GASTROENTEROLOGY 1982;83:357-63
ALIMENTARY TRACT
Effect of 15(R)-15-Methyl Prostaglandin E2
(Arbaprostil) on the Healing of Duodenal
Ulcer
A Double-Blind Multicenter Study
G. VANTRAPPEN, J. JANSSENS, T. POPIELA, J. KULIG,
G. N. J. TYTGAT, K. HUIBREGTSE, R. LAMBERT,
J. P. PAUCHARD, and A. ROBERT
Department of Medicine, University of Leuven, Leuven, Belgium; L Klinik Chirugii, Narutowicz
Hospital, Krakow, Poland; Department of Gastroenterology, Wilhelmina Gasthuis, Amsterdam,
The Netherlands; Department of Gastroenterology, H6pital Edouard Herriot, Lyon, France; and
Department of Experimental Medicine, The Upjohn Company, Kalamazoo, Michigan
A multicenter study was conducted on 173 patients
with active, endoscopically proven duodenal ulcers
(158 men, 15 women). They were randomly as-
signed, in a double-blind manner, to two groups:
those receiving placebo capsules (91 patients) and
those receiving capsules containing 100 p,g of lS(R)-
lS-methyl prostaglandin E2 (arbaprostil) (82 pa-
tients). Each drug was ingested four times a day (1 h
before meals and at bedtime) for 28 days. Endoscopy
was performed on days 0, 14, and 28 after the trial
began. At each examination, the ulcer size was
measured and whether the ulcer had healed was
recorded. Arbaprostil increased the incidence of
ulcer healing to approximately the same degree as
reported in most extensive studies with cimetidine.
Received June 30, 1981. Accepted March 2, 1982.
Address requests for reprints to: Dr. Andre Robert, Department
of Experimental Sciences, The Upjohn Company, Kalamazoo,
Michigan 49001.
This study was made possible through the dedicated participa-
tion of the following individuals: P. Rutgeerts and L. Broeckaert,
Leuven, Belgium; D. Karcz and W. Nowak, Krakow, Poland; M.
Schneider, T. Vosmaer, and H. Stamer, Amsterdam, The Nether-
lands; and S. Beorchia and A. Martin, Lyon, France.
We acknowledge the active participation of Dr. Dean 1. Griffith,
Department of Experimental Medicine, The Upjohn Company, in
the gathering and analysis of the data.
We are also indebted to Dr. Arthur E. Hearron, Department of
Biostatistics, The Up john Company, for the statistical evaluation
of the data.
Arbaprostil is the approved generic name (United States Adopt-
ed Names Council) for 15(R)-15-methyl prostaglandin Ez.
The subjects who participated in this study signed an informed
consent release, and the study was approved by Institutional
Review Boards at each clinical center.
1982 by the American Gastroenterological Association
0016-5085/82/080357-07$02.50
At 14 days, three times as many patients were totally
healed in the arbaprostil-treated as in the placebo-
treated group (37% vs. 12%, p < 0.001). At 28 days,
67% of patients receiving arbaprostil were healed
compared with 39% in the group receiving placebo
(p < 0.001). Similarly, the ulcer size, measured
endoscopically, was much smaller after arbaprostil
administration than in the group receiving placebo
after both 14 and 28 days (p < 0.001). Side effects
attributable to treatment consisted primarily of
loose stools and diarrhea (34%). Smoking retarded
healing in the placebo-treated group (p < 0.05), but
did not significantly retard healing in patients treat-
ed with arbaprostil. We conclude that arbaprostil
markedly accelerates the healing rate of active duo-
denal ulcers. This effect may be due to inhibition of
acid secretion as well as to gastric cytoprotection.
Numerous reports have shown that prostaglandin Ez
(PGE z) and certain methyl analogs of PGE z inhibit
gastric acid secretion in animals (1,2) and humans
(3,4), and that they prevent the formation of experi-
mental gastric and duodenal ulcers (1,2). Arbaprostil
[15(R)-15-methyl prostaglandin Ezl is one of the
potent analogs of PGE z. Its mode of action requires
conversion of the "(R)" configuration at carbon 15 to
the "(S)" configuration. This epimerization is effect-
ed in an acid pH, such as found in the stomach, as
shown by studies in dogs (5). Gastric ulcers healed
faster after a 2-wk treatment with arbaprostil or its
methyl ester than after placebo (6,7). Similarly,
15(S)-15-methyl PGE z, methyl ester, and 16,16-di-
methyl PGE z, methyl ester, given orally for 2 wk,
accelerated the healing of duodenal ulcers (8). Arba-
358 V ANTRAPPEN ET AL. GASTROENTEROLOGY Vol. 83, No.2

