Viral Hepatitis
Copyright ©The Author(s) 2003. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 15, 2003; 9(11): 2480-2483
Published online Nov 15, 2003. doi: 10.3748/wjg.v9.i11.2480
Oxymatrine therapy for chronic hepatitis B: A randomized double-blind and placebo-controlled multi-center trial
Lun-Gen Lu, Min-De Zeng, Yi-Min Mao, Ji-Qiang Li, Mo-Bin Wan, Cheng-Zhong Li, Cheng-Wei Chen, Qing-Chun Fu, Ji-Yao Wang, Wei-Min She, Xiong Cai, Jun Ye, Xia-Qiu Zhou, Hui Wang, Shan-Ming Wu, Mei-Fang Tang, Jin-Shui Zhu, Wei-Xiong Chen, Hui-Quan Zhang
Lun-Gen Lu, Min-De Zeng, Yi-Min Mao, Ji-Qiang Li, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Second Medical University, Shanghai 200001, China
Mo-Bin Wan, Cheng-Zhong Li, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
Cheng-Wei Chen, Qing-Chun Fu, Liver Disease Research Center, Nanjing Military Command, Shanghai 200233, China
Ji-Yao Wang, Wei-Min She, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Xiong Cai, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
Jun Ye, Shanghai Putuo District Central Hospital, Shanghai 200062, China
Xia-Qiu Zhou, Hui Wang, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China
Shan-Ming Wu, Mei-Fang Tang, Shanghai General Hospital of Infectious Diseases, Shanghai 200083, China
Jin-Shui Zhu, Wei-Xiong Chen, Shanghai No.6 People's Hospital, Shanghai 200230, China
Hui-Quan Zhang, Shanghai Shibei Hospital, Shanghai 200073, China
Author contributions: All authors contributed equally to the work.
Supported by the Key Project of Shanghai Medical Development Foundation (NO: 99ZDI001) and grants from 1999 Foundation of Chinese Liver Diseases Association for Yong Scholars
Correspondence to: Lun-Gen Lu, MD, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Second Medical University, Shanghai 200001, China. lulungen@online.sh.cn
Telephone: +86-21-33070834 Fax: +86-21-63364118
Received: May 13, 2003
Revised: June 12, 2003
Accepted: June 19, 2003
Published online: November 15, 2003

Abstract

AIM: To evaluate the efficacy and safety of capsule oxymatrine in the treatment of chronic hepatitis B.

METHODS: A randomised double-blind and placebo-controlled multicenter trial was conducted. Injection of oxymatrine was used as positive-control drug. A total of 216 patients with chronic hepatitis B entered the study for 24 wk, of them 108 received capsule oxymatrine, 36 received injection of oxymatrine, and 72 received placebo. After and before the treatment, clinical symptoms, liver function, serum hepatitis B virus markers, and adverse drug reaction were observed.

RESULTS: Among the 216 patients, six were dropped off, and 11 inconsistent with the standard were excluded. Therefore, the efficacy and safety of oxymatrine in patients were analysed. In the capsule treated patients, 76.47% became normal in ALT level, 38.61% and 31.91% became negative both in HBV DNA and in HBeAg. In the injection treated patients, 83.33% became normal in ALT level, 43.33% and 39.29% became negative both in HBV DNA and in HBeAg. In the placebo treated patients, 40.00% became normal in ALT level, 7.46% and 6.45% became negative both in HBV DNA and in HBeAg. The rates of complete response and partial response were 24.51% and 57.84% in the capsule treated patients, and 33.33% and 50.00% in the injection treated patients, and 2.99% and 41.79% in the placebo treated patients, respectively. There was no significance between the two groups of patients, but both were significantly higher than the placebo. The adverse drug reaction rates of the capsule, injection and placebo were 7.77%, 6.67% and 8.82%, respectively. There was no statistically significant difference among them.

CONCLUSION: Oxymatrine is an effective and safe agent for the treatment of chronic hepatitis B.




