The Journal of International Medical Research

2010; 38: 449 – 457

A Randomized, Controlled, Crossover

Trial to Investigate Times to Onset of the
Perception of Soothing and Cooling by
Over-the-counter Heartburn Treatments
V STRUGALA1, PW DETTMAR1, K SARRATT2, J SYKES2, P BERRY3 AND E THOMAS3
1
Technostics Ltd, Hull, UK; 2Reckitt Benckiser Healthcare (UK) Ltd, Hull, UK; 3Reckitt
Benckiser Group plc, Slough, UK

This was a randomized, controlled, four-
way crossover study in 45 subjects with a
tendency to suffer from moderate
heartburn following some meals. The
study was designed to assess the time to
onset of the perceived soothing and
cooling effects of the alginate raft-forming
products, Gaviscon Liquid (peppermint),
Gaviscon Double Action Liquid
(peppermint) and Gaviscon Powder
Formulation (fresh tropical), compared
with a non-active sublingual control. All
three Gaviscon products provided
significantly faster soothing and cooling
effects compared with the control. Based
on the upper 95% confidence limits for the
median, time to onset of soothing was
perceived within 3.15 min, 3.08 min and
4.05 min for Gaviscon Liquid, Double
Action Liquid and Powder Formulation,
respectively. Similarly, time to onset of
cooling was perceived within 1.95 min,
1.23 min and 11.22 min for Gaviscon
Liquid, Double Action Liquid and Powder
Formulation, respectively. The results
show that Gaviscon Liquid and Gaviscon
Double Action soothe within 3.15 min and
cool within 1.95 min.

KEY WORDS: GASTRO-OESOPHAGEAL REFLUX DISEASE; POST-PRANDIAL HEARTBURN; GAVISCON;

ALGINATE-RAFT FORMING AGENTS; REFLUXOGENIC MEAL; DEMULCENT EFFECTS; DUAL-STOPWATCH TECHNIQUE

Introduction an over-the-counter (OTC) medication to

Many people experience symptoms of
heartburn and regurgitation, indicative of
gastro-oesophageal reflux disease, to a mild-
to-moderate extent in response to food.1 This
post-prandial heartburn is often related to
specific food triggers such as fatty, spicy, rich
or large meals.2,3 The sufferer, realizing the
lifestyle-related nature of the symptoms and
that they are not serious, tends not to consult
their general practitioner (GP) but purchases
relieve the symptoms.1,4 OTC medications for
the relief of heartburn include a wide variety
of antacids for bulk neutralization of
stomach acid, alginate reflux suppressants
that form a raft to suppress reflux and also
H2-receptor antagonists (H2RAs) and proton
pump inhibitors (PPIs) that pharmaco-
logically block/inhibit acid secretion.
The patient requires the OTC medication
for rapid and effective control of the symptoms

