GASTROENTEROLOGY 1988:94:1383-g

Comparison of Delayed-Release
5-Aminosalicylic Acid (Mesalazine) and
Sulfasalazine as Maintenance Treatment
for Patients With Ulcerative Colitis
S. A. RILEY, V. MANI, M. J. GOODMAN, M. E. HERD, S. DUTT,
and L. A. TURNBERG
Department of Medicine, University of Manchester Medical School, Hope Hospital, Salford;
Leigh Infirmary and Departments of Medicine and Histopathology, Bury General Hospital,
Manchester, United Kingdom

To assess the safety and efficacy of delayed-release will allow delivery of the therapeutically active
mesalazine (5-aminosalicylic acid) as maintenance moiety, 5-ASA (8,9), to the colon (10).
treatment for patients with ulcerative colitis, 100 Delayed-release mesalazine is one such formula-
patients with quiescent colitis were randomly tion. Initial short-term studies with the drug have
grouped to receive either delayed-release mesala- been encouraging (ll,l2). The aim of the present
zine or an equivalent dose of enteric-coated study was, therefore, to compare the long-term effi-
sulfasalazine in a 48-wk trial. Groups were compa- cacy and toxicity of delayed-release mesalazine with
rable for age, sex, and duration and extent of dis- enteric-coated sulfasalazine in the maintenance of
ease. Relapse rates at 48 wk were as follows: ulcerative colitis remission.
sulfasalazine 38.6% (95% confidence limits, 24%-
54%) and mesalazine 37.5% (95% confidence limits,
Materials and Methods
24%-53%), x2 = 0.01, p > 0.90. Mean time to
relapse, cumulative relapse rate, rind relapse sever- Selection of Patients
ity were similar in the two groups. Headaches and
Patients were recruited from three hospitals in
upper gastrointestinal symptoms-common at trial geographic proximity (Hope Hospital, Leigh Infirmary, and
entry-improved to a greater extent in patients Bury General Hospital). The study population comprised
receiving mesalazine. Delayed-release mesalazine adult outpatients with chronic ulcerative colitis diagnosed
is an effective tpeatment for maintaining ulcerative on the basis of clinical history and previous sigmoidoscop-
colitis remission and is associated with fewer side ic and histologic findings. All patients had been in clinical
effects than equivalent doses of enteric-coated remission for a minimum period of 1 mo before trial entry,
sulfasalazine. as judged by the absence of blood in the stool. All had the
macroscopic appearance of either normal mucosa or only
erythema on sigmoidoscopy at the time of trial entry. Each

S
ulfasalazine has a well-established role in the patient had previously taken sulfasalazine maintenance
management of patients with ulcerative colitis. It treatment. Those taking other drugs known to have an
is of some benefit in mildly active colitis (1,2) but its effect on colitis activity were excluded. No patient had
received either oral or rectal steroids within 1 mo of trial
main value lies in its ability to reduce the rate of
entry. Patients with significant hepatic or renal disease
disease relapse (3-5). For this reason, life-long main-
and those with a history of salicylate allergy were also
tenance treatment is usually recommended.
excluded. The study protocol was approved by the three
The major problem with this drug is that its independent hospital ethical committees and patients
association with a high incidence of side effects gave written, informed consent before trial entry.
limits its use in many individuals (6). Sulfasalazine
consists of Ei-aminosalicylic acid (5-ASA) linked by
an azo bond to sulfapyridine. Because the majority of
Abbreviation used in this paper: 5-ASA, 5-aminosalicylic
side effects are the result of intolerance to the sulfa- acid.
pyridine moiety of the molecule (77, attempts have 0 1988 by the American Gastroenterological Association
