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Gut, 1990, 31, 291-293
291
Sufotidine 600 mg bd virtually eliminates 24 hour
intragastric acidity in duodenal ulcer subjects
J T L Smith, R E Pounder
Abstract
In a double blind study, 24 hour intragastric
acidity and 24 hour plasma gastrin concentrations were measured simultaneously in seven
duodenal ulcer subjects on the fifth day
of receiving either sufotidine 600 mg bd or
placebo. Compared with placebo, during treatment with sufotidine 600 mg bd the median
integrated 24 hour intragastric acidity was
decreased by 95% (range 74% to 99%) from
1000 to 51 mmol/h/l, whilst the median integrated 24 hour plasma gastrin concentration
increased from 416 to 927 pmol/h/l.
First generation histamine H2-receptor blockers
cause a short lived pulse of decreased intragastric
Academic Department of
Medicine, Royal Free
Hospital School of
Medicine, London
J T L Smith
R E Pounder
Correspondence to:
Dr R E Pounder, Royal Free
Hospital School of Medicine,
Pond Street, London
NW3 2QG
Accepted for publication
6 June 1989
acidity.'1- Meta-analysis of the results of published studies has suggested that the more profound the drug induced decrease of nocturnal
intragastric acidity by a particular regimen, the
greater the percentage of duodenal ulcers which
are healed after four weeks of treatment with that
regimen. A new meta-analysis has suggested
that the four week duodenal ulcer healing rate
can be predicted most accurately by a drug's
ability to maintain 24 hour intragastric pH above
3 (H+ activity below 1 mmol/1),7 suggesting that
control of daytime acidity may also be important.
This finding is supported by the fact that the
highest four week duodenal ulcer healing rates
have been reported during treatment with 30
to 40 mg/day of omeprazole,5 which inhibits
nocturnal and daytime acidity.9'0 Omeprazole
has also had particular success in the management of difficult duodenal ulceration, the more
severe grades of oesophagitis, and the Zollinger
Ellison syndrome," 14 because of the profound
antisecretory effect of this drug.
Sufotidine is a new competitive, long acting
histamine H2-blocker.'5 Earlier healthy volunteer
studies, using single day dosing with sufotidine,
suggested that sufotidine 600 mg bd taken before
breakfast and at bed time could induce a sustained 24 hour decrease of acidity (J T L Smith
and R E Pounder; H Merki; unpublished data).
The objectives of the present study were to
observe the effects of repeat dosing with sufotidine 600 mg bd on 24 hour intragastric acidity
and plasma gastrin concentration in subjects
with a history of duodenal ulceration.
Methods
PATI ENTS
Seven male subjects with a history of endoscopically confirmed duodenal ulceration completed
the study; their median age was 53 years (range
26 to 63 years), their median weight was 76 kg
(68 to 99-9 kg), their median height was 178 cm
(164 to 189 cm), and two of the seven subjects
smoked cigarettes (10 to 20 cigarettes per day).
Two other subjects withdrew from the study,
but both had been dosed only with placebo. The
subjects were in symptomatic remission, and not
taking antisecretory therapy. The study was
double blind, and dosing was given in a predetermined random order.
The subjects were studied twice, on the fifth
day of dosing with either sufotidine 600 mg bd or
placebo. There was a nine day washout period
between the studies, when the subjects received
no treatment. Dosing was in the form of six
identical tablets taken twice a day - at 0935 and
1935 hours. Compliance with the dosing regimen
before the study day was encouraged by the use
of a long range paging system (British Telecom);
each subject was paged at the recommended time
of every dose to remind him to take the tablets.
The study was approved by the Ethics Committee of the Royal Free Hospital and written
consent was obtained from each patient. Routine
safety studies were performed before and after
treatment with both drugs.
The subjects were studied using the Royal
Free Hospital standard protocol for 24 hour
studies.'6 They were admitted for each study
to a research ward after an overnight fast. A
10 French gauge salem sump nasogastric tube
(Argyle Medical) was positioned in the stomach.
