 60 min after treatment, the
`following treatments showed statistically significantly
`greater mean oesophageal pH (Table 1; P < 0.05)
`compared to placebo: chewable 750 mg, 1500 mg
`and 3000 mg, swallowable 750 mg and 3000 mg
`and effervescent bicarbonate solution. Effervescent
`bicarbonate solution and chewable 750 mg, 1500 mg
`and 3000 mg showed statistically significantly greater
`
`Figure 6. Summary of duration of action
`(minutes) for calcium carbonate formula-
`tions and effervescent bicarbonate on
`oesophageal and gastric pH. n (cid:136) 20. The
`duration of action for chewable 3000 mg
`continued until the end of the observation
`period. Ch, chewable antacid tablets; Sw,
`swallowable antacid tablets; Bicarb,
`effervescent bicarbonate solution.
`
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`ANTAC ID FORMULATION AND OESOPHAGEAL A CIDITY
`
`441
`
`than swallowable 750 mg and
`mean pH values
`1500 mg (Table 1; P < 0.05). During this period, there
`were also significant differences among the mean gastric
`pH values of
`the eight
`treatments, with chewable
`3000 mg, swallowable 750 mg and 3000 mg and the
`effervescent bicarbonate solution all neutralizing acid
`significantly better than placebo (Table 1). The effer-
`vescent bicarbonate solution achieved significantly
`greater elevation of intragastric pH than the other six
`active treatments (P < 0.05).
`
`DISCUS SION
`
`Numerous studies,4, 7–10 including the present one, have
`demonstrated that antacids probably relieve heartburn
`pain by neutralizing acid directly within the oesophageal
`lumen and not necessarily within the gastric lumen. It is
`reasonable to suggest, therefore, that even small doses of
`chewed antacid tablet should provide more effective
`oesophageal pH control
`than quite large doses of
`swallowed antacids. The present study supports this
`suggestion and also explains the otherwise counter-
`intuitive notion that antacids with lower ANC might
`surpass those with far higher ANC. In our study, the
`onset of antacid effects seemed far slower than might be
`anticipated. It is likely, however, that the presence of
`food in the stomach with refluxed food in the oesophagus
`(from the early postprandial period) undoubtedly
`obscures, to some extent, the true antacid onset.
`Antacids are widely used for the self-treatment of
`episodic heartburn,13–15 although many physicians
`tend to dismiss the therapeutic value of such ‘low tech’
`therapy. Most over-the-counter antacids used by
`consumers range between 15 and 40 mmol ANC per
`dose. The doses of antacids selected for this study
`represent a range of ANCs used by consumers. For
`example, Tums, Tums E-X and Tums Ultra contain
`calcium carbonate with total ANC values of 10, 15 and
`20 mmol per tablet.16 Rolaids antacid tablets contain
`calcium carbonate and magnesium hydroxide with an
`ANC of 14.7 mmol per tablet.16 Maalox and Maalox
`extra-strength tablets contain aluminium and mag-
`nesium hydroxide with ANCs of 10 and 23 mmol per
`tablet, respectively.16 Mylanta in a gelcap formulation
`contains calcium carbonate and magnesium hydroxide
`with an ANC of 23 mmol when taking two tablets.16
`These doses are far lower than those employed in the
`classical studies by Fordtran et al. for duodenal ulcer
`disease treatment.7
`
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`
`Individuals participating in this study had a history of
`food- and beverage-related episodic heartburn and
`tended to self-medicate with over-the-counter products.
`Such frequent users of antacids in the community have
`previously been characterized15, 17 and, despite clear
`evidence of acidic gastro-oesophageal reflux as the basis
`of such antacid use, more than half of such individuals
`have no evidence of even trivial erosive oesophagitis.17
`The use of a standardized and validated provocative
`meal
`in the present study facilitated a comparative
`definition of the onset, duration and extent of antacid
`activity. Many studies have used provocative meals with
`various noxious components to evaluate antacids and
`antisecretory drugs for heartburn prophylaxis and/or
`treatment.9, 10, 18, 19 The lack of a standardized meal
`has led to studies of the effects of several meals designed
`to reliably produce gastro-oesophageal
`reflux and
`heartburn.11 The refluxogenic meal used in this study
`(chilli with cheese and onions, and a caffeinated soft
`drink) was
`slightly modified from the report by
`et al.,11 and contained no measurable
`Rodriguez
`capsaicin which could be
`considered a noxious
`component. In this previous study, all meals produced
`reflux and heartburn postprandially. However, the chilli
`meal
`induced more severe heartburn compared to
`baseline vs.
