Efcacy and safety of intravenous stronger

neo-minophagen C and S-adenosyl-L-methionine

in treatment of pregnant woman with chronic
hepatitis B: A pilot study
Qing-Feng SunACDEG, Ji-Guang DingABDE, Xiao-Feng WangBCDE, Rong-Quan FuBDF,
Jin-Xian YangBFG, Liang HongBF, Xiao-Jia XuBCD, Jun-Rong WangAF, Jin-Guo WuAF,
Dao-Zhen XuAF
Department of Infectious Diseases, 3
rd
Afliated Hospital of Wenzhou Medical College, Ruian, Zhejiang, P.R. China
Source of support: This work was supported by grants from Science Foundation from Health Bureau of Wenzhou
City (2006B056) and Sci-Tech Committee of Ruian City (20082092)
Summary
Background: There have been no studies evaluating the efcacy and potential risks of stronger neo-minopha-
gen C (SNMC) in pregnant women with chronic hepatitis B CHB
Material/Methods: A total of 36 pregnant women with CHB, but without severe complications, were randomized to
intravenously receive SNMC or S-adenosyl-L-methionine (SAM) daily for 4 weeks or until birth.
Normalization of serum alanine transaminase (ALT) and aspartate transaminase (AST) levels and
changes in ALT and AST levels from baseline were determined. All neonates were regularly exam-
ined for up to 1 year.
Results: Treatment with SNMC and SAM resulted in normalization of ALT levels at 4 weeks in 64.3% and
21.4% of patients, respectively (OR=6.60, 95% CI: 1.23-35.44, P=0.0540). SNMC and SAM signi-
cantly decreased ALT (from 558.28390.24 to 47.0724.94 IU/L, P<0.0001 and from 525.61483.87
to 117.4385.44 IU/L, P=0.0041, respectively) and AST (from 419.72409.49 to 38.1418.87 IU/L,
P=0.0016, and from 510.78621.58 to 79.9363.25 IU/L, P=0.0152, respectively) at 4 weeks relative
to baseline values. Hypokalemia was observed in 4 SNMC-treated patients and in 2 SAM-treated pa-
tients and hypernatremia in 3 SNMC-treated and in 3 SAM-treated patients. Hypertension was ob-
served in 1 SNMC-treated patient. There was no signicant difference in the volume of amniotic
uid or meconium between SNMC-treated and SAM-treated groups. All the neonates were physi-
cally normal at birth and at the 1-year follow-up examination.
Conclusions: Both SNMC and SAM improve liver function, with SNMC appearing more effective, in pregnant
women with chronic hepatitis B without impact on fetal development.
key words: stronger neo-minophagen C S-adenosyl-L-methionine hepatitis B pregnancy neonate
liver function
Full-text PDF: http://www.medscimonit.com/fulltxt.php?ICID=881083
Word count: 2661
Tables: 2
Figures: 1
References: 33
Authors address: Ji-Guang Ding, Department of Infectious Diseases, 3
rd
Afliated Hospital to Wenzhou Medical College, Wansong
Road 108, Ruian, Zhejiang, 325200, P.R. China, e-mail: djg5011@163.com
Authors Contribution:
A Study Design
B Data Collection
C Statistical Analysis
D Data Interpretation
E Manuscript Preparation
F Literature Search
G Funds Collection
Received: 2009.11.14
Accepted: 2010.04.06
Published: 2010.08.01
PR9
Preliminary Report
WWW.MEDSCIMONIT.COM
Med Sci Monit, 2010; 16(8): PR9-14
PMID: 20671623
PR
Current Contents/Clinical Medicine IF(2009)=1.543 Index Medicus/MEDLINE EMBASE/Excerpta Medica Chemical Abstracts Index Copernicus
BACKGROUND
Over 300 million people worldwide are chronic carriers of
hepatitis B virus (HBV), and about 75% of these carriers
live in Asian-Pacic countries. HBV is transmitted from the
mother to the neonate or between close contacts in ear-
ly childhood [1]. Chronic hepatitis B (CHB) is a leading
cause of liver cirrhosis, liver failure, liver cancer, and death
[2,3]. In China, CHB is a common in pregnant women [4].
HBV-infected pregnant women have a higher probability of
developing liver failure and mortality than non-pregnant
women with the infection [5]. Thus, development of HBV
infection-associated complications during the pregnancy
is a major problem.