prostil also inhibited basal, pentagastrin, and meal-
stimulated gastric secretion in human volunteers
(4,9) and duodenal ulcer patients (10,11).
In the present multicenter study, 15(R)-15-methyl
PGE 2 (arbaprostil) was administered orally for 4 wk to
patients with duodenal ulcers. The study was dou-
ble-blind, and the evolution of the ulcer was fol-
lowed endoscopically. An abstract was published
earlier (12).
Methods
Patients
Of a total of 181 patients entered into the study, 173
completed the 4-wk treatment during which they received
either placebo (91 patients: 82 men, 9 women) or arbapros-
til (82 patients: 76 men, 6 women). The 8 patients who did
not complete the treatment were excluded in the analysis
of ulcer data, but were included in the evaluation of side
effects. Of these, 1 had been assigned to receive placebo
and 7 to receive arbaprostil. The reasons for not complet-
ing the study were as follows: (a) the patient who took the
placebo was lost to follow-up after day 14 of examination
(Lyon); (b) an initial ulcer (day 0) was seen only by
spraying methylene blue, and because the endoscopy was
normal on day 14, the initial presence of ulcer was
uncertain (Lyon); (c) the patient did not follow the treat-
ment schedule (Lyon); (d) the drug was discontinued on
day 24 because of vomiting and diarrhea (Lyon); (e) the
patient had watery diarrhea on day 2 (Leuven); (f) the
patient was hospitalized after 7 days of treatment for
vomiting due to gastric obstruction (Leuven); (g) the pa-
tient was hospitalized on day 1 because of upper gastroin-
testinal bleeding; (h) the patient had three ulcers at first
endoscopy (Krakow).
The conditions of the study and the patient characteris-
tics are given in Table 1. The patients were predominantly
men and in each group they were well matched for age, the
number of smokers, and for the number of alcohol and
coffee users.
Inclusion Criteria
The following criteria were used for patient inclu-
sions: (a) Patients were between the ages of 18 and 70 yr,
except 2 men, 1 74 yr old and the other 76 yr old, both of
whom were assigned to placebo therapy. (b) The presence
of an active, symptomatic ulcer was visualized by endos-
copy. (c) Patients had no prior gastrointestinal surgery. (d)
Patients had no overt gastrointestinal bleeding during the
month preceding the entry into the study. (e) No patient

Table 1. Patient Characteristics

Initial
Mean ulcer size,
length of longest Cigarette Alcohol
Center and Sex Mean ageD (yr) dimension smokers users
No. of ulcer disease
treatment patients M F M F historya (mm) Yes No Yes No
Krakow
Placebo 33 33 0 32.4 5.0 9.5 25 8 9 24
(21-54) (1-15) (7-14)
Arbaprostil 34 34 0 33.3 6.8 10.2 33 1 14 20
(18-57) (1-25) (6-15)
Leuven
Placebo 22 18 4 43.7 43.3 10.0 7.2 15 7 7 15
(28-76) (35-59) (0-30) (4-13)
Arbaprostil 16 13 3 45.5 48.3 8.1 6.2 12 4 3 13
(29-68) (47-49) (1-20) (4-10)
Amsterdam
Placebo 21 16 5 41.8 45.8 9.6 6.3 18 3 14 7
(24-70) (34-62) (1-30) (4-12)
Arbaprostil 19 16 3 47.6 44.7 5.6 5.5 15 4 7 12
(28-62) (32-52) (1-27) (3-10)
Lyon
Placebo 15 15 0 34.9 5.2 8.0 7 8 8 7
(23-56) (0-18) (3-20)
Arbaprostil 13 13 0 35.9 7.9 7.2 8 5 6 7
(26-70) (1-22) (4-15)

Total
Placebo 91 82 9 37.5 44.7 7.4 8.0 65 26 38 53
(21-76) (34-62) (0-30) (3-20)
Arbaprostil 82 76 6 40.6 46.5 6.9 7.8 68 14 30 52
(18-70) (32-52) (1-27) (3-15)

a Numbers in parentheses denote range .