been made to develop alternative formulations that 0016.5085/88/$3.50
1384 RILEY ET AL.
Table 1. Sigmoidoscopic and Histologic Grading Systems
Sigmoidoscopic grading
Grade Macroscopic appearance
0 Normal, vascular pattern clearly visible
1 Erythema with loss of vascular pattern
2 Erythema with loss of vascular pattern, plus contact
bleeding
3 Erythema with loss of vascular pattern, plus spontane-
ous bleeding
4 Erythema with loss of vascular pattern, plus obvious ul-
ceration
Study Design and Protocol
The study followed a randomized, double-blind,
parallel group design. Randomization was governed by a
centrally held pharmacy code and medication was pre-
packaged to ensure an equal and random allocation at each
center. Given the proven efficacy of sulfasalazine mainte-
nance treatment in chronic ulcerative colitis, a placebo-
controlled trial was considered unethical. Patients were,
therefore, assigned to either enteric-coated sulfasalazine
(Salazopyrin EN; Pharmacia, Uppsala, Sweden) or an
equivalent dose of delayed-release mesalazine (Asacol;
Tillots Laboratories) for a period of 48 wk. Because the
tablets differ in shape, size, color, and amount of 5-ASA, a
double-dummy technique was utilized, each patient re-
ceiving both sets of medication, one placebo and one
active.
Trial dose was determined by pretrial maintenance dose
of sulfasalazine and was based on a scale of 1 g sulfasala-
zine to 400 mg mesalazine. Patients not taking sulfasala-
zine maintenance treatment on entry were randomized
into the lowest dose stratum (2 g sulfasalazine or 800 mg
mesalazine, daily). Tablets were dispensed in four 12-wk
batches.
Throughout the study period all clinical assessments
were made by one investigator. Upon entry a complete
history was taken, and physical examination and rigid
sigmoidoscopy were performed. The macroscopic appear-
ances of the rectal mucosa were graded using a scale
similar to that described by Baron et al. (Table l), as this
has been shown to minimize observer variation (13). The
severity of the mucosal changes was recorded at three sites
within the rectum: in the lowest 5 cm, between 5 and 10
cm, and above 10 cm with reference to the anal margin. A
rectal biopsy specimen was taken from the anterior rectal
wall between ?I ahd 10 cm.
Hematologic variables (full blood count, sedimentation
rate, serum and red blood dell folate levels) and biochem-
ical variables [multichannel analysis) were measured
upon entry. A urine sample was tested for blood and
protein using a semiquantitative dip stick (Multistix,
Ames) and positive results were followed by microscopic
examination of the urinary sediment.
After inclusion in the study, patients discontinued
sulfasalazine maintenance treatment and were given the
first batch of trial medication to be taken on a twice-daily
GASTROENTEROLOGY Vol. 94, No. 6
Histologic grading
Grade Microscopic appearance
0 Normal
1 Mild increase in chronic inflammatory cell infiltrate, no
tissue destruction
2 Moderate increase in chronic inflammatory cell infil-
trate, no tissue destruction
3 Marked increase in chronic inflammatory cell infiltrate,
mild tissue destruction
4 Marked increase in chronic inflammatory cell infiltrate,
obvious tissue destruction
basis. Each patient kept a daily symptom diary in which he
recorded stool frequency, bleeding, mucus, abdominal
pain, possible side effects, and other symptoms believed to
be relevant.
Patients were asked to report for follow-up at 4, 12, 24,
36, and 48 wk, and at any other time should they wish.
Upon each visit to the clinic, bowel habit was recorded
and corroborated with the symptom diary. General well-
being was graded on a four-point scale (fit, slightly under
par, moderately ill, poor) and patients were Questioned
about the occurrence and frequency of a list of 15 possible
side effects. Vital signs were recorded, and abdominal
examination was performed. A urine specimen was tested
for blood and protein at each visit, and blood tests were
repeated at 24 wk and on termination of the study. To
assess drug compliance, patients were asked to return
unused medications at each visit and a tablet count was
undertaken.
Patients were followed to either felapse or completion at
48 wk, at which time further clinical assessment including
sigmoidoscopy and biopsy was performed. Throughout
the study patients were asked to promptly report unex-
plained symptomatic deterioration. Sigmoidoscopy was
then undertaken, and relapse was confirmed if the macro-
scopic grade of the rectal mucosa appeared to be worse.
Trial medications were then discontinued, and oral
sulfasalazine and appropriate corticosteroid treattient
were prescribed.
On completion of the study, histologic analysis of the
biopsy specimens was undertaken. Paraffin-embedded sec-
tions (5 pm thick) were stained with hematoxylin and
eosin, and were coded. Each section was examined inde-
pendently by two histopathologists who had no knowl-
edge of either the patients or treatments given. The his-
tologic changes were graded on a predetermined five-point
scale (Table l), the final grade being the mean of the two
assessments.