S-adenosyl-l-methionine (SAM) is the methyl donor for the
majority of methyltransferases that modify DNA, RNA, his-
tones, and other proteins [6,7]. In clinical settings, adminis-
tration of this supernutrient antagonizes the toxicity of free
oxygen radicals generated by various pathogens in the liver
[8]. In pregnant women with mild intrahepatic cholestasis,
SAM effectively improves liver function and decreases the
concentration of serum bile acids [9]. Combined with ur-
sodeoxycholic acid, SAM also synergistically improves bio-
chemical parameters in pregnant women with intrahepatic
cholestasis [10]. Although SAM has been used in pregnant
women with chronic hepatitis B (CHB) to ameliorate liver
function [11], the effect of the treatment with SAM on the
fetus has not been systematically assessed.
Stronger neo-minophagen C (SNMC) is an herbal prepara-
tion composed of glycyrrhizin (or glycyrrhizic acid), a main
component of Radix glycyrrhizae, and is known to be an ef-
fective anti-inammatory and cytoprotective agent [12]. In
Japan and China, SNMC has been widely used for the treat-
ment of CHB. Intravenous treatment improves liver func-
tions in patients with subacute hepatic failure, chronic hep-
atitis, and active liver cirrhosis, and decreases mortality in
patients with subacute liver failure [13,14]. Various geno-
toxic studies have indicated that glycyrrhizin is neither tera-
togenic nor mutagenic, and may even possess anti-genotox-
ic properties [1417]. However, there have been no studies
evaluating the efcacy and potential risks of SNMC in preg-
nant women with CHB.
In this study, we evaluated the efcacy and safety of treat-
ment with SNMC or SAM in pregnant women with CHB.
Moreover, we assessed the effect of treatment with SNMC
or SAM on fetal development.
MATERIAL AND METHODS
Patients
This study was approved by the Medical Ethics Committee
of The Third Afliated Hospital, Wenzhou Medical College.
Women with CHB who were 2841 weeks pregnant were
provided with information about the study before they gave
written consent to participate. They were informed that
chronic hepatitis is associated with some complications,
which are usually more severe in pregnant women than
in non-pregnant women, and that they would be random-
ly assigned to receive either SNMC or SAM to determine
which treatment would most improve their liver function.
They were also informed that both SNMC and SAM have
been shown to have no genotoxic or teratogenic effects in
animal experiments.
CHB in pregnant women was diagnosed based on National
Prevention and Treatment Proles of Viral Hepatitis (2000)
and American Association for the Study of Liver Diseases
(AASLD) guidelines on chronic hepatitis B [18,19]. The
presence of a living fetus was conrmed by ultrasonography.
Those women with hypertension, hypokalemia, severe ede-
ma, cirrhosis, fatty liver of pregnancy, cholestasis of pregnan-
cy, hepatic failure, or infection with another type of hepati-
tis virus or HIV were excluded from the study.
From July 1, 2004 through June 30, 2006, a total of 36 preg-
nant women diagnosed as having CHB with liver dysfunction
(i.e., serum alanine transaminase, ALT, levels 2-fold of the up-
per limit of normal) were enrolled in the study, and random-
ized to receive either 80 ml SNMC containing 160 mg glycyr-
rhzin, 1600 mg glycine and 80 mg L-cysteine (Minophagen
Pharmaceutical, Tokyo, Japan), or 1000 mg SAM (Abbott
Pharmaceutical, Italia). SNMC or SAM and 500 mg vitamin
C were dissolved in 250 ml 5% glucose. The drugs were ad-
ministered intravenously once daily for 4 weeks or until birth.
Assessments of endpoints
The primary objective of this study was to determine wheth-
er treatment with SNMC or SAM improves liver function, as
indicated by normalization of the serum ALT (i.e., to <55
IU/L) with or without normalization of serum aspartate
transaminase (AST, to <60 IU/L) in pregnant women with
CHB after 4 weeks of treatment. Thus, the primary end-
point was the normalization of the serum levels of ALT af-
ter 4 weeks of treatment. The secondary endpoints includ-
ed the serum levels of AST after 4 weeks of treatment, the
serum levels of ALT and AST after 2 weeks of treatment,
and comparison of levels of ALT and AST to baseline (i.e.,
prior to treatment) levels. Morning fasting-state vein blood
samples were collected before and 2 and 4 weeks after the
treatment, and serum levels of ALT and AST were measured.
The secondary objectives were to determine whether SNMC
and SAM produced any adverse effects in pregnant women
with CHB and/or their fetuses, and to compare the efca-
cy and safety proles of SNMC and SAM. Thus, the second-
ary endpoints also included blood pressure and serum elec-
trolytes (such as potassium, sodium, and magnesium) in the
pregnant women, fetal movement, fetal heart rate, volume of
amniotic uid, meconium, spontaneous abortion, preterm
birth, neonatal asphyxia, fetal death, body weight, Apgar
score and congenital abnormalities or defects of the neonates.