INTRODUCTION

Oxymatrine is a kind of alkaloid extracted from a Chinese herb Sophora alopecuraides L.[1]. Basic and clinical researches suggested that oxymatrine had the following pharmacological effects such as anti-virus, protecting hepatocytes, anti-hepatic fibrosis, immune regulation, etc.[2-7]. In particular, wide attention was paid to its inhibitory effect on hepatitis B virus (HBV) in recent years. Oxymatrine has been proved to have distinct anti-virus effect in the treatment of chronic hepatitis B (CHB)[8-11]. But no information is available about the therapeutic efficacy and safety of oxymatrine capsule treated CHB. In this paper, we evaluated the therapeutic efficacy and safety of oxymatrine (kurorinone) capsule in the treatment of CHB based on a randomized multi-centre, double-blind and placebo-controlled clinical trial.

MATERIALS AND METHODS
Research design

This study was a clinical trial characterized by multi-centre, randomization, double blinding and placebo-control, which was fulfilled by Renji Hospital of Shanghai Second Medical University, Zhongshan Hospital of Fudan University, Changhai Hospital of Second Military Medical University.

Selection of subjects

Enrolled criteria: Age: 18-65 years old, regardless of sex, positiveness of serum HBsAg and HBV DNA for at least 6 mo before enrolling, positiveness of serum HBeAg for at least 6 mo before enrolling, abnormal serum value of alanine transaminase (ALT) twice or more with a value 1.2 times greater than normal upper limit and a duration more than 8 wk between two tests within 6 mo before enrolling, the serum level of ALT was more than normal upper limit when screening, total serum bilirubin (TB) level less than or equal to 85.5 μmol/L, non-history of administrating antiviral and immunoregulating drugs, signing in the informed consent form, promising not to receive other drugs in clinical trial and systemic anti-viral agents, cytotoxic agents, hormone, immunoregulators, drugs capable of reducing serum enzyme activity and bilirubin level and Chinese traditional medicines, etc.

Exclusion criteria Patients with positive laboratory test of HIV, positiveness of serum anti-HCV and/or HCV RNA, uncompensable liver diseases, suggestive of autoimmune diseases with antinuclear antibody (ANA) titer greater than a 1:160 dilution, abnormality of serum creatinine with a value of 1.5 times greater than normal, concurrence of other associated severe diseases which might affect the present treatment, hypersensitive to oxymatrine capsule, women with pregnancy and during breast-feeding period.

Treatment procedures and drugs

A total of 216 selected patients were randomly divided into 3 groups: 108 in capsule oxymatrine group, 36 in injection oxymatrine group and 72 in placebo group. Both capsule oxymatrine and injection oxymatrine were provided by Ningxia Pharmaceutic Institute, Ningxia, China (Batch numbers 990426 and 990325, respectively). The magnitude, colour, shape and taste of the vacant placebo capsule were consistent with capsule oxymatrine. Capsule oxymatrine group: 300 mg oxymatrine capsules orally 3 times a day. Injection oxymatrine group: 400 mg intramuscularly once a day. Placebo group: 3 tablets, three times a day. Treatment course of the 3 groups was 24 wk. After completion of selection and assessment, qualified subjects were allocated randomly into capsule oxymatrine group, injection oxymatrine group and placebo group for a treatment course of 24 wk according to the treatment code based on stratified randomization.

Observing indexes and assessment

Clinical manifestations Weakness, pain in hepatic region, jaundice, hepatomegaly, splenomegaly, etc.

Liver function indexes Serum levels of total protein, albumin, ratio of albumin and globulin, ALT, aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), total bilirubin (TB), direct bilirubin (DB) and alkaline phosphatase (ALP).

Detection of serum markers of HBV HBV DNA was measured by dot blotting assay. HBsAg, anti-HBsAg, anti-HBc, HBeAg and anti-HBe were measured by Abbott kit before the treatment, 12 and 24 wk after the treatment.

Analysis of blood and urine All parameters including electrolytes and renal function were measured before the treatment, 12 and 24 wk after the treatment.

Assessment criteria of therapeutic effect and safety

Mainly evaluated indexes were negatively converting rate of serum HBV DNA and HbeAg, and the normalization rate of serum ALT. The assessment criteria of therapeutic effect were as follow. Complete response: negative conversion of HBeAg and HBV DNA, and normalization of serum ALT. Partial response: negative conversion of HBeAg and HBV DNA or normalization of serum ALT. Nonresponse: the effect didn't reach the above criteria. Any abnormal clinical manifestations and laboratory tests occurred during the treatment were recorded and filled in a report form of side effects in time whether they were associated with drugs for trial or not.