449
 V Strugala, PW Dettmar, K Sarratt et al.
Gaviscon for rapid relief of heartburn symptoms
that they are experiencing. Antacids have a
rapid but short-lived effect and H2RAs and
PPIs, whilst highly effective, have a long
latency before symptom relief is seen.5,6 In
contrast, alginate raft-forming reflux
suppressants have a rapid onset of action with
prolonged control of symptoms.7 – 9
Subjectively, patients have reported the
demulcent effects of cooling and soothing
with alginate products but this has never
been robustly evaluated. Techniques exist to
evaluate the onset of subjective sensorial
observations in short time frames using a
stopwatch.10 A pilot study was successfully
carried out to show the validity of using this
stopwatch technique in heartburn sufferers
to assess the time to onset of soothing and
cooling effects in response to treatment.11,12
The aim of the present study was to
document robustly the time to onset of
consumer-perceived soothing and cooling
effects in the oesophagus after taking OTC
alginate products, compared with a non-
active sublingual control, to treat post-
prandial heartburn. In order to do this a
prospective, randomized, controlled, four-
way crossover study was performed using a
dual-stopwatch technique.
Subjects and methods
STUDY DESIGN
The study was a randomized, controlled,
four-way crossover study in a single centre
with partial blinding. A single dose of test
drug was evaluated in subjects experiencing
post-prandial heartburn. The study was
carried out at Simbec Research Ltd, Merthyr
Tydfil, UK. The study was conducted in
accordance with the Declaration of Helsinki
as referenced in EU Directive 2001/20/EC and
complied with the International Conference
on Harmonisation (ICH) Good Clinical
Practice requirements. Ethical approval for
the study was given by South East Wales
450
Local Research Ethics Committee (December
2008). All subjects provided written informed
consent.
STUDY POPULATION
Subjects were recruited from the community
who were 18 – 65 years of age and
experienced post-prandial heartburn but
who were otherwise healthy and not
receiving prescribed treatment for heartburn
from their GP.
Each subject attended two screening visits
(at least 48 h apart), the second of which was
used to confirm the presence of moderate
heartburn (assessed on a self-rating scale)
within 60 min of consumption of a standard
refluxogenic meal (60% fat). Subjects who
met this criterion were invited to participate in
the study.
Exclusion criteria were recent
unexplained weight loss of 6 – 7 kg in the
last 6 months, gastrointestinal (GI) bleeding
in the last 12 months, difficulty swallowing,
history of (or symptoms suggestive of)
Zollinger–Ellison syndrome, gastric
carcinoma, peptic ulcer disease, pernicious
anaemia, Barrett’s oesophagus or systemic
sclerosis, or receipt of treatment for reflux or
upper GI conditions from their GP. Subjects
using antacids, H2RAs, motility stimulants,
prokinetics or other medicines for the relief of
reflux within 24 h of screening visit 2 or PPIs
within 48 h prior to screening visit 2 were
also excluded.
Other exclusion criteria were hypo-
phosphataemia, phenylketonuria, severe
constipation or colonic stenosis, intolerance or
allergy to the study drugs or formulation
constituents (sodium alginate, calcium
carbonate, sodium bicarbonate, parabens),
lactose, soya or wheat, and patients who were
on steroids or non-steroidal anti-
inflammatory drugs. In addition, subjects
with a history of cardiovascular disorders,
 V Strugala, PW Dettmar, K Sarratt et al.
Gaviscon for rapid relief of heartburn symptoms
drug, solvent and alcohol abuse, or with
diabetes were excluded, as were pregnant or
lactating women or those who were seeking to
get pregnant, as well as subjects who, in the
opinion of the study investigator, were unable
to comply with the study requirements.
STUDY PROTOCOL
Subjects who satisfied the inclusion criteria
attended the study unit at 08:00 h on four
separate occasions (2 – 7 days between visits)
and received a light breakfast before fasting
for 4 h. At the first visit, subjects were
allocated a study number and randomized to
one of four schedules for allocating
treatments to visits based on a Latin Square
design. Subjects were given a standard
refluxogenic meal comprising 60% fat and
asked to lie in a supine position after the
meal and until they experienced heartburn
of at least moderate severity on a self-rating
scale. At this point they were changed to a
sitting position and dosed with their
randomly allocated study medication for
that visit. The subjects were provided with
two stopwatches that were started by the
study staff at the time of dosing. One was to
record the time to first perception of a
soothing effect in the throat/oesophagus and
the other to record the time to first perception
of a cooling effect in the throat/oesophagus.
Subjects were instructed to stop the
stopwatch when the relevant effect was
perceived. If no feeling of soothing/cooling
was perceived within 30 min the result was
censored at 30 min. Subjects failing to report
heartburn within 60 min of the meal were
not dosed.
At the end of the 30-min treatment period,
the subject was asked if they would be
willing to use the product again, if they
would be willing to replace their current OTC
therapy and if they experienced any adverse
events.
451
A post-study visit took place 3 – 7 days
after the last treatment to check on any
adverse events that may have been