August 1982
had serious abnormalities detectable by a thorough physi-
cal examination, electrocardiogram, and routine blood and
urine laboratory tests, which were performed within 1 wk
of entry into the study. (f) Patients had not taken antisecre-
tory drugs (e.g., anticholinergics, cimetidine) or antiin-
flammatory drugs (including aspirin) during the week
before entry into the study. (g) Women were included only
if they were not of child-bearing potential or if they were
taking oral contraceptives.
Medication
The structure of arbaprostil is shown in Figure 1.
The dose of arbaprostil was 100 J.Lg, contained in a soft-
elastic capsule. Matching placebo capsules were prepared.
Design of the Study
The patients were randomized within each center
in a double-blind manner. Only the hospital pharmacist,
who distributed the drug, was in possession of the code.
The patient, the endoscopist, and the attending clinician
were not aware of the treatment given until all 173 patients
had completed the treatment. The subjects were outpa-
tients , and they were told to follow their usual diets.
Ninety-one patients received the placebo (82 men, 9 wom-
en) and 82 received arbaprostil (76 men, 6 women). The
patients were given a bottle containing capsules of either
placebo or the prostaglandin in quantities enough to last 2
wks. They were instructed to take one capsule four times a
day (1 h before meals and at bedtime). They were also
given an unlabeled bottle of antacid tablets , each containing
200 mg of magnesium hydroxide and 200 mg of aluminum
hydroxide. These tablets were to be taken only for the
relief of severe pain. A diary was given to each patient to
record pain frequency and severity, number of antacid
tablets consumed, side effects, and number and consisten-
cy of stools per day. Diarrhea was defined as watery stools
for 6 days or more, consecutive or not, during the 28 days
of the clinical trial.
Endoscopic Examination
The first endoscopic examination was done within
48 h before the start of treatment. It was repeated on days
14 and 28. Each time, the ulcer was measured either with a
biopsy forceps (Leuven, Lyon), or with a measuring device
(American Cytoscope Makers, Inc. , Stamford, Conn.) (Am-
o duration of the disease (in years) was compared between
~ \\" _ ......................
\\ ~- ~ '" COOH
HO
15(!!)-15-methyl PGE2
Figure 1. Structure of 15(R)-15-methyl PGE z (arbaprostil).
PROSTAGLANDIN IN DUODENAL ULCER 359
sterdam, Krakow). The longest and shortest diameters
were recorded on special forms. For almost every patient, a
color photograph of the ulcer was made at each endoscop-
ic examination. An ulcer was diagnosed as healed when
the crater had disappeared and the original lesion was
covered with what was considered to be new epithelium.
Possible Factors Influencing Ulcer Healing
On the basis of other studies, the possible influence
of certain habits were assessed. In particular, the patients
were asked whether they were habitual smokers, alcohol
users, or coffee drinkers. The incidence of healing in these
subgroups was compared to that of nonusers.
Assessment of Results
Most patients were seen at weekly intervals; all
were seen on days 14 and 28. At each visit, the diary was
examined. Any uncertainty was discussed and , whenever
possible, clarified. In addition to recording the number of
antacid tablets taken each day, the patients were asked to
bring back the medication capsules as well as the antacid
bottles at each visit so that the number of remaining tablets
could be counted. The initial ulcer size was compared
with the size measured at days 14 and 28.
Statistical Methods
Initial ulcer sizes were compared by analysis of
variance with treatment , country, and treatment by coun-
try effects in the model (13) . The mean ulcer size on days
14 and 28 was determined, and the percent difference from
day a was calculated. Both groups were compared by using
the Student's t-test (14). A similar log-linear model was
used to compare ulcer healing rates among countries (15).
Results from this latter method are reported as likelihood
ratio X2 statistics. The Fisher's exact test (16) was used to
compare dichotomous variables , including the overall
incidence of ulcer healing. Continuous variables such as
age and laboratory assays were analyzed by Student's t-test
(14) . The episodes of " ulcer pain" were evaluated statisti-
cally in terms of frequency and severity (minimal, moder-
ate, severe) for each week, as well as for the status
immediately before the start of the study. The physician
who saw the patients at weekly intervals made a final
assessment of pain on the basis of the diary and the
interviews; the physician was unaware of the treatment
given. All tests were two-sided and the results considered
statistically significant for p < 0.05. The effect of the
patients who healed and those who did not. For this
purpose, the Wilcoxon rank-sum test was used (17) .
Results
Total Healing
Arbaprostil markedly accelerated the inci-
dence of ulcer healing. At 14 days, 11 of 91 patients
360 VANTRAPPEN ET AL. GASTROENTEROLOGY Vol. 83. No . 2

c=J PLACEBO Ulcer Size

_ 1 5 (R)-15-METHYL PGE 2 Changes in ulcer size in both groups after 14

and 28 days are shown in Figure 3. At 14 days, the
ULCERS HEALED (%) mean ulcer size was reduced by 32% in patients
receiving placebo and by 56% in patients receiving
70 P<O.OOl arbaprostil (p < 0.01). At 28 days, the corresponding
values were 48% for placebo therapy and 83% for
arbaprostil therapy (p < 0.001).
60
Effect of Duration of Ulcer Disease

