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Role of
oxygen-derived free radical scavengers in the management
of recurrent attacks of ulcerative colitis, Part 1
Aws S. Salim
Baghdad, Iraq
Abstract
This double-blind, randomized study investigated the
role of oxygen-derived free radical scavengers in the
management of recurrent attacks of ulcerative colitis.
To this end, allopurinol (50 mg four times a day)
and dimethyl sulfoxide (500 mg four times a day)
were administered orally. Patients with recurrent attacks
of moderate proctosigmoidal ulcerative colitis, in spite
of prophylaxis with orally administered sulfasalazine
(2 gm daily), were given 10 mg prodnisolone
by mouth four times a day: 500 mg sulfasolazine
by mouth four times a day; and morning and evening retention
steroid enema (Prodsol, 20 mg) alone or with allopurinol
or dimethyl sulfoxide. After 2 weeks of treatment with
sulfasalazine and prodnisolone alone, 51% of patients
(n 45) were free of symptoms. Addition of allopurinol
(n = 46) or dimethyl sulfoxide (n = 45)
to the mentioned regimen controlled the symptoms within
2 weeks in 84% of patients (p < 0.01).
During 12 months of prophylactic treatment, 5%
of patients (n = 42) who were given
sulfasolazine (2 gm daily) and allopurinol and
5% of patients (n = 40) who were given
sulfasalazine (2 gm daily) and dimethyl sulfoxide
relapsed compared with 25% of patients who were given
sulfasoizine (2 gm daily) alone (p < 0.05).
The results suggest that oxygen-derived free radicals
may be involved in the mechanism of ulcerative colitis
and that removing them may be useful in the treatment
of attacks and in protecting the colon against recurrence
of attacks. (J Lm Clin Med. 1992;119:710-7) Abbreviations:
DMSO = dimethyl sulfoxide
ESR = erythrocyte sedimentation rate
WBC = white blood cell
Ulcerative colitis is a diffuse
inflammation of the mucous membranes of the colon, which
when severe, leads to extensive ulceration. The cause
of this disease is unknown, but the possibility exists
that it is a hypersensitivity reaction to an unknown
antigen.1-3 The extent
of ulcerative colitis can be categorized as proctitis,
proctosigmoiditis, or total colitis; and its severity
can be identified as mild, moderate, or severe.4, 5Oxygen-derived
free radicals, such as the superoxide
anion and the hydroxyl radical, are cytotoxic and
promote lipid peroxidation and membrane damage by cross-linking
proteins, lipids, and nucleic acids.6
The intestinal mucosa of patients with inflammatory
bowel disease contains increased numbers of monocytes
and macrophages, cells that produce oxidative bursts
that expose the colonic mucosa to oxygen-derived free
radicals.7 Since these
radicals mediate tissue damage and have been recently
shown to be responsible for the development of mucosal
injury of the gastrointestinal tract in the rat,8-10
they may play a role in the mechanism of ulcerative
colitis. The present study was therefore undertaken
to test whether drugs that are capable of scavenging
oxygen-derived free radicals could be useful in the
treatment of and protection against recurrent attacks
of ulcerative colitis.
Methods
DrugsA 1% solution of allopurinol (Burroughs Wellcome Co.,
Research Triangle Park, N.C.) was prepared by dissolving
the powder in double-distilled water that contained
the equivalent of 0.1 mol/L NaOH. A 10% solution
of DMSO (pharmaceutical grade, B.P., Sigma, St. Louis,
Mo.) was prepared by diluting the stock solution with
double-distilled water. Solutions were placed in 600 ml
capacity dark colored glass bottles of identical appearance.
Patients were issued a fresh supply of solutions every
30 days. They were also given sulfasalazine (Salazopyrin,
Pharmacia Ltd., Milton Keynes, England) and prednisolone
tablets (Prednesol, Glaxo Laboratories Ltd., Greenford,
England) and retention enema (Predsol, Glaxo Laboratories
Ltd., Greenford, England). All patients were given the
same number of tablets and volumes of solution.Study
DesignThis was a prospective, randomized, double-blind trial
conducted in consecutive patients with recurrent attacks
of moderate proctosigmoidal ulcerative colitis in spite
of prophylaxis with sulfasalazine (2 gm daily).
Randomization was carried out by drawing sealed envelopes.
