Chinese Journal of Digestive Diseases 2002; 3; 7074

Ulinastatin in the treatment of acute pancreatitis:

A multicenter clinical trial
Shi Yao CHEN & Ji Yao WANG for the Shanghai Collaboration Group on Ulinastatin Clinical Trials*
Department of Gastroenterology, Zhong Shan Hospital, Fudan University, Shanghai, China

OBJECTIVE: To assess the effectiveness of Chinesemade ulinastatin in the treatment of patients with
acute edematous pancreatitis (AEP) and acute hemorrhagic and necrotic pancreatitis (AHNP).
METHODS: A multicenter randomized controlled
clinical trial was performed. Stratified by AHNP or
AEP, patients were randomly allocated into either the
treatment group (with ulinastatin) or the control group
(treatment with cabexate or octreotide). Clinical
symptoms and signs were scored as none, mild,
moderate or severe. Laboratory tests included serum
amylase, liver and renal function tests, routine blood
tests, serum glucose, calcium, blood pH and PaO2.
Clinical results were assessed as cured, significantly
effective, effective and non-effective. All adverse
effects were recorded.

of severe pancreatitis. The study showed that the

global effective rates of ulinastatin and cabexate in
treating AEP were 100%, whereas the cured rate for
ulinastatin was 83.3%, which was a little higher than
that for cabexate (71.4%), but this difference was not
statistically significant. Clinical symptoms, such as
abdominal pain and distension, almost disappeared
within 35 days in both groups for both treatment
protocols. The global effective rate of ulinastatin in
treating AHNP was similar to that of octreotide (78.6
vs 81.9%; P = 0.840). The main complication in
AHNP was pancreatic pseudocyst. Only one case
showed increased levels of alanine aminotransferase.
No adverse effects, including allergy, skin rash and
decreases in the white blood cell count, were noted.
No abnormalities in liver and renal function, electrolytes or routine blood tests were noted.

RESULTS: From April to July 2000, a total of 94

patients with acute pancreatitis were enrolled into the
study (50 males; 44 females). In this patient group,
there were 68 cases of mild pancreatitis and 26 cases

CONCLUSIONS: Ulinastatin was shown to be effective in treating AEP and AHNP with few adverse
effects.

KEY WORDS: acute pancreatitis, cabexate, octreotide, treatment, ulinastatin.

Correspondence to: Ji Yao WANG, Department of Gastroenterology,

Zhong Shan Hospital, Fudan University, Shanghai 200032, China.
Email: jywang@shmu.edu.cn
*The members of the Shanghai Collaboration Group on Ulinastatin
Clinical Trials include: Zhong Shan Hospital, Fudan University
(Ji Yao WANG, Hou Yu LIU, Shi Yao CHEN and Tian Shu LIU);
Rui Jin Hospital, Shanghai Second Medical University (Yao Zong
YUAN and Shi Hu JIANG); Xin Hua Hospital, Shanghai Second
Medical University (Ding Guo LI); Shanghai 1st Peoples Hospital
(Xing Peng WANG); Ren Ji Hospital, Shanghai Second Medical
University (De Kai QIU); Shanghai Hua Dong Hospital (Gen Sheng
WANG); Chang Hai Hospital, 2nd Military Medical University
(Zhao Shen LI and Guo Ming XU).
Originally published as: Chin J Dig 2001; 21: 2936.

INTRODUCTION
Ulinastatin is a refined glycoprotein taken from
human urine that is able to inhibit the action of proteolytic enzymes, such as pancreatic protease, elastinase
and plasmin, and some carbohydrases, such as
hyaluronidase, amylase and lipase.13 Ulinastatin is
produced by Guangdong Tian Pu Biochemical Company
(Guangzhou, China; drug permission no. X1990133).
In previous clinical trials, ulinastatin has been shown
to be effective, with few side-effects, in the treatment
of acute edematous pancreatitis.47 To further evaluate