50 In each group (placebo and arbaprostil), the

duration of the ulcer disease did not influence the
percentage of patients who were totally healed, ex-
cept at 14 days, in the arbaprostil-treated group. In
40
these patients, those who had healed (n = 30) had a
mean duration of 7.5 yr of ulcer disease whereas
those who had not healed (n = 49) had a mean
30 duration of 4.0 yr of disease (p < 0.02).

Symptoms
20
Ulcer symptoms were rated "moderate-to-se-
vere" at the start in both groups. After 1 wk, they
were rated "minimal-to-moderate" with no statisti-
10
cal difference between groups.

Antacid Use

Figure 2 . Percent of patients completely healed.

(12.1%) receiving placebo were healed, compared
with 30 of 82 patients (36.6%) receiving arbaprostil
(Figure 2). At 28 days, complete healing was seen In
35 of 91 patients (38.5%) receiving placebo and in 55
of 82 patients (67.1%) receiving arbaprostil. On each
of these 2 days, the differences were statistically
significant (Fisher's exact test, p < 0.001) (Figure 2).
Variations existed among locations, especially at
14 days (Table 2). Regardless of the treatment given,
fewer patients were completely healed in Krakow
than in other centers, whereas the highest percentage
of healed patients was in Leuven.
In both groups, the number of patients using
antacids decreased gradually during the 4-wk of
treatment. For each week, fewer patients receiving
arbaprostil used antacids than those receiving place-
bo, although the difference was not statistically sig-
nificant. In both groups, those who used antacids
consumed approximately the same number of tablets
per day.
Smokers Versus Nonsmokers
At day 28, the number of patients who had
taken placebo and whose ulcer was healed was
much higher among nonsmokers (17 out of 26 or
65.4%) than among smokers (18 out of 65 or 27.7%);

Table 2. Number and Percentage of Patients Healed

14 Days 28 Days
Placebo 15 (R) PGE 2 Placebo 15 (R) PGE 2
Krakow 3/33 (9 .1% ) 7/34 (20.6% ) 6/33 (18.2 % ) 19/34 (55.9% )
Leuven 6/22 (27.3%) 14/16 (87.5%) 15/22 (68 .2% ) 15/16 (93 .8%)
Amsterdam 0/21 (0%) 5/19 (26.3 %) 7/21 (33.3 %) 13/19 (68.4 %)
Lyon 2/15 (13.3%) 4/13 (30.8%) 7/15 (46.7 % ) 8/13 (61.5%)
Total 11/91 (12.1 %) 30/82 (36.6%) 35/91 (38 .5%) 55/82 (67 .1%)
P < 0 .001 <0.001
August 1982 PROSTAGLANDIN IN DUODENAL ULCER 361

90 D PLACEBO or arbaprostil. No difference was detected between

groups. The details were reported separately (18) .
15 (R)-15-METHYl PGE2
80
Side Effects
70 (-32"10) Side effects were reported by 11 patients
= (12%) receiving placebo and by 37 patients (41%)
'>
c[ receiving arbaprostil. In the placebo-treated group, 4
Q 60
u.. patients (4%) experienced diarrhea; in the arbapros-
o
I- (-48"10) til-treated group there were 31 patients (34%). Two
as 50
c..;I
P<O.OOl of these discontinued treatment because of diarrhea.
cc
L.I.I
( -56"10 Patients in the placebo-treated group averaged 1.3
Q..
stools/day, compared with 1.8 in the arbaprostil-
W 40 treated group. One patient receiving arbaprostil had
!::::!
en abdominal discomfort, 2 had nausea, and 1 patient
cc
~ 30 was hospitalized after 7 days of treatment because of
...J
:::::I
vomiting attributed to duodenal obstruction. The
side effects reported by the placebo-treated group
20 were varied: fatigue , dizziness, semisolid stools,
neck and leg pains, and an unspecified skin lesion of
10 both legs. In both groups , no significant changes
were seen in laboratory assays.