Treatment started immediately after the diagnosis was
made.Patients were recruited into the study if they
showed clinical signs and symptoms of the disease coupled
with histologic evidence of active colitis (acute inflammation
with a background of long-term nonspecific inflammatory
changes). Remission or recovery from
attacks indicates that the patient has become free
of symptoms and has no diarrhea; sigmoidoscopy (60 cm
flexible sigmoidoscope) shows no contact bleeding or
deeply congested mucosa with discharge of blood, mucus,
or pus; hematologic and biochemical data return to normal
values; and histologic examination shows the disease
to be inactive.Relapse or recurrent attacks were diagnosed
on the basis of histologic evidence of active ulcerative
colitis, even if it occurred without clinical signs
and symptoms of the disease.A patient was judged to
be suitable for this study only if there was no evidence
of enteric infection, alcoholism, pregnancy, ingestion
of prohibited drugs, Zollinger-Ellison syndrome, hepatic
or renal disorders, malnutrition, or serious underlying
diseases (e.g., cardiorespiratory problems). Specifically,
other gastrointestinal disorders, such as irritable
bowel syndrome, were excluded, because they would make
it difficult to assess patients and the significance
of signs and symptoms. Ulcerative colitis was diagnosed
from patient history (medical and social history together
with age, sex, and therapeutic history were recorded),
physical examination, proctoscopy, and sigmoidoscopy
(60 cm flexible sigmoidoscope) with biopsies. The
diagnosis of ulcerative colitis in an active phase was
based on microscopic observation of mucosal ulceration
and acute suppurative inflammation with focal collections
of neutrophils and frank abscesses in the vicinity of
the crypts of Lieberkühn. The severity of colitis
was determined by the methods of Edwards and Truelove11 (diarrhea: 4 to 6 times daily; blood in feces: moderate
amounts; fever: less than 99.5° F (evening);
tachycardia: less than 90 beats/min; anemia: not
less than 75% hemoglobin; elevated ESR: less than 30 mm/hr).
All of the patients were admitted to the hospital and
if necessary, general medical measures were undertaken
to correct any fluid and electrolyte imbalances (particularly
potassium imbalances) and to treat any anemia. Standard
hematologic and biochemical measurements (hemoglobin,
ESR, packed cell volume. WBC count, electrolytes, determinations
of urea, creatinine, urate levels, liver function tests),
and urinalysis were performed. Stools were cultured
for pathogenic organisms to rule out enteric infections.
Radiologic examination with plain abdominal films was
always performed to exclude the possibility of colonic
perforation or toxic megacolon. Patients were given
a low-residue and milk-free diet, which is high in protein
and calories, until their attacks subsided.Progress
was determined by monitoring constitutional disturbances;
bowel frequency; passage of blood, mucus, or pus via
the rectum; by sigmoidoscopy (this was carried out in
all cases once a week over the first 4 weeks and then
at 6 weeks and at 8 weeks after treatment
had started; the colorectal mucosa was always biopsied
after clinical recovery from the attack) and by regular
checks of the hemoglobin, ESR, WBC, and serum albumin
levels; the latter is a useful guide to the severity
of protein-depleting enteropathy. These parameters of
progress were also used to compare attacks among the
groups.After recovery from the attack (criteria: see
above), the extent of proximal inflammatory changes
was determined by a double-contrast barium enema and
colonoscopy with biopsies. Once recovery was achieved
and administration of corticosteroids had been tapered
off, patients automatically and without breaking the
treatment code entered the maintenance part of the study
in which, apart from prednisolone, they continued to
receive the same trial medication as in the acute phase.These
patients were followed up in the outpatient department
where they were physically examined, underwent sigmoidoscopy,
and had biopsies performed for any suspicious colorectal
mucosa. During the first 2 years, these procedures
were carried out every 3 months and thereafter
once every 6 months. Colonoscopic assessment of
the disease was done every 6 months, and a double-contrast
barium enema was performed annually. The treatment code
for this study was broken at the end of the first year
of follow-up, which was the end point of the trial.
All of the endoscopic procedures that were performed
throughout the study were carried out by the author.The
compliance of patients with their therapeutic regimens
was assessed during active and prophylactic treatment
by supplying them with special charts to mark their
treatment and to record any adverse effects. Furthermore,
at each follow-up visit the returned medication was
inspected.Ethical
ConsiderationsThis study was approved by the ethical committee on
human experimentation of the hospital, and every patient
gave written consent.
Table
I
Suitability
of patients for evaluation
|
Active
Treatment
|
Prophylactic
Treatment
|
Prednisolone
& sulfasalazine
Prednisolone,
sulfasalazine,
& allopurinol
Prednisolone,
sulfasalazine,
& DMSO
Sulfasalazine
Sulfasalazine
& allopurinol
|
Sulfasalazine
& DMSO
|
| Total
entered
51
50
52
45
46
|
45
|
| Suitable
for evaluation
45
46
45
40
42
|
40
|
Not suitable for evaluation because of: |
| Intolerance
--
--
1
--
--
|
1
|
| Adverse
events
3
1
2
1
--
|
--
|
| Noncompliance
1
1
2
1
1
|
1
|
| Deteriorated
and underwent surgery
2
2
2
2
--
|
--
|
| Prohibited
drugs used
--
--
--
1
1
|
--
|
| Failed
to attend for follow-up
--
--
--
--
2
|
3
|
| Total
not evaluable
6
4
7
5
4
|
5
|
Study
GroupsOne hundred and fifty-three consecutive patients with
recurrent attacks of moderate proctosigmoiditis were
divided into three groups.