Statistical analysis

Statistical analysis of the data was performed with SAS 6.12 software kit.

RESULTS
Number of subjects

A total of 216 patients were enrolled in the study, of them 108 in capsule oxymatrine group, 36 in injection oxymatrine group, and 72 in placebo control group. Twelve cases withdrew, and the withdrawal rate was 2.78%. Eleven cases were excluded for not conforming selection criteria, and the excluding rate was 5.09%. One hundred and ninety-nine cases entered statistical analysis of therapeutic effect included 102 cases in capsule oxymatrine group, 30 cases in injection oxymatrine group, and 67 cases in placebo control group.

General state of patients in three groups before treatment

Before treatment, the following data were similar among three groups (P > 0.05, respectively), including sex, age, duration of hepatitis, abnormality of serum ALT and AST 2-fold higher than normal elevation, etc. There were no significant differences among three groups in symptoms and signs before treatment (P > 0.05).

Negative conversion of serum virus markers

Negative conversion rate of serum HBsAg in capsule oxymatrine group, injection oxymatrine group and placebo group was 1.98%, 3.33%, and 0.00%, respectively (Table 1). There were no obvious differences among 3 groups (P = 0.269). The negative conversion rate of HBV DNA was 38.61%, 43.33% and 7.46% respectively in the above groups. There were obvious differences between capsule oxymatrine group and placebo group or between injection oxymatrine group and placebo group (P = 0.001), but there were no significant difference between capsule oxymatrine group and injection oxymatrine group (P = 0.643). The negative conversion rate of serum HBeAg was 31.91%, 39.29% and 6.45% respectively in the above groups. There was an obvious difference between capsule oxymatrine group and placebo group or between injection oxymatrine group and placebo group (P = 0.001), but no significant difference between capsule oxymatrine group and injection oxymatrine group (P = 0.469).

Table 1 Negative conversion rates of serum HBsAg and comparison among capsule oxymatrine group, injection oxymatrine group and placebo group.
IndexGroupPositive numberNumber of negative conversionNegative conversionrate (%)Comparison among 3 groups
χ²P value
HBsAgCapsule10121.98
Injection3013.330.269
Placebo6700.00
HBV DNACapsule1013938.61
Injection301343.3322.7160.001
Placebo6757.46
HBeAgCapsule943031.91
Injection281139.2917.0420.001
Placebo6246.45
Normalization rate of serum ALT

The normalization rate of serum ALT in capsule oxymatrine group, injection oxymatrine group and placebo group was 76.47%, 83.33% and 40.00%, respectively. There was an obvious difference between capsule oxymatrine group and placebo group or between injection oxymatrine group and placebo group (P = 0.001, Table 2), but no significant difference between capsule oxymatrine group and injection oxymatrine group (P = 0.425).

Table 2 Normalization rate of serum ALT and comparison among capsule oxymatrine group, injection oxymatrine group and placebo group.
GroupNumber of ALT abnormality before treatmentNumber of ALT normalization after treatmentNormalizationrate (%)Comparison among 3 groups
χ²P value
Capsule1027876.47
Injection302583.3328.3520.001
Placebo652640.00
Comparison of therapeutic effect among 3 groups of chronic hepatitis B

The complete and partial response rates were 24.51% and 57.84% in capsule oxymatrine group, 33.33% and 50.00% in injection oxymatrine group, 2.99% and 41.79% in placebo group. There was an with obvious difference between capsule oxymatrine group and placebo group or between injection oxymatrine group and placebo group (P = 0.001, Table 3), but no significant difference between capsule oxymatrine group and injection oxymatrine group (P = 0.4589).

Table 3 Comparison of therapeutic effect among 3 groups with chronic hepatitis B.
GroupComplete responsePartial responseNon-responseComparison among 3 groups
χ²P value
Capusle (n = 102)25 (24.51%)59 (57.84%)18 (17.65%)
Injection (n = 30)10 (33.33%)15 (50.00%)5 (16.67%)35.9570.0001
Placebo (n = 67)2 (2.99%)28 (41.79%)37 (55.22%)
Adverse effects

In this study, 8 patients had adverse effects in capsule oxymatrine group with an incidence of 7.77%, 2 patients in injection oxymatrine group with an incidence of 6.67%, and 6 patients in placebo group with an incidence of 8.82%. The difference among 3 groups had no statistical significance (P = 0.931). The adverse effects were mild or moderate and mainly manifested as symptoms of upper alimentary tract, rash, bad taste. No severe adverse effect occurred. The statistical analysis of adverse effects included 2 cases withdrawn because of side effects.