14 DAYS 28 DAYS Compliance

Figure 3. Mean ulcer size on days 14 and 28, expressed as
percent of size measured on day 0 (before treatment).
this difference was significant (p < 0.05) . In the
group treated with arbaprostil, the difference in ulcer
healing between the two subgroups was not statisti-
cally significant (11 out of 14 or 78.5% among
nonsmokers compared with 44 out of 68 or 64.7%
among smokers).
Alcohol Users Versus Nonusers
In the placebo-treated group, the incidence of
ulcer healing was approximately the same in alcohol
users (5 out of 38 or 13.2%) as in nonusers (6 out of
53 or 11.3%). In the arbaprostil-treated group, how-
ever, more nonusers were healed at day 14 (24 out of
52 or 46.2%) than users (6 out of 30 or 20%) (p <
0.05). The difference between alcohol users and
nonusers was not significant at day 28.
Coffee Users Versus Nonusers
No difference in ulcer healing was noted rela-
tive to habitual coffee drinking.
Serum Gastrin
In one center (Amsterdam), basal and meal-
stimulated serum gastrin was determined before
treatment and after 4-wk of treatment with placebo
The compliance to treatment was estimated in
two centers by counting the number of capsules
returned to the clinic at the end of the trial. Compli-
ance was 92% in Lyon and 84% in Amsterdam.
Discussion
This study demonstrates that oral treatment
with 15(R)-15-methyl PGE 2 (arbaprostil) accelerates
the incidence of healing of active, endoscopically
proven duodenal ulcers . The benefit of arbaprostil
was particularly evident during the first 2 wk of
treatment. Complete healing after 2 wk occurred in
three times as many patients as in the placebo-
treated group (36.6% vs. 12.1%). The ulcer was also
significantly reduced in size in the group receiving
arbaprostil. Similar increases in the incidence of
ulcer healing were reported in most large studies
with cimetidine given for 2 and 4 wk (19-26).
The lower healing rate in Krakow can be ascribed
to two factors. First, the ulcers were initially larger
than in other countries (Table 1). Second, it was
discovered, after the study was completed, that all
patients in Krakow that had been selected for the
study had previously failed to respond to medical
therapy and had in fact been referred for surgery.
They can be classified as intractable. Differences in
healing rates existed also between Amsterdam and
Leuven, for which an explanation is not apparent.
Although ulcer pain is difficult to quantitate, pain
appeared to be relieved about equally in both groups.
However, as an indirect assessment of pain, the
362 VANTRAPPEN ET AL.
number of patients requmng antacid tablets was
consistently less in the arbaprostil-treated group
than in the placebo-treated group. This difference
was maintained for each of the 4 wk of the trial.
The duration of ulcer disease had little effect on
the incidence of healing. A statistical difference was
found only after 14 days of treatment with arbapros-
til (higher incidence of healing in patients with a
longer duration of disease). Binder et al. (19Lreport-
ed that patients with a recent onset of ulcer disease
(2-3 yr) appeared to have more frequent healing
regardless of therapy (cimetidine or placebo).
Smoking retarded healing significantly in the pla-
cebo-treated group, but not significantly in patients
treated with arbaprostil. A similar effect of smoking,
also limited to patients receiving placebo, was noted
in clinical trials with antacids (27) and cimetidine
(22). The reverse was true for alcohol users; alcohol
consumption did not influence healing in the place-
bo-treated group, but in the group receiving arba-
prostil fewer users were healed on day 14 than
nonusers (20% vs. 46.2%). The reason for this is not
apparent. Coffee drinking did not appear to influ-
ence ulcer healing.
Side effects attributable to treatment were primari-
ly loose stools and diarrhea. Two patients were
discontinued from the study because of this side
effect.
The enhanced healing in arbaprostil-treated pa-
tients cannot be explained by changes in serum
gastrin levels because there was no statistical differ-
ence between both groups. The antiulcer effect of
arbaprostil may be due to a dual mechanism, name-
ly, to inhibition of acid secretion and to cytoprotec-
tion. This latter property was demonstrated for PGE z
in animals and for a variety of PGE z analogs, includ-
ing several methyl analogs of PGE z (28,29). This
property was also demonstrated in humans. Prosta-
glandin Ez prevented gastric bleeding produced by
aspirin (30) and indomethacin (31). Arbaprostil pre-
vented development of gastric mucosal injury pro-
duced by aspirin as assessed endoscopically (32).
Prostaglandin Ez, given orally, prevented gastric
cellular desquamation, measured as deoxyribonucle-
ic acid in gastric washings, produced by intragastric
administration of 40% ethanol (33). Because cyto-
protection is usually manifest after very low doses of
prostaglandins, arbaprostil might still accelerate ul-
cer healing at a dose lower than the one used in the
present study (100 p.,g q.i.d.). A lower dose would not
cause loose stools while retaining antiulcer activity.
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