Serum samples were prepared at the baseline, and 2 and 4
weeks after the treatment, and sent to the Department of
Biochemistry Laboratory of the hospital for biochemical
and hematological examinations, including liver and renal
functions. Serum ALT, AST, electrolytes, alkaline phospha-
tase, gamma-glutamyl transferase, total proteins and albu-
min/globulin ratio were measured by an automatic bio-
chemical analyzer, Olympus AU2700 (Holliston, MA, USA).
The Apgar score was calculated according to the protocol
previously described [20,21]. Briey, the general physical
Preliminary Report Med Sci Monit, 2010; 16(8): PR9-14
PR10
condition of neonates was determined by assigning a value
of 0, 1, or 2 to each of 5 criteria: heart rate, respiratory ef-
fort, muscle tone, skin color, and response to stimuli. The
5 scores were added together, with a perfect score being 10.
Apgar scores were evaluated at 1 minute and 5 minutes after
birth. The meconium was graded as: 1) (thin), light green
or ecking of otherwise clear liquor, which is not an indi-
cation of fetal hypoxia; 2) (medium) brown, thin but uni-
form staining of the labor, which is usually an indication of
post-maturity but also can be associated with hypoxia; and
3) (thick), bright green or brown thick uniform staining
of the liquor [22].
The neonates were regularly examined at local maternal-
infant healthcare centers, where their health status, includ-
ing body weight, height, chest and head circumferences,
was assessed.
Statistical analysis
Quantitative data showing normal distribution were ex-
pressed as mean standard deviation (SD). The signicance
of the decrease of ALT and AST levels from the baseline in
the pregnant women was determined by using a Students
2-tailed paired t test. The differences in the categorical
variables between the groups were determined by the chi-
square test with Yates correction for continuity if necessary,
or Fishers exact test. The differences between the groups of
neonates in body weight and Apgar score, volume of amni-
otic uid, height, and chest and head circumferences were
compared using a Students 2-tailed unpaired t test. A P val-
ue of less than 0.05 was considered statistically signicant.
All data were processed and analyzed using the SPSS 10.0
Data Editor (SPSS Inc., Chicago, Illinois, USA).
RESULTS
Baseline characteristics of patients
At baseline there was no difference in the average age (27.5
vs. 25.8 years) or age range (2138 vs. 2136 years) or in the
average number of weeks of gestation (32.2 vs. 31.8; range,
28-39 vs. 2841) between patients to be treated with SNMC
and those with SAM (Table 1). The baseline laboratory pa-
rameters, including blood glucose levels, main electrolytes,
ALT, AST, AKP, GGT, TP and A/G ratio were comparable
between the 2 groups (Table 1).
Effect of SNMC and SAM treatment on liver function
All patients completed the 2 weeks of treatment and 8 pa-
tients (4 from each group) gave birth during the sched-
uled treatment period of time. No patients discontinued
the study due to reasons other than birth.
Overall, liver function was signicantly improved in both
groups, as shown by the normalization of ALT and AST lev-
els, and the decrease in the levels of ALT and AST from the
baseline (Figure 1A, B). Specically, the normalization of
ALT at 4 weeks was achieved in 64.3% (9/14) of patients
treated with SNMC, and in 21.4% (3/14) of those treat-
ed with SAM (OR=6.60, 95% CI: 1.235.44, P=0.054). The
rates at 2 weeks were 22.2% (4/18) and 0% (0/18), respec-
tively in the SNMC and SAM groups (OR=11.48, 95% CI:
0.57230.99, P=0.104). The AST levels were normalized at
2 and 4 weeks in 33.3% (6/18) and 85.7% (12/14) of pa-
tients treated with SMNC, and in 16.7% (3/18) and 42.9%
(8/14) patients treated with SAM, respectively. The differ-
ences between treatment groups were not signicantly dif-
ferent (OR=2.50, 95% CI: 0.5112.14, P=0.443 for week
2 and OR=4.50 95% CI: 0.7228.15, P=0.209 for week 4).
ALT and AST levels were signicantly decreased in both
SNMC and SAM groups 2 and 4 weeks after the treatment
compared with the baseline levels. In the SMNC group,
ALT decreased from 558.28390.24 to 144.088.50 IU/L
(P=0.0001) at 2 weeks and to 47.0724.94 IU/L (P<0.0001)
at 4 weeks, whereas AST decreased from 419.72409.49 to
92.5661.92 IU/L (P=0.00198) at 2 weeks and to 38.1418.87
IU/L (P=0.0016) at 4 weeks (Figure 1A, B). In SAM group,
ALT and AST levels were deceased from 525.61483.87
IU/L to 218.61121.52 IU/L and 117.4385.44 IU/L, and
from 510.78621.57 IU/L to 156.33108.74 IU/L and
79.9363.26 IU/L, respectively, at 2 and 4 weeks (all P<0.05)
(Figure 1A, B).