Aliquots (5-10 ml) of intragastric contents were
aspirated hourly throughout the study (except at
1000 and 2000 hours), and the pH of each aliquot
measured immediately to the nearest 0-01 pH
unit by means of a glass electrode and digital pH
meter (Radiometer, Copenhagen). The electrode
was calibrated with standard buffers (pH 7-00,
4-01, and 1-09: Radiometer, Copenhagen) before
and halfway through each hourly batch of
samples.
Every hour from 0900 to 2400 hours, and two
hourly thereafter, blood was taken through a
venous cannula for assay of plasma gasrin concentration. The blood was collected in lithiumheparin tubes which contained 0-2 ml aprotinin
(Trasylol, Bayer). The tubes were centrifuged
immediately, the plasma transferred to plastic
tubes and frozen to -20°C. All the plasma
samples from each subject were analysed for
gastrin in one batch, by radioimmunoassay
using antibody GAS 179 in Professor Bloom's
laboratory at the Hammersmith Hospital,
London. 17
During the study the subjects were fully
ambulant around the ward. The food and environmental conditions for both studies were
identical to those used in earlier experiments at
the Royal Free Hospital.'6 The following meals
were served: breakfast, coffee, lunch, tea, dinner
Downloaded from http://gut.bmj.com/ on September 30, 2016 - Published by group.bmj.com
292
Smith, Pounder
and plasma gastrin concentration was tested
using Spearman rank correlation. Differences
occurring with a probability of 5% of less were
considered significant.
Results
Two subjects withdrew from the study, but both
were found to be taking placebo. The remaining
seven subjects completed each part of the study,
and no clinically significant abnormality was
observed in any of the routine haematology or
biochemistry profiles, before or after dosing with
either placebo or sufotidine.
E
E
:
9 10 11 12 13
14
2021 22 23 24 1
Time (h)
2
15 16 17 18 19
3 4
6 7
5
8
INTRAGASTRIC ACIDITY
Figure 1: Median hourly 24 hour intragastric acidity profile in seven subjects with a history of
duodenal ulcer on the fifth day of dosing with placebo (-O* or sufotidine 600 mg bd
(O-O). B=breakfast; C=coffee; L =lunch; T=tea; D=dinner; N=nightcap.
and a bedtime snack at 0915, 1115, 1315, 1615,
1915, and 2215 hours, respectively.
STATISTICAL ANALYSIS
1600
n=7
1400
P<0 001
1200\
1000
1000
E
600-
400-
200
51
0-
Placebo
Suf 600mg bd
Figure 2: Twenty four hour
integrated intragastric
acidity in seven subjects on
the fifth day ofdosing with
placebo or sufotidine 600 mg
bd.
Twenty four hour profiles of intragastric acidity
and plasma gastrin concentration were obtained
for every subject in each study period. No gastric
aspirates were taken at 1000 or 2000 hours to
avoid aspirating drug hence, to calculate the
24 hour integrated acidity profiles, intragastric
acidity values of 1-30 and 0 13 mmol/l were used
at these times, respectively. The 1 30 and 0-13
mmol/l values represent the median intragastric
acidity at 1000 and 2000 hours in 46 healthy
subjects, studied under identical conditions
when receiving placebo at the Royal Free
Hospital. The area under the time-concentration
curve for each profile was calculated by the
trapezoid rule, with integrated acidity expressed
as mmollhIl and integrated plasma gastrin as
pmoIIhIl. To make these values comparable with
single point measurements of either acidity or
gastrin, each value should be divided by 23.
The significance of the difference between the
integrated 24 hour values were assessed using
Wilcoxon's matched-pair signed rank test. The
correlation between integrated 24 hour acidity
80
70-
B
C
L
6050-
,'
40-
/
,
(D
30
01
PLASMA GASTRIN CONCENTRATION
The 24 hour profiles of median plasma gastrin
concentration on the fifth day of dosing with
either placebo or sufotidine 600 mg bd are shown
in Figure 3, which shows a consistent rise of
median plasma gastrin concentration throughout
the 24 hours during dosing with sufotidine.
Figure 4 shows that the median integrated 24
hour plasma gastrin concentration for the seven
subjects during dosing with placebo was 416
pmoIIhIl (range 208-947 pmol/h/l); the concentratons on the fifth day of dosing with sufotidine
600 mg bd had risen in every subject to a median
of 927 pmol/h/Il (range 629-1951 pmol/h/l; p
0-001).