70

Ulinastatin treatment for acute pancreatitis

the effectiveness and side-effects following the use of

ulinastatin in the treatment of acute pancreatitis in
patients in the Shanghai area, seven hospitals participated in a multicenter clinical study (Shanghai Zhong
Shan Hospital, Rui Jing Hospital, Xin Hua Hospital,
First People's Hospital, Ren Ji Hospital, Hua Dong
Hospital, Chang Hai Hospital).
MATERIALS AND METHODS
Study design
The present study was a multicenter randomized
clinical trial. According to severity, acute pancreatitis
(AP) was divided into two groups: (i) acute edematous pancreatitis (AEP; mild); and (ii) acute
hemorrhagic necrotic pancreatitis (AHNP; severe). All
patients were randomly divided into treatment and
control groups and received planned appropriate
clinical intervention and follow up.
Patient selection
The inclusion criteria were as follows: (i) patient age
from 18 to 65 years; (ii) diagnosis of AP by clinical
symptoms and signs; (iii) serum amylase levels
increased to diagnostic values; (iv) AP confirmed by
ultrasound or computed tomography (CT); and (v) an
acute phase, with a history of less than 1 week.
Exclusion criteria were as follows: (i) a history of
hypersensitivity or allergy to any drugs; (ii) pregnancy
or lactation; and (iii) being prescribed sandostatin or
aprotinin, cabexate or calcitonin. The diagnosis of
AHNP was based on the following criteria: (i) any one
of the extra-abdominal systems affected (Banks
criteria); (ii) any organ failure (shock, pulmonary
failure, renal failure or gastrointestinal bleeding) or
any local complication diagnosed by CT (pancreatic
necrosis, abscess and pseudocyst; International
Pancreatic Discussion Criteria, 1992 Atlantic8); (iii)
any three or more of the following eight items: age
> 55 years, white blood cells (WBC) count > 15 109/L,
fasting blood glucose (FBG) > 180 mg/dL, lactate
dehydrogenase (LDH) > 600 U/L, blood urea nitrogen
> 16.065 mmol/L, albumin < 32 g/L, calcium < 2 mg/L,
PaO2 < 60 mmHg (Glasgow criteria8); (iv) APACHE II
criteria8 (including all 12 physiological items: body
temperature, mean arterial pressure, heart rate, breath
rate, PaO2, pH, serum Na, K, creatinine, hematocrit,
WBC and coma score), age ranks score and another
five items of chronic diseases, including liver, heart,
pulmonary, renal, immunology); severe cases were
diagnosed if the summed total score was greater
than 8.

71

Treatment procedure and course

Treatment groups
For mild cases, treatment consisted of ulinastatin
50 000 U dissolved in 250 mL of 5% glucose or
normal saline, given as an intravenous drip for 2 h,
b.d., for 3 days, then changed to q.d. (50 000 U/day)
for 5 days.
For severe cases, treatment consisted of ulinastatin
100 000 U dissolved in 250 mL of 5% glucose or
normal saline, infused intravenously for 2 h, b.d., for
3 days, then changed to q.d. (50 000 U/day) for 510
days; if no effect was observed after 5 days, treatment was changed to other drugs commonly used to
treat AP.

Control groups
For mild cases, cabexate (Changzhou Jin Yuan Pharmaceutics, Changzhou, China) 100 mg was dissolved
in 250 mL of 5% glucose or normal saline and was
given as an intravenous infusion for 2 h, b.d, for
3 days, then changed to q.d (100 mg/day) for 5 days.
For severe cases, 0.1 mg, i.v., octreotide (Sandostatin;
Novatis Pharmacy, Basel, Switzerland) was given,
followed by 0.3 mg octreotide dissolved in 500 mL of
5% glucose as an i.v. drip for 12 h (total amount
0.7 mg/day), for 3 days, which was then changed to
0.1 mg/day for 510 days.
All patients were simultaneously given 654-II (hydrochloride anisodamine), or antibiotics if there were
any signs of infection and were kept fasting. A
nasogastric tube was intubated if necessary. Relevant
medications were administered if any multiorgan
failure developed.

Outcome measurement
The main symptoms were pain, nausea, vomiting,
fever, shock or electrolyte disorders, whereas the
main signs were abdomen rigidity, upper abdominal
pain and rebounding pain. All symptoms and signs
were ranked on a four-point scale: 0, the disappearance of symptoms and signs; 1, mild symptoms and
signs; 2, medium symptoms and signs; 3, severe
symptoms and signs. Laboratory indices included
amylase, liver function, routine blood tests, blood
glucose, serum calcium, renal function, blood pH and
PaO2.