DISCUSSION

Hepatitis B virus is a DNA virus that produces both acute and chronic infections of the liver in humans. It has been estimated that over 300 million people worldwide are chronically infected with HBV and that over 250000 people would die each year due to HBV-associated complications of cirrhosis and primary hepatocellular carcinoma[12-18]. For many years, alpha interferon has been the only approved therapy for chronic HBV infection in most countries. Interferon was effective in 30%-40% of patients, and it must be given by injection and was frequently associated with fever and influenza-like symptoms[19-23]. Recently, lamivudine was approved for the treatment of chronic HBV infection in many regions of the world. Although convenient and well-tolerated, lamivudine's efficacy rate was similar to interferon and prolonged administration of lamivudine was associated with development of resistance[24-30]. New agents, such as adefovir dipivoxil, offered a promise either alone or in combination with lamivudine in the treatment of individuals who were 'treatment naïve' have developed lamivudine resistance[31-33]. Up to date, no specific therapy is available for chronic hepatitis B. The following factors may be associated with its pathogenesis such as virulence of HBV strains, number of infected hepatocytes and host immune response, antiviral agents, immunomodulators and drugs might be capable of improving liver function[12-15,34-41].

Traditional Chinese medicine has been widely used for the treatment of liver disease in China[11]. Oxymatrine extracted from Sophora alopecuraides L. has been shown to have a remarkable HBV suppressing effect with 40% serum conversion rate for HBeAg and HBV DNA, similar to that of alpha interferon[8,9,11]. Experiment in vitro indicated that oxymatrine had an inhibitory role in the secretion of HBsAg and HBeAg by 2.2.15 cell line transfected with HBV DNA and the inhibitory rates increased gradually following increased oxymatrine concentration and the extension of effect time within a definite range[42]. In vivo study of HBV transgenic mouse showed that when mice were injected intraperitoneally oxymatrine at 100 mg/kg, 200 mg/kg and 300 mg/kg once a day for 30 d, the quantity of HBsAg and HBeAg in the liver decreased obviously compared with control group, and there was no significant difference among 3 doses[10]. Clinical research suggested that the normalization rates of serum ALT and TB, and the negative conversion rates of serum HBsAg and HBV DNA were similar to alpha interferon when oxymatrine was applied to treatment of chronic hepatitis B. The results in present study were similar to the therapeutic effect of interferon in the treatment of chronic hepatitis B at home and abroad[9,11,17,43], indicating that capsule oxymatrine is an effective and safe agent for treatment of chronic hepatitis B.