experienced by the subjects post-treatment.
TEST PRODUCTS
The four study drugs were provided by
Reckitt Benckiser Healthcare (UK) Ltd
Investigational Material Supplies Unit (Hull,
UK) and were as follows: Gaviscon Liquid
(GL) – peppermint (500 mg sodium alginate,
267 mg sodium bicarbonate, 160 mg
calcium carbonate per 10 ml liquid dose);
Gaviscon Double Action Liquid (GDAL) –
peppermint (500 mg sodium alginate, 213
mg sodium bicarbonate, 325 mg calcium
carbonate per 10 ml liquid dose); Gaviscon
Powder Formulation (GPF) – fresh tropical
(500 mg sodium alginate, 267 mg sodium
bicarbonate, 160 mg calcium carbonate per
1.428 g sachet powder dose); and non-active
sublingual control tablet (50.1 mg lactose,
30 mg mannitol per 100 mg sublingual
tablet dose). The control sublingual tablet
was not a placebo in the strictest sense of the
word since the format and appearance was
different to the test products. This format was
chosen as it was unlikely to provide a
soothing or cooling effect upon the
oesophagus. Gaviscon products were
provided in a blinded fashion to both
subjects and study staff although, due to the
difference in formulation, the control
sublingual tablet was administered open-
label.
DETERMINATION OF SAMPLE SIZE
A pilot study was performed using 20
subjects with a four-way crossover format to
evaluate the methodology.11,12 Post-hoc
review of the data using Kaplan–Meier
methods showed that the median time of
onset of soothing was 1.37 min for GL and
1.17 min for GDAL. The Kaplan–Meier
 V Strugala, PW Dettmar, K Sarratt et al.
Gaviscon for rapid relief of heartburn symptoms
medians for time of onset of cooling were
0.57 min for GL and 0.45 min for GDAL.
Although methods do not exist to assess the
power of a study to provide Kaplan–Meier
medians with a prospectively defined level
of precision, it was considered that a study
with 40 subjects would be sufficient to
substantiate the claims ‘soothes within 3
min’ and ‘cools within 2 min’ for GL and
GDAL and, potentially, for GPF (the latter
was not tested in the pilot study). Post-study
review of the data for the pilot study also
indicated that a study in 40 subjects would
have > 90% power to demonstrate that the
times to onset of soothing and cooling were
statistically shorter for the Gaviscon
products compared with the control using
Kaplan–Meier survival analysis
methodology.
STATISTICAL ANALYSIS
Times to first perceived soothing and cooling
effects were recorded. Minimum and
maximum values as well as mean ± SD were
calculated and the number of censored
measurements recorded. The Kaplan–Meier
medians and their 95% confidence intervals
(CI) were calculated for each parameter and
treatment. Comparison between treatments
was performed using a Cox regression model
adjusted for repeated events. The design
factors, treatment sequence and study period
were included in this model. An overall
comparison of the difference in the times to
first perception of soothing and cooling
between treatment groups was analysed
using analysis of variance (ANOVA) and
pairwise comparisons between active
treatments and the control.
Answers to yes/no questions were
compared using a χ2-test for independence,
and pairwise comparison between treatments
and control were evaluated, if deemed
appropriate. A P-value < 0.05 was considered
452
to be statistically significant. Statistical
analysis was performed using the software
package SAS version 9.1.3 (SAS Institute Inc.,
Charlotte, NC, USA) for Windows®.
Results
SUBJECT DEMOGRAPHICS
Sixty-four subjects were screened; 45
demonstrated moderate heartburn in
response to a refluxogenic meal at screening
visit 2 and were randomized to participate in
the study. The study population comprised
17 males and 28 females of mean ± SD age
35.7 ± 11.2 years. All subjects were
Caucasian apart from one African-
Caribbean. Mean ± SD height was 169.5 ±
10.6 cm, weight was 75.8 ± 16.3 kg and body
mass index was 26.2 ± 4.0 kg/m2. One
subject was withdrawn prior to dosing at
treatment visit 3 for a positive screen for drug
use (having received two treatments) and
one subject did not experience heartburn on
the fourth treatment visit and so did not
receive the final scheduled treatment. Data
collected for these two patients for visits prior
to their withdrawal were included in the
analysis.
TIME TO FIRST PERCEPTION OF
SOOTHING
Efficacy data for the time to first perception
of a soothing effect in the throat/oesophagus
following dosing of each of the four study
drugs are presented in Table 1. In the
majority of subjects, the control drug did not
generate a soothing effect, with 70% having
results censored at 30 min. All subjects
perceived soothing within 30 min for GDAL
and GPF, but two subjects (4.5%) failed to
report soothing within 30 min with GL. The
Kaplan–Meier median time to first
perception of soothing was 2.26 min for GL,
2.12 min for GDAL and 2.97 min for GPF.
Soothing was noted for all Gaviscon
 TABLE 1:
Time to first perception of soothing and cooling effects in the throat/oesophagus of the test and control products in subjects
with at least moderate heartburn in response to a refluxogenic meal
Kaplan–Meier
Mean ± SD time Time range Median time No. censored at
Effect/Product n (min) (min) (min) 95% CI 30 min
Soothing effect
GL (peppermint) 44 4.21 ± 6.48 0.18 – 30.00 2.26 1.55 – 3.15 2
GDAL (peppermint) 44 3.72 ± 5.09 0.27 – 27.83 2.12 1.58 – 3.08 0
GPF (fresh tropical) 45 3.98 ± 3.49 0.53 – 17.75 2.97 2.25 – 4.05 0