Chinese Journal of Digestive Diseases 3, 7074

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Shanghai Collaboration Group on Ulinastatin Clinical Trials

Table 1.

Demographic and baseline data of the two groups of patients with either mild or severe pancreatitis
Mild pancreatitis
Treatment

Control

Gender (M/F)
25/23
4/10
Age (years)
54 12
48 7
Percentage of patients with the following characteristics (%)
>55 years of age
43.8
14.3
Serum Ca <2.0 mmol/L
7.1
21.4
Serum glucose >10.08 mmol/L
8.9
7.1
WBC count >15 109/L
25.0
7.1
Abnormal ALT
45.8
64.3
Abnormal AST
50.0
42.9
Serum K <3.5 mmol/L
17.0
0.0
Total bilirubin >34.4 mmol/L
21.3
7.1
Biliary origin
29.2
27.1
APACHE score

Severe pancreatitis
P

Treatment

Control

0.121
0.057

8/6
54 13

7/4
44 15

0.742
0.091

0.045
0.134
0.838
0.148
0.224
0.640
0.180
0.228
0.066

42.9
57.1
14.3
35.7
20.8
23.1
28.6
0.0
21.4
5.36 4.14

36.4
22.2
30.0
45.5
36.4
36.4
0.0
18.2
36.4
3.82 3.87

0.742
0.099
0.350
0.622
0.772
0.476
0.053
0.180
0.409
0.353

Treatment, patients treated with ulinastatin (see Materials and methods for details); Control, patients treated with either cabexate (mild
pancreatitis) or octreotide (severe pancreatitis); M, male; F, female; Ca, calcium; WBC, white blood cells; ALT, alanine aminotransferase;
AST, aspartate aminotransferase; K, potassium.

Evaluation of effectiveness

Evaluation of adverse effects

Treatment effectiveness was classified into the

following four categories:

All adverse events that occurred during the course of

the trial were recorded and were noted as either associated, probable, not probable, not associated or
beyond evaluation.

1.

2.

Cured. For mild cases, patients deemed as cured

had all symptoms and signs disappear within
5 days of the initiation of treatment and laboratory tests normalized. For severe cases, there was
an improvement achieved within 10 days or the
APACHE score decreased over 75%.
Significantly effective. For mild cases, treatment
was classed as significantly effective if symptoms
and signs improved 2 or more points within 5
days, or over 75% of laboratory tests were normalized. For severe cases, treatment was deemed
significantly effective if an improvement was
achieved within 10 days or if the APACHE score
decreased over 50%.

3.

Effective. For mild cases, symptoms and signs

improved at least 1 point within 5 days or over
50% of laboratory tests were normal. For severe
cases, an improvement was achieved with 10 days
or the APACHE score decreased over 30%.

4.

No effect. For mild cases, treatment was classed as

having no effect if symptoms or signs did not
change or worsen within 5 days, whereas for
severe cases, treatment was deemed to have had
no effect if symptoms or signs did not change or
worsen within 10 days, the APACHE score did
not decrease over 30% or the patient died.

Chinese Journal of Digestive Diseases 3, 7074

Statistical analysis
Students t-test, 2 test or Fishers exact test were used
and P < 0.05 was considered significant.
RESULTS
There were 94 AP patients enrolled in this study from
April to July 2000, including 50 males and 44 females.
There were 68 cases of AEP and 26 cases of AHNP. On
the basis of the inclusion and exclusion criteria, seven
cases were excluded from the study. The reasons for
exclusion included recent octreotide treatment (five
cases), a prescription of more than three therapeutic
drugs (one case) and one extremely severe case who
died 1 day after ulinastatin treatment was initiated
and in whom the death was considered to be related
directly to the underlying condition. Thus, there was a
total of 87 cases eligible for inclusion in the study,
including 62 mild cases (48 in the treatment group
and 14 in the control group) and 25 severe cases (14
in the treatment group and 11 in the control group).
The baseline data of the two groups are shown in
Table 1.
In the present study, because of a poor response one
patient being treated with ulinastatin was discharged
on the 5th day and one patient being treated with