Footnotes

Edited by Zhang JZ and Wang XL

References
1.  Lai JP, He XW, Jiang Y, Chen F. Preparative separation and determination of matrine from the Chinese medicinal plant Sophora flavescens Ait by molecularly imprinted solid-phase extraction. Anal Bioanal Chem. 2003;375:264-269.  [PubMed]  [DOI]
2.  Liu J, Manheimer E, Tsutani K, Gluud C. Medicinal herbs for hepatitis C virus infection: A Cochrane hepatobiliary systematic review of randomized trials. Am J Gastroenterol. 2003;98:538-544.  [PubMed]  [DOI]
3.  Dong Y, Xi H, Yu Y, Wang Q, Jiang K, Li L. Effects of oxymatrine on the serum levels of T helper cell 1 and 2 cytokines and the expression of the S gene in hepatitis B virus S gene transgenic mice: A study on the anti-hepatitis B virus mechanism of oxymatrine. J Gastroenterol Hepatol. 2002;17:1299-1306.  [PubMed]  [DOI]
4.  Xiang X, Wang G, Cai X, Li Y. Effect of oxymatrine on murine fulminant hepatitis and hepatocyte apoptosis. Chin Med J (. Engl). 2002;115:593-596.  [PubMed]  [DOI]
5.  Yang W, Zeng M, Fan Z, Mao Y, Song Y, Jia Y, Lu L, Chen CW, Peng YS, Zhu HY. [Prophylactic and therapeutic effect of oxymatrine on D-galactosamine-induced rat liver fibrosis]. Zhonghua Ganzangbing Zazhi. 2002;10:193-196.  [PubMed]  [DOI]
6.  Chen Y, Li J, Zeng M, Lu L, Qu D, Mao Y, Fan Z, Hua J. [The inhibitory effect of oxymatrine on hepatitis C virus in vitro]. Zhonghua Ganzangbing Zazhi. 2001;9 Suppl:12-14.  [PubMed]  [DOI]
7.  Li J, Li C, Zeng M. [Preliminary study on therapeutic effect of oxymatrine in treating patients with chronic hepatitis C]. Zhongguo Zhongxiyi Jiehe Zazhi. 1998;18:227-229.  [PubMed]  [DOI]
8.  Chen YX, Mao BY, Jiang JH. [Relationship between serum load of HBV-DNA and therapeutic effect of oxymatrine in patients with chronic hepatitis B]. Zhongguo Zhongxiyi Jiehe Zazhi. 2002;22:335-336.  [PubMed]  [DOI]
9.  Yu YY, Wang QH, Zhu LM, Zhang QB, Xu DZ, Guo YB, Wang CQ, Guo SH, Zhou XQ, Zhang LX. [A clinical research on oxymatrine for the treatment of chronic hepatitis B]. Zhonghua Ganzangbing Zazhi. 2002;10:280-281.  [PubMed]  [DOI]
10.  Chen XS, Wang GJ, Cai X, Yu HY, Hu YP. Inhibition of hepatitis B virus by oxymatrine in vivo. World J Gastroenterol. 2001;7:49-52.  [PubMed]  [DOI]
11.  Wang BE. Treatment of chronic liver diseases with traditional Chinese medicine. J Gastroenterol Hepatol. 2000;15 Suppl:E67-E70.  [PubMed]  [DOI]
12.  Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000--summary of a workshop. Gastroenterology. 2001;120:1828-1853.  [PubMed]  [DOI]
13.  Gow PJ, Mutimer D. Treatment of chronic hepatitis. BMJ. 2001;323:1164-1167.  [PubMed]  [DOI]
14.  Arguedas MR, Fallon MB. Prevention in liver disease. Am J Med Sci. 2001;321:145-151.  [PubMed]  [DOI]
15.  Maddrey WC. Update in hepatology. Ann Intern Med. 2001;134:216-223.  [PubMed]  [DOI]
16.  Ryder SD, Beckingham IJ. ABC of diseases of liver, pancreas, and biliary system: Chronic viral hepatitis. BMJ. 2001;322:219-221.  [PubMed]  [DOI]
17.  Pramoolsinsup C. Management of viral hepatitis B. J Gastroenterol Hepatol. 2002;17 Suppl:S125-S145.  [PubMed]  [DOI]
18.  Yuen MF, Lai CL. Treatment of chronic hepatitis B. Lancet Infect Dis. 2001;1:232-241.  [PubMed]  [DOI]
19.  Feld J, Locarnini S. Antiviral therapy for hepatitis B virus infections: new targets and technical challenges. J Clin Virol. 2002;25:267-283.  [PubMed]  [DOI]
20.  Rivkina A, Rybalov S. Chronic hepatitis B: current and future treatment options. Pharmacotherapy. 2002;22:721-737.  [PubMed]  [DOI]
21.  Wai CT, Lok AS. Treatment of hepatitis B. J Gastroenterol. 2002;37:771-778.  [PubMed]  [DOI]