Effect of SNMC and SAM treatment on general health of
the pregnant women and the development of fetuses
Hypokalemia was observed in 4 SNMC-treated patients and
in 2 SAM-treated patients and hypernatremia in 3 SNMC-
treated and 3 SAM-treated patients after 4 weeks of treat-
ment. In addition, hypertension (156/89 mmHg) occurred
SNMC (n=18) SAM (n=18)
Age (years) 27.5(2138) 25.8(2136)
Duration of pregnancy
(weeks)
32.2 (2839) 31.8 (2841)
Blood pressure
(systolic/diastolic,
mmHg)
116.99.32/
74.88.67
117.38.34/
73.17.02
Blood sodium (mM) 138.293.07 138.521.95
Blood potassium (mM) 4.010.38 3.930.36
Blood magnesium (mM) 0.81 0.07 0.800.10
ALT (IU/L) 558.33390.24 525.6483.90
AST (IU/L) 419.70409.49 510.78621.60
ALP (IU/L) 163.2599.18 185.73142.96
GGT (IU/L) 54.8141.21 50.8036.36
Total proteins (g/L) 59.076.97 60.016.14
Albumin/globulin ratio 1.030.28 1.070.20
Table 1. Baseline demographic and laboratory characteristics of
SNMC-treated and SAM-treated pregnant women with
chronic hepatitis B.
Values are mean standard deviation or average (range) where
appropriate. There was no signifcant between the two groups in any
of the parameters. ALT alanine alanine transaminase;
AST aspartate transaminase; ALP alkaline phosphatase;
GGT Gamma-glutamyl transferase.
Med Sci Monit, 2010; 16(8): PR9-14 Sun Q-F et al SNMC and SAM for treatment of chronic hepatitis B in pregnant
PR11
PR
in 1 case in SNMC group. The blood potassium levels ranged
3.05 mM to 3.47 mM in the 4 SNMC-treated patients with hy-
pokalemia, and were 3.25 mM and 3.40 mM in the 2 SAM-
treated patients with hypokalemia. The blood sodium levels
ranged from 145.2 mM to 149.7 mM in the 3 SNMC-treated
patients with hypernatremia, and ranged from 146.1 mM
and 147.0 mM in the 3 SAM-treated patients. The blood so-
dium levels ranged from 145.2 mM to 149.7 mM in the 3
SNMC-treated patients with hypernatremia, and were 147.0
mM and 146.1 mM in the 2 SAM-treated patients.
Hypokalemia disappeared in all cases after oral administra-
tion of potassium chloride sustained-release tablets (1.0 g,
p.o., b.i.d.). No treatment was given for patients with hyper-
tension or hypernatremia, and the both conditions disap-
peared after completion of the treatment.
Overall, 36 full-term neonates were born to the 36 mothers.
There was no signicant difference in the volume of amni-
otic uid (735.378.9 ml vs. 729.484.9 ml) or in the num-
ber of cases with meconium (1 vs. 3 cases) between SNMC
and SAM groups. Abdominal delivery was performed on 3
SNMC-treated and 4 SAM-treated women; all other births
were normal. There were no signicant differences in the
weights or Apgar scores at birth between the 2 groups
(Table 2). None of the neonates died and none had physi-
cal abnormalities or defects at birth.
Infant development and general health during the 1-year
follow-up
At 1-year examination, the community maternal-infant
healthcare centers did not detect any physical and mental
abnormalities or defects in any infants. There were no sig-
nicant differences between SAM and SNMC groups in ma-
jor health and development indicators. The body weights,
heights, chest circumferences, and head circumferences of
the infants were 9.290.67 kg, 74.651.57 cm, 45.532.30
cm and 45.751.35 cm in the SNMC group, and 9.48+0.72
kg, 75.451.48 cm, 45.632.16 cm and 45.801.30 cm in
the SAM group.
DISCUSSION
The present study demonstrated that SNMC and SAM sig-
nicantly improved liver function in pregnant women with
CHB during late pregnancy, without any serious adverse
events. Moreover, SNMC and SAM did not produce any
harmful or toxic effects on fetal development.