453
Control 44 23.96 ± 10.15 1.38 – 30.00 NAa NAa 31
Cooling effect
GL (peppermint) 44 4.88 ± 9.23 0.15 – 30.00 1.08 0.58 – 1.95 4
GDAL (peppermint) 44 1.95 ± 4.04 0.10 – 25.85 0.83 0.55 – 1.23 0
GPF (fresh tropical) 45 11.96 ± 12.83 0.20 – 30.00 3.95 2.33 – 11.22 14
Control 44 24.51 ± 10.05 2.32 – 30.00 NAa NAa 33
GL, Gaviscon Liquid – peppermint (500 mg sodium alginate, 267 mg sodium bicarbonate, 160 mg calcium carbonate per 10 ml liquid dose); GDAL,
Gaviscon Double Action Liquid – peppermint (500 mg sodium alginate, 213 mg sodium bicarbonate, 325 mg calcium carbonate per 10 ml liquid dose);
GPF, Gaviscon Powder Formulation – fresh tropical (500 mg sodium alginate, 267 mg sodium bicarbonate, 160 mg calcium carbonate per 1.428 g sachet
V Strugala, PW Dettmar, K Sarratt et al.

powder dose); Control, non-active sublingual control tablet (50.1 mg lactose, 30 mg mannitol per 100 mg sublingual tablet dose); CI, confidence
interval; NA, not applicable.
Gaviscon for rapid relief of heartburn symptoms

aData were not calculated due to high number of censored observations.

 V Strugala, PW Dettmar, K Sarratt et al.
Gaviscon for rapid relief of heartburn symptoms

products, within a median (Kaplan–Meier for GPF. According to ANOVA, a significant

analysis) of 3 min of dosing. Fig. 1A shows
the Kaplan–Meier curves for the four
products. Based on the upper 95% CI for the
median times of onset, perception of
soothing in the throat/oesophagus during an
episode of heartburn occurred within 3.15
min for GL, 3.08 min for GDAL and 4.05 min
overall difference in time to first perception
of soothing was noted between treatments (P
< 0.0001). Pairwise comparison revealed that
the time to first perception of soothing was
significantly shorter for all three Gaviscon
products compared with the control (all P <
0.0001).