22.  Schalm SW, De Man RA, Janssen HL. Combination and newer therapies for chronic hepatitis B. J Gastroenterol Hepatol. 2002;17 Suppl 3:S338-S341.  [PubMed]  [DOI]
23.  Karayiannis P. Hepatitis B virus: old, new and future approaches to antiviral treatment. J Antimicrob Chemother. 2003;51:761-785.  [PubMed]  [DOI]
24.  Marcellin P. Advances in therapy for chronic hepatitis B. Semin Liver Dis. 2002;22 Suppl 1:33-36.  [PubMed]  [DOI]
25.  Zoulim F. Assessing hepatitis B virus resistance in vitro and molecular mechanisms of nucleoside resistance. Semin Liver Dis. 2002;22 Suppl 1:23-31.  [PubMed]  [DOI]
26.  Papatheodoridis GV, Dimou E, Papadimitropoulos V. Nucleoside analogues for chronic hepatitis B: Antiviral efficacy and viral resistance. Am J Gastroenterol. 2002;97:1618-1628.  [PubMed]  [DOI]
27.  Bozdayi AM, Uzunalimoğlu O, Türkyilmaz AR, Aslan N, Sezgin O, Sahin T, Bozdayi G, Cinar K, Pai SB, Pai R. YSDD: A novel mutation in HBV DNA polymerase confers clinical resistance to lamivudine. J Viral Hepat. 2003;10:256-265.  [PubMed]  [DOI]
28.  Torresi J, Locarnini S. Antiviral chemotherapy for the treatment of hepatitis B virus infections. Gastroenterology. 2000;118:S83-103.  [PubMed]  [DOI]
29.  Doo E, Liang TJ. Molecular anatomy and pathophysiologic implications of drug resistance in hepatitis B virus infection. Gastroenterology. 2001;120:1000-1008.  [PubMed]  [DOI]
30.  Zöllner B, Petersen J, Schröter M, Laufs R, Schoder V, Feucht HH. 20-fold increase in risk of lamivudine resistance in hepatitis B virus subtype adw. Lancet. 2001;357:934-935.  [PubMed]  [DOI]
31.  Pessoa MG, Wright TL. Update on clinical trials in the treatment of hepatitis B. J Gastroenterol Hepatol. 1999;14 Suppl:S6-11.  [PubMed]  [DOI]
32.  Galan MV, Boyce D, Gordon SC. Current pharmacotherapy for hepatitis B infection. Expert Opin Pharmacother. 2001;2:1289-1298.  [PubMed]  [DOI]
33.  Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, Goodman Z, Wulfsohn MS, Xiong S. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808-816.  [PubMed]  [DOI]
34.  Rich JD, Ching CG, Lally MA, Gaitanis MM, Schwartzapfel B, Charuvastra A, Beckwith CG, Flanigan TP. A review of the case for hepatitis B vaccination of high-risk adults. Am J Med. 2003;114:316-318.  [PubMed]  [DOI]
35.  Shaw T, Bowden S, Locarnini S. Chemotherapy for hepatitis B: new treatment options necessitate reappraisal of traditional endpoints. Gastroenterology. 2002;123:2135-2140.  [PubMed]  [DOI]
36.  Yao N, Hong Z, Lau JY. Application of structural biology tools in the study of viral hepatitis and the design of antiviral therapy. Gastroenterology. 2002;123:1350-1363.  [PubMed]  [DOI]
37.  Chin R, Locarnini S. Treatment of chronic hepatitis B: current challenges and future directions. Rev Med Virol. 2003;13:255-272.  [PubMed]  [DOI]
38.  Liaw YF. Therapy of chronic hepatitis B: current challenges and opportunities. J Viral Hepat. 2002;9:393-399.  [PubMed]  [DOI]
39.  Lau GK, Carman WF, Locarnini SA, Okuda K, Lu ZM, Williams R, Lam SK. Treatment of chronic hepatitis B virus infection: An Asia-Pacific perspective. J Gastroenterol Hepatol. 1999;14:3-12.  [PubMed]  [DOI]
40.  Farrell GC. Clinical potential of emerging new agents in hepatitis B. Drugs. 2000;60:701-710.  [PubMed]  [DOI]
41.  Zoulim F, Trepo C. New antiviral agents for the therapy of chronic hepatitis B virus infection. Intervirology. 1999;42:125-144.  [PubMed]  [DOI]
42.  Zeng Z, Wang GJ, Si CW. Basic and clinical study of oxymatrime on HBV infection. J Gastroenterol Hepatol. 1999;14:A295-297.  [PubMed]  [DOI]
43.  Chen C, Guo SM, Liu B. A randomized controlled trial of kurorinone versus interferon-alpha2a treatment in patients with chronic hepatitis B. J Viral Hepat. 2000;7:225-229.  [PubMed]  [DOI]