Statistical Methods
All results are expressed as mean ? 1 SD unless
otherwise stated. Relapse data were analyzed using the 2
test and adverse reaction was measured by Fisher’s exact
test. All other data were assessed using the Mann-Whitney
U test (to compare changes between treatment groups) and
Wilcoxon’s matched-pairs test (to compare changes within
treatment groups).
rune 1988 DELAYED-RELEASE 5-ASA IN ULCERATIVE COLITIS 1385

Results
_____m
Patients -5.ASA

One hundred patients were entered into the

study, 51 male and 49 female, with an age range of
20-78 yr. Eight patients were withdrawn, 6 of them !iO-
from the sulfasalazine group and 2 from the mesal- 4O-
azine group. Four of them were withdrawn for 30-
nonattendance, 2 patients for poor compliance, 1 20-
patient was inappropriately included, and 1 patient lo-
(in the sulfasalazine group) developed a severe ul- 0
cerative stomatitis of uncertain etiology 8 wk after II I I II I I I’I I I
0 4 8 12 16 20 24 20 32 36 40 44 48
inclusion. Tim hveaksl

Patient and disease characteristics are shown in Figure 1. Cumulative remission rates assessed at 4-wk intervals
throughout the study period.
Table 2. Both groups were comparable with respect
to age, sex, disease duration, and time from previous
relapse to trial entry. The extent of disease as judged
by either double-contrast barium enema examina- Response to Treatment
tion or the macroscopic appearances of the mucosa
Upon completion of the study, relapse had
at colonoscopy was also similar.
occurred in 17 of 44 patients in the sulfasalazine
All patients had previously taken sulfasalazine
group (38.6%; 95% confidence limits, 25%-54%) and
maintenance treatment, although 5 patients were not
in 18 of the 48 patients in the mesalazine group
taking the drug at the time of trial entry. Of the 92
(37.5%; 95% confidence limits, 24%-53%). The dif-
patients who completed the study, 44 received
ference does not achieve statistical significance (,$+=
sulfasalazine (36 patients, 2 g daily; 7 patients, 3 g
0.01, p > 0.90). Mean time to relapse in the two
daily; and 1 patient, 4 g daily) and 48 received
groups was similar: sulfasalazine, 18.7 t 9.9 wk;
mesalazine (39 patients, 800 mg daily; 8 patients,
mesaiazine, 16.4 + 10.1 wk. The cumulative remis-
1200 mg daily; and 1 patient, 1600 mg daily).
sion rates did not significantly deviate from one
Of the 2 patients [both receiving sulfasalazine)
another at any time during the 48-wk trial period
withdrawn because of noncompliance, 1 patient
(Figure 1).
stopped medication completely and the other took
Six variables were used to assess relapse severity:
~50% of the prescribed doses. Drug compliance in
stool frequency, rectal bleeding, hemoglobin concen-
the remaining patients was remarkably good, with
tration, sedimentation rate, and sigmoidoscopic and
40% of the mesalazine group and 48% of the sulfa-
histologic grade. No significant differences were ap-
salazine group totally compliant. In none of the
parent with respect to these indices upon entry to
remaining patients did noncompliance exceed 5% of
the trial and, as would be expected, these variables
the prescribed doses.
were worse at relapse. Sedimentation rate, however,
failed to @se in the sulfasalazine group at relapse,
Table 2. Patient and Disease Characteristics
resulting in the only significant difference between
Delayed- treatments. All other variables remained closely
release
matched [Table 3).
Sulfasalazine mesalazine
In = 441 (n = 481 Disease activity indices of patients who stayed in
remission throughout the study are shown in Table
Age (~4 45.9 t 15.6 42.1 + 15.5
Sex
4. Although stool frequency was slightly higher at
Male 25 25 trial entry in the group taking mesalazine, no other
Female 19 23 significant within- or between-treatment differences
Disease duration (yr) 9.2 2 9.0 8.1 + 5.9 were apparent with respect to stool frequency, sed-
Disease extent
imentation rate, or sigmoidoscopic or histologic
Total 9 10
Left-sided 10 13
grade.