Severe complications such as liver failure often occur in
pregnant women with CHB. Tan et al. reported that serum
ALT elevation is common in patients with CHB in the peri-
partum period [23]. Thus, it is important to prevent CHB-
related complications in pregnant women. SNMC does not
have antiviral properties; it primarily acts as an anti-inam-
matory or cytoprotective drug, improving liver functions
and reduces mortality in patients with chronic hepatitis,
hepatic cirrhosis and subacute liver failure [12]. SNMC
does not reduce mortality among patients with hepatic cir-
rhosis. SNMC has been used clinically as an anti-hepatitis
agent for the treatment of CHB and chronic hepatitis C in
Asian countries. Although it has no antiviral effects [24],
SNMC decreases aminotransferase levels in patients with
chronic hepatitis [13,25]. SAM has also been shown to im-
prove liver function [11, 26]. Bonessio et al. reported the
case of a pregnant woman with intrahepatic cholestasis,
whose AST and ALT levels were normalized before deliv-
ery by treatment with SAM [26]. SAM was also reported to
show some benecial effect on the treatment of chemother-
apy-induced liver injury and alcoholic liver disease [27,28].
Figure 1. Changes of (A) serum ALT levels and (B) AST levels in
SNMC-treated and SAM-treated pregnant women with
chronic hepatitis B. Values are mean standard deviation.
* P<0.05, SNMC group compared with baseline value;
#
P<0.05, SAM group compared with baseline value.
A
B
SNMC (n=18) SAM(n=18)
Birth weight (mean SD, g) 3312.3447.1 3001.1598.1
Volume of amniotic fuid
(mean SD, ml)
735.378.9 729.484.9
Meconium before birth
grade II (number)
1 3
Apgar score 10 (number) 18 18
Table 2. Birth indicators in neonates born to SNMC-treated and
SAM-treated pregnant women with chronic hepatitis B.
Preliminary Report Med Sci Monit, 2010; 16(8): PR9-14
PR12
A recent study reported that SAM enhanced the antiviral
effect of IFN-a by increasing STAT1 methylation. Patients
with CHB usually show a low response to IFN-a treatment.
However, a combination of IFN-a and SAM effectively in-
creased STAT1 methylation and attenuated STAT1-PIAS1
binding, leading to a signicant reduction in the levels of
HBsAg and HBeAg protein levels and HBV DNA load in the
supernatant of HepG2.2.15 cells [29]. In the present study,
both SNMC and SAM signicantly improved liver function
in pregnant women with CHB who were treated in the late
stages of pregnancy. SNMC treatment led to a higher ALT
normalization rate than did SAM treatment at week 4 (64.3%
vs. 21.4%), although the difference did not reach statisti-
cal signicance, most likely due to our small sample size.
Moreover, our study indicates that both the drugs are safe
for pregnant women and their developing fetuses, and at 1
year has no adverse effects on the physical and mental de-
velopment of infants. Although SAM is more widely used,
and the complete safety prole of SNMC in pregnant wom-
en is yet to be established, our results indicate that SNMC
is probably a better choice than SAM for improving liver
function in pregnant women with CHB.
Several studies have determined the effects of glycyrrhizin
on nidation and on maternal or fetal survival in different
species of animals [30]. Gross and histological examinations
revealed no treatment-related effects in either the soft or
skeletal tissues as compared to untreated animals. From a
study with Wistar rats, Itami et al. concluded that disodium
glycyrrhizin is not teratogenic [31]. This conclusion was
supported by a similar study conducted by Mantovani et al.,
who evaluated the teratogenicity of ammoniated glycyrrhi-
zin in pregnant Sprague-Dawley rats [32]. In a later study
that examined the effects of glycyrrhetic acid on rat fetal
lung development, Hundertmark et al. found no apparent
increase in malformation or fetal death rate and no abnor-
mal behavior in neonatal rats [33]. Our preliminary clini-
cal data indicate that SNMC is safe in pregnant women and
does not have harmful effects on fetal development. The ad-
verse events we observed in a few cases were not severe, and
were either successfully treated (i.e., hypokalemia) during
the study or spontaneously resolved (i.e., hypernatremia)
after completion of the study. We speculate that these ad-
verse events were not drug-related.
The major limitation of the present pilot study was that it
was open-label and had a small sample size. Thus, well-de-
signed clinical trials with a larger sample size are required
to conrm our preliminary study.
CONCLUSIONS
Both SNMC and SAM improve liver function, with SNMC
appearing more effective, in pregnant women with chronic
hepatitis B, without impact on fetal development. However,
a larger, double-blinded, placebo or active drug-controlled
trial of pregnant women with CHB is required to establish
efcacy and, in particular, safety proles.
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