A
100

80
Soothed (% of subjects)

GL
GDAL
60 GPF
Control

40

20

0
0 5 10 15 20 25 30
Time (min)

B
100

80
Cooled (% of subjects)

60

40

20

0
0 5 10 15 20 25 30
Time (min)

FIGURE 1: Kaplan–Meier curves of time to first perception of (A) a soothing effect and
(B) a cooling effect of the test and control products in subjects with at least moderate
heartburn in response to a refluxogenic meal. GL, Gaviscon Liquid – peppermint (500
mg sodium alginate, 267 mg sodium bicarbonate, 160 mg calcium carbonate per 10
ml liquid dose); GDAL, Gaviscon Double Action Liquid – peppermint (500 mg sodium
alginate, 213 mg sodium bicarbonate, 325 mg calcium carbonate per 10 ml liquid
dose); GPF, Gaviscon Powder Formulation – fresh tropical (500 mg sodium alginate,
267 mg sodium bicarbonate, 160 mg calcium carbonate per 1.428 g sachet powder
dose); Control, non-active sublingual control tablet (50.1 mg lactose, 30 mg mannitol
per 100 mg sublingual tablet dose). All test products were significantly different to
control (P < 0.0001; pair-wise comparison)

454
 V Strugala, PW Dettmar, K Sarratt et al.
Gaviscon for rapid relief of heartburn symptoms
TIME TO FIRST PERCEPTION OF
COOLING
Efficacy data for the time to first perception
of a cooling effect in the throat/oesophagus
are presented in Table 1. In the majority of
subjects, the control drug did not generate a
cooling effect, with 75% having results
censored at 30 min. All subjects perceived
cooling within 30 min for GDAL, but four
subjects (9%) failed to feel cooling with GL
and 14 subjects (31%) failed to perceive
cooling with GPF. Kaplan–Meier median
time to first perception of cooling was 1.08
min for GL, 0.83 min for GDAL and 3.95 min
for GPF. Cooling was noted for all Gaviscon
products, within a median (Kaplan–Meier
analysis) of 4 min of dosing. Fig. 1B displays
the Kaplan–Meier curves for all four
products. Based on the upper 95% CI for the
median times of onset, a perception of
cooling in the throat/oesophagus during an
episode of heartburn was observed within
1.95 min for GL, 1.23 min for GDAL and
11.22 min for GPF. According to ANOVA, a
significant overall difference in time to first
perception of cooling was noted between
treatments (P < 0.0001). Pairwise comparison
revealed that the time to first perception of
cooling was significantly shorter for all three
Gaviscon products compared with the
control (all P < 0.0001).
SECONDARY ENDPOINTS
When assessed, a significantly greater
proportion of subjects stated that they would
be willing to use the product again for the
three Gaviscon products compared with the
control (GL 79.5%, GDAL 93.2%, GPF 51.1%,
control 6.8%; P < 0.0001 versus control in
each case). Similarly, when asked whether
they would be willing to replace their current
OTC therapy with the test product there was
a significantly greater proportion willing to
do so for all the Gaviscon products compared
455
with the control (GL 38.6%, GDAL 56.8%,
GPF 26.7%, control 2.3%; P < 0.05 versus
control in each case). It must be noted that
no record of their current therapy was made
or whether they were regular users of
Gaviscon products, although patients
prescribed therapy by their GP were excluded
from the study, so current therapies would
have been self-administered OTC products.
SAFETY EVALUATION
Twelve subjects reported a total of 13
treatment emergent adverse events. One
occurred after treatment with GL, three after
treatment with GDAL, five after treatment
with GPF and four after treatment with the
control. Four events were mild, eight were
moderate and one was classed as severe
(headache) but all resolved with no sequelae.
Eleven adverse events were deemed to be not
related to or unlikely to be related to the
study medication. One event (abdominal
pain) was classified as possibly related to
study medication (GPF) and one event
(flatulence) as probably related to the study
medication (GDAL). There were no serious
adverse events.
Discussion
The present study was a randomized,
controlled trial with four treatment arms
carried out in a crossover format such that
each subject was evaluated after receiving all
four treatments. It was a sensorial study to
assess subjectively the onset of perceived
demulcent effects of soothing and cooling
after using products for the treatment of
heartburn that was instigated by
consumption of a refluxogenic meal. A pilot
study had previously shown the validity of
using a dual-stopwatch method in the
heartburn indication, and in this study
format, in order to record the time to first
perception of soothing or cooling in response