Proctosigmoiditis 15 14
Proctitis 10 11 Side Effects and Laboratory Variables
Time from previous relapse (mo) 15.2 ? 15.2 12.8 2 13.7
Previous relapse frequency For the purposes of the study, only symptoms
More than once yearly 7 16 that were reported on a regular basis were analyzed
Approximately once yearly 21 22 (symptoms at least once per week reported on at
Less than once yearly 16 10
least 50% of clinic visits). Despite the fact that
1386 RILEY ET AL. GASTROENTEROLOGY Vol. 94, No. 6

Table 3. Disease Activity Indices in Patients Who study, improvement was noted by 10 patients (53%)
Relapsed taking sulfasalazine and by all patients taking
Sulfasala- Delayed-release mesalazine (between-treatment difference, p < O.OZ),
zine mesalazine and complete resolution was noted by 7 patients
(n = 17) (n = 18) (37%) in the sulfasalazine group and by 7 patients
Stool frequency E 2.0 2 1.0 2.1 2 1.3 (70%) in the mesalazine group. Two patients in the
(per day) R 4.0 f 2.1 4.8 f 3.2 sulfasalazine group and 3 patients in the mesalazine
p < 0.005 p < 0.005 group developed regular upper gastrointestinal up-
Rectal bleeding E
set not reported at trial entry so that, in total, 14
(per day) R 3.6 " 2.3 3.8 k 3.2
Hemoglobin (g%] E 13.1 k 1.6 12.8 t 1.5
patients taking sulfasalazine and 6 patients taking
R 12.6 + 1.8 12.3 t 2.0 mesalazine reported regular upper gastrointestinal
Sedimentation E 8.5 f 8.5 8.8 f 5.7 upset during the course of the study (p < 0.05). All
rate (mm/h) R 7.9 f 8.7 p < 0.02 22.1 2 20.3 other side effects, e.g., dizziness, imbalance, tinni-
p < 0.01
tus, visual disturbances, and feelings of unreality
Sigmoidoscopic
grade were infrequent in both groups.
O-5 cm E 0.64 2 0.49 0.89 ? 0.32 To avoid masking drug-related hematologic and
R 2.76 k 0.43 2.83 + 0.51 biochemical changes by the processes of colitis re-
p < 0.005 p < 0.005 lapse, laboratory variables have been assessed in
5-10 cm E 0.47 2 0.51 0.78 _' 0.43
patients who stayed in remission throughout the
R 2.35 * 0.70 2.67 k 0.59
p < 0.005 p < 0.005
study period, comparing entry data and completion
Above 10 cm E 0.47 2 0.51 0.72 2 0.46 data.
R 2.41 k 0.94 2.61 _' 0.69 Upon entry to the study, 95 patients were taking
p < 0.005 p < 0.005 sulfasalazine maintenance treatment. Of these pa-
Histologic grade E 1.5 2 0.66 1.22 + 0.86
tients, 10 had macrocytosis (mean corpuscular vol-
R 2.67 T 0.79 3.00 + 0.68
p < 0.005 p < 0.005
ume >lOO fl), and 2 had a mild leucopenia (white
blood count <4 x log/L). No patient had either
E, entry data: R, relapse data. p value printed between data pairs
reticulocytosis (normal ~2%) or Heinz bodies on
indicates between-treatment differences, whereas those printed
below data pairs indicate within-treatment differences. examination of the peripheral blood film. Although
no significant trend in hematologic indices occurred
during 48 wk of sulfasalazine treatment, a small but
patients were thought to be tolerant of sulfasalazine, statistically significant rise in hemoglobin concen-
having previously taken maintenance treatment, tration occurred during mesalazine treatment. This
many reported side effects on direct questioning. change was associated with a rise in red blood cell
Headaches and upper gastrointestinal upset (ano- count and a fall in mean corpuscular volume. How-
rexia, nausea, vomiting, and dyspepsia) were by far ever, mean corpuscular hemoglobin concentration
the most common symptoms reported.