Ulinastatin treatment for acute pancreatitis

73

Table 2. Clinical effectiveness of treatment in the two patient groups with either mild or severe pancreatitis
Evaluation of effectiveness

No. patients cured (%)

No. patients in whom treatment significantly
effective (%)
No. patients in whom treatment effective (%)
No. patients in whom treatment not effective (%)
Cumulative effectiveness (%)

Mild pancreatitis

Severe pancreatitis

Treatment
(n = 48)

Control
(n = 14)

Treatment
(n = 14)

Control
(n = 11)

40 (83.3)
7 (14.6)

10 (71.4)
2 (14.3)

0.171

8 (57.2)
1 (7.1)

5 (45.5)
3 (27.3)

0.595

1 (2.1)
0 (0.0)
100.0

2 (14.3)
0 (0.0)
100.0

2 (14.3)
3 (21.4)
78.6

1 (9.1)
2 (18.2)
81.9

0.840

Treatment, patients treated with ulinastatin (see Materials and methods for details); Control, patients treated with either cabexate (mild
pancreatitis) or octreotide (severe pancreatitis); Cumulative effectiveness, rate of cured + significantly effective + effective. See Materials and
methods for the definition of the categories of treatment effectiveness.

Figure 1. Rate of relief of abdominal pain during the study

period. (), Ulinastatin treatment of patients with acute
edematous pancreatitis (AEP); (), control (cabexate)
treatment of patients with AEP; (), ulinastatin treatment of
patients with acute hemorrhagic and necrotic pancreatitis
(AHNP); (), control (octreotide) treatment of patients with
AHNP.

Figure 2. Decreasing levels of amylase during the treatment

period. (), Ulinastatin treatment of patients with acute
edematous pancreatitis (AEP); (), control (cabexate)
treatment of patients with AEP; (), ulinastatin treatment of
patients with acute hemorrhagic and necrotic pancreatitis
(AHNP); (), control (octreotide) treatment of patients
with AHNP.

octreotide was transferred to surgery in the 7th day;

both cases were classified as no effect. The clinical
evaluation results are shown in Table 2. In mild cases,
treatment with both ulinastatin and cabexate demonstrated good clinical results (global effective rate of 100%
for both drugs). The cured rate in the ulinastatintreated group (83.3%) was a little higher than that for
the cabexate-treated group (71.4%), although this
difference was not statistically significant (P = 0.171).
In severe cases, no significant difference in global
effective rates was found between the ulinastatin- and
octreotide-treated groups (78.6% vs 81.9%; P = 0.840).
Complications occurred only in severe cases, with a
57.2% occurrence rate of complications in the ulinastatintreated group (seven cases of pancreatic pseudocysts
and one case of diabetes) compared with 36.4% in the
control (octreotide-treated) group (three cases of
pancreatic pseuodocysts and one case of multiorgan
failure).

Abdominal pain was relieved in 80% of mild cases

within 5 days in both the ulinastatin-treated and
control (cabexate-treated) groups. It took 710 days
for this rate of relief of abdominal pain to be achieved
in severe cases (Figures 1,2). Abdominal distension
was ameliorated within a shorter period of time in
mild cases than in severe cases (approximately 3 days
vs approximately 4 days; P > 0.05). Serum amylase
decreased rapidly within 23 days and reached
normal level in all groups.
During the trial, WBC levels decreased significantly to
within the normal range, and electrolytes and hematocrit were maintained in normal range in all cases.
Levels of bilirubin, urea nitrogen and creatinine partly
decreased and were maintained at normal levels.
A significant proportion of AP patients showed
abnormal levels of alanine aminotransferase and