`the other meals, at 15–45 min post-
`prandially. Chilli also induced more reflux episodes
`and resulted in oesophageal pH < 4 for 17% of the
`postprandial time period. Because the chilli meal was
`previously shown to produce symptoms, symptoms
`were not recorded in the present study.
`In the current study, mean oesophageal pH dropped
`rapidly following the meal, and remained at 5–5.5 for
`more than 60 min after eating, indicating reflux of meal
`contents (meal pH is approximately 5.0). As expected,
`intragastric pH profiles were low prior to the meal and
`rose to approximately pH 5 (the pH of
`the meal),
`followed by a gradual fall to pre-meal pH values prior to
`antacid dosing.
`The results indicate that effervescent sodium bicar-
`bonate
`solution and
`chewable
`antacids
`provide
`significant elevation of
`intra-oesophageal pH, while
`swallowable calcium carbonate leads to minimal or no
`intra-oesophageal pH elevation. Of the antacid formu-
`lations studied, only effervescent Na+/K+ bicarbonate
`solution reliably elevated intragastric pH. Neither
`swallowable nor chewable antacid tablets led to statis-
`tically significant increases in intragastric pH, and the
`actual rise in intragastric pH with swallowable or
`
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`

`442 M . RO BI N SO N et al.
`
`chewable antacids was minimal over time, as demon-
`strated in Figure 3. These data provide further evidence
`that antacids probably affect acid reflux and related
`heartburn symptoms directly within the oesophageal
`lumen, at least in part by neutralization of refluxed acid,
`rather than by any impact on intragastric acidity.
`In this study, calcium carbonate tablets manifested
`little discernible dose–response effect on oesophageal or
`gastric pH in doses ranging from 750 to 3000 mg. The
`only dose-dependent activity apparent in this study was
`an increase in the duration of action with higher doses
`of chewable CaCO3. This suggests that 750 mg of
`chewable calcium carbonate may be the optimal dose
`and form to control intra-oesophageal pH in subjects
`with intermittent or episodic heartburn or acid reflux.
`Several earlier studies9, 10 compared the effects of
`different antacids on intragastric and intra-oesophageal
`pH using various provocative meals. Chewable tablets
`containing either aluminium/magnesium hydroxide or
`calcium carbonate and two liquid antacids containing
`aluminium/magnesium hydroxide differing in ANC
`were studied. Similar results were demonstrated in both
`of these studies: a rapid and prolonged increase in
`oesophageal pH coupled with modest changes
`in
`intragastric pH. As with the current study, these data
`strongly suggest
`that
`the lower oesophagus is the
`primary site of antacid action for heartburn relief.
`Although there have been no definitive individual
`studies reporting a direct correlation between the
`control of
`intragastric pH/intra-oesophageal pH and
`symptom relief, meta-analyses by the group at
`McMaster University in Ontario20, 21 suggest a strong
`relationship between the level of acid suppression or
`neutralization and symptom relief as well as mucosal
`healing (when applicable). In a study recently published
`by our group, we found that there was a close temporal
`relationship between heartburn and oesophageal acid-
`ity, but that a relatively large decrease in oesophageal
`acid exposure appeared to be necessary to produce a
`statistically significant decrease in heartburn severity.22
`The present study was conducted in a pertinent target
`population, i.e. one with a history of frequent heartburn
`using over-the-counter antacids for relief. This group
`comprises a very large segment of heartburn sufferers in
`the community. Many such individuals have no dis-
`cernible mucosal damage if endoscopy is undertaken.23
`It may be concluded that chewable and effervescent
`antacids lead to rapid elevation of intra-oesophageal pH
`and that such effects may or may not be associated with
`
`concomitant changes in gastric pH. The review of pH
`records showed a rapid rise of oesophageal pH within
`5 min of antacid administration, although this did not
`become statistically significant until later postprandially.
`It is not known whether a larger population might
`have shown an earlier onset of effects or if the effects of
`the meal and saliva would always obscure early antacid
`effects. The admixture of saliva and chewable antacid
`would be expected to be more effective than even quite
`large doses of swallowable antacid tablets. It should be
`possible to develop improved antacid formulations by
`increasing oesophageal mucoadherence, if this is indeed
`one mode of action of antacids.
`
`ACKNOWLEDGEMENTS
`
`This study was supported by Pfizer Consumer Health-
`care, NJ, USA and GlaxoSmithKline, NC, USA.
`
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