Upon entry to the study, 18 patients in the
sulfasalazine group and 10 patients in the mesal- Table 4. Disease Activity Indices of Patients Who
azine group reported that they had headaches at least Stayed in Remission
once each week on a regular basis. During the study Sulfasala- Delayed-release
period, improvement was noted by 10 patients (55%) zine mesalazine
in the sulfasalazine group and by all but I patient In = 271 In = 301

(90%) in the mesalazine group (between-treatment Stool frequency E 1.4 f 0.6 p < 0.01 2.0 k 1.0
difference, p < 0.1). Complete resolution of head- (per day1 C 1.7 2 0.9 2.0 -r-0.8
Sedimentation rate E 7.1 + 4.1 7.1 + 5.2
aches occurred in 9 patients (50%) in the sulfasala-
(mm/h) C 8.8 + 6.7 9.4 IT 12.1
zine group and 8 patients (80%) in the mesalazine Sigmoidoscopic
group. Three patients in the sulfasalazine group and grade
2 patients in the mesalazine group developed head- O-5 cm 0.70 k 0.46 0.73 * 0.45
aches not reported at trial entry so that, in total, 12 0.37 2 0.49 0.47 f 0.57
5-10 cm 0.40 f 0.50 0.50 k 0.51
patients taking sulfasalazine and 4 patients taking
0.22 2 0.42 0.30 k 0.46
mesalazine reported regular headaches during the Above 10 cm 0.33 T 0.48 0.36 t 0.49
course of the study (p < 0.02). 0.22 2 0.42 0.23 " 0.43
Similar results were found with respect to upper Histologic grade 0.92 " 0.64 1.15 2 0.64
gastrointestinal upset. Upon entry, 19 patients in the 0.90 -t 0.65 1.31 2 0.83

sulfasalazine group and 10 patients in the mesala- E, entry data: C, completion data. p value printed between data
zine group reported regular symptoms. During the pairs indicates between-treatment differences.
June 1988 DELAYED-RELEASE 5-ASA IN ULCERATIVE COLITIS 1387

Table 5. Laboratory Variables of Patients Who Stayed in This acrylic-based resin disintegrates, releasing
Remission 5-ASA above pH 7 (17), the prevailing pH of the
Sulfasala- Delayed-release distal small intestine and colon (18). Radiologic
zinc mesalazine studies of barium-containing tablets confirm that the
(n = 27) (n = 30) tablets disintegrate in the terminal ileum and colon
Hemoglobin E 13.4 + 1.3 13.4 2 1.2 (19,20). A recent open study suggests the drug is of
(8%) c 13.5 2 1.2 13.9 2 1.2 value in active colitis (21), and two maintenance
p < 0.02 studies have also shown promising results (ll,l2).
Red blood cell E 4.44 2 0.42 4.45 t 0.57
Unfortunately, in the latter studies the length of
number c 4.41 + 0.34 p < 0.02 4.67 t 0.37
(xlo’*/L) p < 0.005
follow-up was short and neither study was large
MCV Ifl) E 91.3 t 4.6 91.9 2 6.2 enough to exclude a major treatment difference.
C 91.7 t 5.6 p < 0.05 86.6 2 15.5 The present study of 100 patients shows that
p < 0.0005 delayed-release mesalazine is as effective as sulfasal-
MCHC (%) E 33.3 2 0.8 33.1 + 1.0
azine in the long-term maintenance of ulcerative
C 33.2 t 1.3 33.4 + 0.9
White blood cell E 6.5 f 2.1 6.6 t 1.5 colitis remission. After 48 wk of treatment, 37% of
number C 6.2 k 2.1 p < 0.02 7.2 + 1.3 patients receiving mesalazine and 38% of patients
(X109/L) p < 0.02 receiving sulfasalazine had suffered a relapse of their
Serum folate E 3.5 k 2.1 4.2 + 3.3 disease. Although it is not ideal to compare the
C 3.8 f 2.1 4.3 t 2.6
results of different clinical trials, these figures com-
Red blood cell E 274 k 186 245 + 141
folate C 240 * 116 241 t 94 pare favorably with the 75% and 80% 12-mo relapse
rates quoted for untreated patients (3,22). The size of
E, entry data; C, completion data; MCHC, mean corpuscular
the present study provides a 95% probability of
hemoglobin concentration; MCV, mean corpuscular volume. p
values printed between data pairs indicate between-treatment finding a significant difference in a two-tailed 5%
differences, whereas those printed below data pairs indicate test between a 37.5% and a 75% relapse rate.