- In the first group patients were given prednisolone
by mouth 10 mg four times a day, sulfasalazine
by mouth, 500 mg four times a day, the vehicle
solution of allopurinol by mouth, 5 ml four times
a day, and corticosteroid retention enemas that contained
prednisolone-21-phosphate (Predsol, 20 mg) in
the morning and evening.
In the second group, patients had the same regimen
in addition to allopurinol by mouth, 5 ml (500 mg)
four times a day.
- In the third group, patients were treated like the
first group and in addition, received DMSO by mouth,
5 ml (500 mg) four times a day.
Patients who still had symptoms after treatment for
2 weeks or those whose conditions were deteriorating
were treated with higher doses of corticosteroids. Once
symptoms ceased, patients continued their respective
therapeutic regimens for 1 month, and then the corticosteroids
were tapered over the following 3 weeks (i.e.,
for the acute attack steroids were given until patients
became free of symptoms and were stopped 7 weeks
later). Thereafter, they were maintained on their remaining
oral regimens (prophylaxis) for 1 year.
Exclusion
on patients from evaluation
The decision to regard patients as not suitable for
efficacy analysis was made before the treatment code
was broken. Additional intention-to-treat analyses were
performed and reincluded such patients with various
theoretically possible outcomes to examine what influence
their exclusion might have had on the conclusion reached.
Statistical
analysis
Results are expressed as percentages or means ± SEM.
A sample size of 135 patients with 45 in each group
was initially chosen. On the basis of a two-tailed t
test, such a size should detect a significant difference
of 30% between therapy with and therapy without radical
scavengers (p < 0.05) with a probability
of 80% for the overall sample. Because of the anticipated
problems of some patients, who were not suitable for
evaluation, which could weaken any conclusions drawn,
the aim was to enter at least 50 patients in each group.
The Wilcoxon signed-rank test for paired nonparametric
data was used to determine the statistical significance
(p < 0.05) of observed differences
within each group and the Mann-Whitney U test for nonparametric
data or the X² test with Yates' correction were
used for comparisons among the groups.Life-table analyses
with Mantel-Cox (log rank) and Breslow-generalized Wilcoxon
statistics12 were used
to evaluate the statistical differences among treatments.
Pairwise comparisons were made between groups with or
without radical scavengers. Cox proportional hazard
models were then used to investigate the effects of
radical scavengers on the outcome of treatment and prophylaxis
by conventional agents; other patient factors were taken
into account as covariates.
Results
Patient characteristics are detailed in Tables
I and II. Treatment and follow-up
results are shown in Tables
III and IV.
Patient
Characteristics
Active
Treatment: Fifty-one patients (28 women and
23 men with an age range of 18 to 63 years; mean,
32 years) were randomized to the sulfasalazine
and prednisolone group. Fifty patients (27 women
and 23 men with an age range of 20 to 61 years;
mean, 34 years) were randomized to the allopurinol
group. Fifty-two patients (28 women and 24 men
with an age range of 19 to 67 years; mean, 31 years)
were randomized to the DMSO group. These patients were
randomized to the groups for a period of 2 years
and 11 months. The patients who were excluded
from evaluation are presented in Table
I. The characteristics of those remaining (Table
II) were similar among the three groups in terms
of number, age, sex ratio, and history of colitis.
Table
II
|
Active
treatment
|
Prophylactic
treatment |
| Prednisolone
& sulfasalazinePrednisolone
&sulfasalazine, & sulfasalazinePrednisolone
sulfasalazine, & DMSOSulfasalazineSulfasalazine
& allopurinol |
Sulfasalazine
& DMSO |
| n |
4546454042 |
40 |
| Age
(yr) |
|
| Mean |
3333303432 |
31 |
| Range |
18-6320-5719-6418-6321-57 |
19-61 |
| Women
(no.) |
2425252022 |
22 |
| Men
(no.) |
2121202020 |
18 |
| Mean
length of history (yr) |
8.97.68.3 |
|
| Mean
time since last acute attack (mo) |
5.86.15.5 |
|
| Mean
no. of relapses in previous 3 years |
2.93.73.1 |
|
| Last
treatment used for the acute attack (no.) |
| Prednisolone |
454645 |
|
| Sulfasalazine |
454645 |
|
| History
of treatment of acute attacks by other than the
above agents |
NoneNoneNone |
|
| History
of maintenance of remission by other than sulfasalazine |
NoneNoneNone |
|
| Previous
response rate to treatment of acute attacks (%) |
100100100 |
|
Prophylactic treatmentForty-five patients (24 women and 21 men
with an age range of 18 to 63 years; mean, 33 years)
were given sulfasalazine. Forty-six patients (25 women
and 21 men with an age range of 20 to 57 years;
mean, 33 years were given sulfasalazine with allopurinol.
Forty-five patients (25 women and 20 men with
an age range of 19 to 64 years; mean, 30 years)
were given sulfasalazine with DMSO. After exclusion
of the patients who could not be evaluated (TableI),the
characteristics of those in the three groups were comparable
in regard to age and sex ratio (Table
II).
The number of patients excluded from active or prophylactic
treatment was not significantly different among the
groups.
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