 V Strugala, PW Dettmar, K Sarratt et al.
Gaviscon for rapid relief of heartburn symptoms
to the medication.11,12 Subjects were able to
distinguish clearly between the sensorial
effects of soothing and cooling.
In the present study, three OTC Gaviscon
product variants were evaluated compared
with a non-active sublingual control tablet
in 45 subjects. The control sublingual tablet
was not a placebo in the strictest sense of the
word since the format and appearance was
different to the test product. This format was
chosen for the control as it was unlikely to
provide a soothing or cooling effect upon the
oesophagus; however, this difference in
formulation meant that blinding of the
investigators and study subjects to the
control tablet was not feasible. In all cases,
the times to first perception of soothing and
cooling were significantly faster with the
Gaviscon products compared with the
control.
Gaviscon products have been described as
having a rapid onset of action in comparison
with H2RAs and PPIs over the first hour after
dosing using objective measures of reflux.7 It
has, however, been suggested by the
manufacturers and users of Gaviscon
products that relief of symptoms can be
identified rapidly (in a matter of minutes) in
subjective assessment. The present study was
designed to substantiate the claims of
‘soothes within x minutes’ and ‘cools within
y minutes’ and to generate robust data as to
the time to onset of these sensorial effects.
Based on the upper 95% CI for the median
times of onset, this study showed that for GL
a perception of soothing in the
throat/oesophagus during an episode of
heartburn was observed within 3.15 min,
while cooling was perceived within 1.95 min.
GDAL, which has additional acid
neutralization capacity,13 demonstrated a
slightly quicker onset of both soothing and
cooling compared with GL (soothing in 3.08
min and cooling in 1.23 min). GPF was less
456
effective, achieving soothing within 4.05 min
and cooling only within 11.22 min. The
impact of cooling may be related to the
peppermint flavouring in the liquid
formulations and the known cooling effect of
menthol.14
The limitations of the present study were,
first, that due to formulation constraints, full
blinding was not possible and as a result
investigators and study subjects were blinded
to the active Gaviscon drugs but not the
inactive sublingual control. Secondly, the
subjects’ current OTC therapy was not
recorded, which goes some way to
explaining the low response to the secondary
endpoint question regarding willingness to
replace current therapy with the evaluated
treatment.
Reflux causes an irritant action upon the
oesophagus leading to the burning and
painful sensation of heartburn. A perception
of soothing in the oesophagus may,
therefore, indicate the cessation of the
irritant effect upon the oesophageal mucosa.
This demulcent effect in the oesophagus
following ingestion of Gaviscon products
demonstrates a rapid local mode of action
upon dosing prior to generation of the
alginate raft within the stomach, the
primary mode of action.15 A demulcent effect
has been previously reported, based upon a
subjective assessment of throat pain on
swallowing in response to a product, thereby
justifying such a claim for Gaviscon
products.16
In conclusion, this randomized,
controlled, four-way crossover trial has
shown that the three Gaviscon products
tested provided a significantly faster onset of
action compared with the non-active control
compound in terms of perceived soothing
and cooling effects within the oesophagus.
The GL (peppermint) and GDAL
(peppermint) formulations can provide a
 V Strugala, PW Dettmar, K Sarratt et al.
Gaviscon for rapid relief of heartburn symptoms

soothing, demulcent effect on average within of the study drugs.

3.15 min and a cooling effect on average
within 1.95 min of dosing in subjects
experiencing post-prandial heartburn.
Acknowledgement
This study was funded by Reckitt Benckiser
Healthcare (UK) Ltd, Hull, UK, manufacturer
Conflicts of interest
K Sarratt, J Sykes, P Berry and E Thomas are
employees of Reckitt Benckiser Healthcare
(UK) Ltd. V Strugala and PW Dettmar had no
conflicts of interest to declare in relation to
this article.

• Received for publication 23 October 2009 • Accepted subject to revision 9 November 2009
• Revised accepted 9 February 2010
Copyright © 2010 Field House Publishing LLP

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Author’s address for correspondence

Professor Peter Dettmar
Technostics Ltd, The Deep Business Centre, Hull HU1 4BG, UK.
E-mail: peter.dettmar@technostics.com

457