within-treatment differences. Normal ranges as follows: hemoglo- Previous trials assessing the efficacy of sulfasal-
bin concentration: male = 13.5-18.0 g%, female = 11.5-16.5 g%; azine maintenance treatment have reported varying
red blood cell number: male = 4.4-6.5 X lO”/L, female = 3.9-5.6
results. Earlier studies of patients in prolonged clin-
X lOl’/L; mean corpuscular volume = 76-96 fl; mean corpuscular
hemoglobin concentration = 32%-36%; white blood cell number ical and histologic remission report 6-mo relapse
= 4-11 X log/L; serum folate = 1.6-13.2 pg/L; red blood cell rates of 12% and 14% (4,5), whereas in less selected
folate >125 pg/L. patients 6-mo relapse rates of 20% and 24% are
quoted (23,241. The only similar 12-mo maintenance
trials report relapse rates of 29% and 30% (3,25),
and serum and red blood cell folate levels, which figures comparable to those of the present study.
were matched on entry, remained unchanged. A Mean time to relapse, cumulative relapse rate,
small but significant rise in white blood cell count and, with the exception of sedimentation rate, re-
was also apparent during mesalazine treatment (Ta- lapse severity were all remarkably similar in the two
ble 5). treatment groups. The reason sedimentation rate
Biochemical variables showed no consistent failed to rise in the sulfasalazine group at relapse,
changes during treatment with either sulfasalazine however, remains obscure. As all other indices were
or mesalazine. In particular, there was no evidence so closely matched, it seems unlikely that this rep-
of renal impairment as judged by urinalysis and resents a difference in relapse severity.
serial plasma urea and creatinine concentrations. The main advantage of delayed-release mesal-
azine, to date, is its improved toxicity over sulfasal-
azine. Most patients unable to take sulfasalazine
Discussion
tolerate delayed-release mesalazine well (26,271, al-
Enemas with 5-ASA are an effective treatment though a small number of patients suffer side effects
for patients with active distal colitis (14-16). For similar to those experienced with sulfasalazine.
maintenance therapy, however, oral formulations Sulfasalazine-induced male infertility and seminal
are preferable, and they necessitate colonic delivery impairment also respond favorably to mesalazine
systems. Two methods of colonic delivery have been substitution (28).
developed: one utilizes the azo principle, in which Although the main purpose of the study was to
5-ASA is azo-linked to a less toxic carrier than assess drug efficacy, the results also suggest a greater
sulfapyridine, and the other relies on slow-release or improvement of side effects in patients changing to
delayed-release coatings. mesalazine than in those continuing sulfasalazine.
Delayed-release mesalazine (Asacol) relies on its This was apparent even though patients were osten-
coating, Eudragit S, to deliver 5-ASA to the colon. sibly tolerant to sulfasalazine treatment, thereby
1388 RILEY ET AL. GASTROENTEROLOGY Vol. 94, No. 6

lessening the chance of showing benefit with a less dose of sulphasalazine for maintenance treatment of ulcer-
toxic drug. Unfortunately, the two treatment groups ative colitis. Gut 1980;21:232-40.
6. Taffet SL, Das KM. Sulfasalazine. Adverse effects and desen-
were not matched with respect to side effects at trial
sitization. Dig Dis Sci 1983;28:833-42.
onset, making comparisons less than ideal. However, 7. Das KM, Eastwood MA, McManus JPA, Sircus W. Adverse
the greater improvement in headaches and upper reactions during salicylazosulphapyridine therapy and the
gastrointestinal upset in patients receiving mesalaz- relation with drug metabolism and acetylator phenotype. N
ine suggests that the sulfapyridine component of Engl J Med 1973;289:491-5.
8. Azad Khan AK, Piris J, Truelove SC. An experiment to
sulfasalazine is responsible for such side effects.
determine the active therapeutic moiety of sulphasalazine.
Other adverse reactions were too infrequent to Lancet 1977;ii:892-5.
assess. It is worth noting, however, that stool fre- 9. Klotz U, Maier K, Fischer C, Heinkel K. Therapeutic efficacy
quency was unaffected by mesalazine treatment (Ta- of sulfasalazine and its metabolites in patients with ulcerative
ble 5). This is in marked contrast to reports of other colitis and Crohn’s disease. N Engl J Med 1980;303:
1499-1502.
new 5-ASA formulations where diarrhea seems to be
10. Hawkey CJ. Salicylates for the sulfa-sensitive patient with
a particular problem (29-31). ulcerative colitis? Gastroenterology 1986;90:1082-4.