Chinese Journal of Digestive Diseases 3, 7074

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Shanghai Collaboration Group on Ulinastatin Clinical Trials

aspartate aminotransferase when they were enrolled

into the study. These abnormal levels gradually
recovered when the infection was controlled and
pancreatitis was ameliorated. In order to rule out
the possibility of drug-induced liver damage, the
present study investigated whether abnormal alanine
aminotransferase/aspartate aminotransferase levels
occurred after treatment in cases in which they had
been normal before treatment. The results showed
that this occurred in only one case in the ulinastatin
treatment group and in two cases in the cabexatetreated control group.
DISCUSSION
Biliary and alcohol-related causes of AP are well
known; however, the common characteristic for the
pathogenesis of AP is activation of various enzymes
released from the pancreas, which induce selfdigestion of pancreatic tissues, with a clinical manifestation of persistent upper-abdominal pain and increased
levels of serum amylase.9 Ulinastatin is a broadspectrum enzyme inhibitor and has been used in the
treatment of AP.10
Results from studies abroad show that the effective
rates for the relief of symptoms, the amelioration of
signs and normalization of laboratory test results are
82, 79 and 80%, respectively.11 A phase II clinical trial
conducted in Beijing, Guangzhou and Nanjing (GZ
Pan, pers. comm., 1997) showed that the cured and
effective rates for Chinese-made ulinastatin in the
treatment of AP were 66.7 and 84.3%, respectively. In
the present randomized controlled clinical trial, the
therapeutic effects of Chinese-made ulinastatin in the
treatment of AEP and AHNP were evaluated. The
results showed that, in cases of AEP, the global
effective and cured rates were 100.0 and 83.3%,
respectively. The latter was a little higher than that
obtained for cabexate (71.4%), but the difference was
not significant. The symptoms of upper-abdominal
pain and distension could be relieved within 35 days
of initiating treatment with ulinastatin and cabexate.

Chinese Journal of Digestive Diseases 3, 7074

The global effective rate for ulinastatin in the treatment of AHNP was similar to that of octreotide (78.6
vs 81.9%; P = 0.840).
Pancreatic pseudocyst was the main complication of
AHNP treated with ulinastatin and octreotide. Except
for one case with slightly increased alanine aminotransferase levels in the ulinastatin-treated group, no
other adverse effects, including allergy, skin rash and
severe leukocytopenia, were noted. The biochemical
profiles of hepatic and renal function, electrolytes and
routine blood tests demonstrated the safety of
ulinastatin.
REFERENCES
1 Muramatu M, Mori S, Matsuzawa Y, Horiguchi Y, Nakanishi Y,
Manaka M. Purification and characterization of urinary
trypsin inhibitor, UT168, from normal human urine, and its
cleavage by human uropepsin. J Biochem (Tokyo) 1980; 88:
131729.
2 Kobayashi H, Hirashima Y, Sun GW et al. Identity of urinary
trypsin inhibitor-binding protein to link protein. J Biol Chem
2000; 275: 21 18591.
3 Ohnishi H, Kosuzume H, Ashida Y, Kato K, Honjo I. Effects
of urinary trypsin inhibitor on pancreatic enzymes and
experimental acute pancreatitis. Dig Dis Sci 1984; 29: 2632.
4 Kashima K, Kataoka K, Umehara K. Treatment of acute
pancreatitis. Nippon Naika Gakkai Zasshi 1992; 81: 19127
(in Japanese).
5 Takeda K. Protease inhibitors in the treatment of pancreatitis.
Nippon Rinsho 1991; 49: 21259 (in Japanese).
6 Ota K, Namiki A, Takahashi I, Iwasaki H, Ujike Y. Effects of
ulinastatin on operative stress in major surgery. Masui 1989;
38: 5405 (in Japanese).
7 Banks PA. Predictors of severity in acute pancreatitis. Pancreas
1991; 6 (Suppl. 1): S712.
8 Mckay CJ, Imrie CW. Staging of acute pancreatitis: Is it
important? Surg Clin N Am 1999; 79: 73343.
9 Siech M, Weber H, Letko G et al. Similar morphological and
intracellular biochemical changes in alcoholic acute
pancreatitis and ischemic acute pancreatitis in rats. Pancreas
1997; 14: 328.
10 Wang CY, Zhao G, Zhang WK. Effectiveness of ulinastatin in
treating severe acute pancreatitis and the mechanisms. Clin
Surg 2000; 8: 172174 (in Chinese).
11 Maekawa K, Tanimoto T, Okada S. Ulinastatin Reference
Standard (Control 971) of the National Institute of Health
Sciences. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokolu
1997; 115: 199201 (in Japanese).

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