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Efficacy 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. A total of 36 pregnant women with CHB, but without severe complications, were randomized to intravenously receive SNMC or SAM. Treatment with SNMC and SAM resulted in normalization of ALT levels at 4 weeks in 64.
Efficacy 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. A total of 36 pregnant women with CHB, but without severe complications, were randomized to intravenously receive SNMC or SAM. Treatment with SNMC and SAM resulted in normalization of ALT levels at 4 weeks in 64.
Efficacy 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. A total of 36 pregnant women with CHB, but without severe complications, were randomized to intravenously receive SNMC or SAM. Treatment with SNMC and SAM resulted in normalization of ALT levels at 4 weeks in 64.
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. REFERENCES: 1 Kao JH, Chen DS: Global control of hepatitis B virus infection. Lancet Infect Dis, 2002; 2: 395403 2 Liaw YF, Tai DI, Chu CM, Chen TJ: The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology, 1988; 8: 49396 3 Chang MH, Chen CJ, Lai MS et al: Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med, 1997; 336: 185559 4 Yang H, Chen R, Li Z et al: Analysis of fetal distress in pregnancy with hepatitis B virus infection. 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