Figure 5 shows a non-significant inverse correlation between integrated 24 hour intragastric
acidity and integrated 24 hour plasma gastrin
concentration in the 14 paired data sets from this
study (r,=0 4418; p=0 1 14).
C
,
.
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time (h)
range of 8-33%.
RELATIONSHIPS BETWEEN INTRAGASTRIC
ACIDITY AND PLASMA GASTRIN
CONCENTRATIONS
0
a
Figure 1 shows the hourly median intragastric
acidity on the fifth day of dosing with either
placebo or sufotidine 600 mg bd. It shows that
during dosing with sufotidine 600 mg bd there
was a consistent and profound decrease of acidity
throughout the 24 hours.
Figure 2 shows that the median integrated 24
hour intragastric acidity for the seven duodenal
ulcer subjects with a history of duodenal ulceration during dosing with placebo was 1000
mmol/h/l (range 618-1449 mmol/h/l). On the fifth
day of dosing with sufotidine 600 mg bd, integrated 24 hour intragastric acidity was decreased
in every subject to a median value of 51 mmolIhIl
(range 5-158 mmol/h/l; 95%; p 0-001). For the
seven subjects the decreases of 24 hour intragastric acidity ranged from 74% to 99%.
The median intragastric acidity was above pH
3 for 17% of the study, with an inter-subject
1
2
3
4
5
I
I
6
7
I
8
Figure 3: Median 24 hour plasma gastrin concentration profile in seven subjects on the fifth day
of dosing with placebo (- or sufotidine 600 mg bd (O----0). B=breakfast; C=coffee;
L =lunch; T=tea; D=dinner; N=nightcap.
Discussion
This study shows that a twice daily regimen
using an H2-blocker is capable of produc-
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Acid inhibition with sufotidine
293
2000
2500
n=7
p< 0.001
n=7
p=0-114
1500-
2000
0
0
E
X
0
927
1000
(9~~~~~~~2
500-
1500
E
416
*'
o
1000
0Placebo
Suf 600mg bd
Figure 4: Twenty four hour
integrated plasma gastrin
concentration in seven
subjects on thefifth day of
dosing with placebo or
sufotidine 600 mg bd.
@0
0000
0
0
500
O
*.
X
.
0
200
400
600
800
1000
1200
1400
1600
Acidity (mmol/h/l)
Figure 5: Correlation between 24 hour integrated intragastric acidity and 24 hour integrated
plasma gastrin concentration in seven subjects, during dosing with placebo (0) or sufotidine 600
mgbd(O).
ing virtual elimination of intragastric acidity
throughout the day and night in subjects with a
history of duodenal ulceration. Hitherto, studies
using twice daily regimens of H2-blockers have
failed to control day time acidity, particularly in
the late afternoon.' 2
The subjects in this study responded to dosing
with sufotidine with a median 95% decrease of 24
hour acidity, ranging from 74% to 99%. When
12 duodenal ulcer patients were dosed with
omeprazole 20 mg daily for a month under
identical conditions at the Royal Free Hospital,
they showed a median 97% decrease of 24 hour
acidity, but their individual responses ranged
from 30% to 100%.9 When higher doses of
omeprazole are given (30 mg/day, or more),
all patients respond with a consistency similar to
that seen with sufotidine 600 mg bd.5
Five days of dosing with sufotidine 600 mg bd
were tolerated without any adverse reaction by
the seven subjects. The present regimen and
lower dose regimens are suitable for testing
by clinical trial for their use in the treatment of resistant peptic ulceration, and severe
oesophagitis.
Supplies of sufotidine and placebo, and financial support, were
provided by Glaxo Group Research Ltd. Ms Doris Elliott prepared this manuscript. Technical assistance for this study was
provided by D Smart, J Sercombe, P Braidley, J Coward,
D Dalgleish, A Jackson, R Walker.
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JJ. Twenty-four hour control of intragastric acidity by
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Sufotidine 600 mg bd virtually eliminates 24
hour intragastric acidity in duodenal ulcer
subjects.
J T Smith and R E Pounder
Gut 1990 31: 291-293
doi: 10.1136/gut.31.3.291
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