The hematologic side effects of sulfasalazine are 11. Dew MJ, Hughes P, Harries AD, Williams G, Evans BK,
well documented (5,32-35). In the present study, Rhodes J. Maintenance of remission in ulcerative colitis with
hematologic indices in the two treatment groups oral preparation of 5-aminosalicylic acid. Br Med J 1982;285:
1012.
were closely matched upon entry, and patients who
12. Dew MJ, Harries AD, Evans N, Evans BK, Rhodes J. Mainte-
continued on sulfasalazine maintenance treatment nance of remission in ulcerative colitis with 5-amino salicylic
showed no significant changes. In those receiving acid in high doses by mouth. Br Med J 1983;287:23-4.
mesalazine, however, improvements were seen in 13. Baron JH, Connell AM, Lennard-Jones JE. Variation between
hemoglobin concentration, red blood cell count, observers in describing mucosal appearances in proctocolitis.
Br Med J 1964;1:89-92.
mean corpuscular volume, and white blood cell
14. Campieri N, Lanfranchi GA, Bazzocchi G, et al. Treatment of
count. It seems likely that maintenance sulfasalazine ulcerative colitis with high-dose 5-aminosalicyclic acid ene-
treatment exerts a subclinical toxic effect on red and mas. Lancet 1981;ii:270-1.
white blood cell populations and that mesalazine 15. Campieri N, Lanfranchi G, Brignola C, Bazzocchi G, Minguzzi
substitution allows recovery of these abnormalities. M, Calari M. 5-Aminosalicylic acid as rectal enema in ulcer-
ative colitis patients unable to take sulfasalazine. Lancet
High doses of 5-ASA given intravenously to rats
1984;i:403.
can cause both renal tubular and renal papillary 16. Sutherland LR, Martin F, Greer S, et al. 5-Aminosalicylic acid
necrosis (36,37). It was therefore reassuring to find enema in the treatment of distal ulcerative colitis, proctosig-
no evidence of nephrotoxicity after 48 wk of moiditis, and proctitis. Gastroenterology 1987;92:1894-8.
mesalazine treatment. However, relatively low doses 17. Lehmann K. Programmed drug release from oral dosage
forms. Pharmacol International 1971;3:1-16.
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18.
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delayed-release mesalazine is as effective as sulfasal- 19. Dew MJ, Hughes PJ, Lee MG, Evans BK, Rhodes J. An oral
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Pharmacol 1982;14:405-8.
large group of patients studied for almost 1 yr. The
20. Dew MJ, Ryder REJ, Evans N, Evans BK, Rhodes J. Colonic
drug appears to be safe when taken on a long-term release of 5-aminosalicylic acid from an oral preparation in
basis and seems to be associated with fewer side active ulcerative colitis. Br J Clin Pharmacol 1983;16:185-7.
effects than equivalent doses of enteric-coated 21. Schroeder KW, Tremaine WJ. Oral 5-aminosalicylic acid
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31. Sandberg-Gertzen H, Jarnerot G, Bukhave K, Lauriston K, Received September 24, 1987. Accepted January 4, 1988.
Rask-Madsen K. Effect of azodisal sodium and sulphasalazine Address requests for reprints to: S. A. Riley, Department of
on ileostomy output of fluid and PGEz and PGF2, in subjects Medicine, Clinical Sciences Building, Hope Hospital, Eccles Old
with a permanent ileostomy. Gut 1986;27:1306-11. Road, Salford M6 8HD, United Kingdom.
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karyocytosis, histiocytosis and plasmacytosis. Minn Med The authors thank the staff of the Department of Pathology at
1972;55:545-8. Bury General Hospital for processing biopsy material, Alison
33. Spriggs AI, Smith RS, Griffith H, Truelove SC. Heinz-body Littlewood of Hope Hospital for coding and packaging trial drugs,
anaemia due to salicylazosulphapyridine. Lancet 1958;i: Joan Hartley and Julie Rostron for their secretarial assistance, and
1039-42. the Department of Medical Illustration, Hope Hospital, for pro-
34. Evans RS, Ford WP. Studies of the bone marrow in immuno- viding the figure.