Chinese Herbal Cure for Hepatitis-B
An UC Berkeley study from the US
A randomized control trial led by the University of California,
Berkeley, discovered a new Chinese-herbal treatment for chronic
hepatitis B. Researchers analyzed 27 clinical trials in which chronic
hepatitis B patients using Chinese herbal medicine alone or with
interferon alfa, were compared with a control group of patients that
were taking only interferon alfa. The results found were very
encouraging from the patients who used a combination of Chinese herbal
treatments with interferon alfa.
The ingredients in the herbal treatments included mixtures of plant and
root extracts, and they varied from study to study. A couple of studies
looked specifically at bufotoxin, an extract from the skin of the toad
bufo gargarizans. Another two studied kurorinone, an extract from the
root of the pant sophorae flavescentis.
The study conducted required data on at least one of three markers of
infection; levels of hepatitis B surface antigen (HBsAg), hepatitis B e
antigen (HBeAg) and hepatitis B virus (HBV) DNA. All three measures
indicate an active infection.
It was seen that combination of Chinese herbal treatments with
interferon alfa were 1.5 to 2 times more effective as interferon alfa in
reducing the hepatitis B viral load to undetectable level for all three
measure of infection. In particular bufotoxin combined with interferon
alfa was significantly more effective than interferon alfa alone in
measures of HbeAg & HBV DNA, but not form the measures of the surface
antigen. Kurorinone was nearly as effective as interferon alfa in the
two studies that tested it.
"Bufotoxin and Kurorinone have been signaled out as having the best
potential for being investigated for drugs" a licensed acupuncturist for
16 years. The investigators also showed that the quality of the studies
left much room for improvement. Many of the studies were having
incomplete information on how patients were randomized, & "blinding" of
patients and also the type of treatment administered by the doctors did
not occur in most of the studies.
Dr. Jack Colford, associate professor of epidemiology said that we
cannot take firm conclusion about the use of these medicines, but the
findings revealed by this analysis certainly justify additional
investigation of these herbal therapies in more rigorous trials.
Anti TNF monoclonal antibody finds a new
role in treatment of acute alcoholic hepatitis (AH).
The abstracts of two recent publications narrated here explores the new
found role of a monoclonal antibody to a well known pro-inflamatory
molecule, TNF-Alpha (Tumor necrosis factor-alpha), in treatment of a
vexing disorder that affects hundreds of young Indians which is acute
alcoholic hepatitis. When this disorder is progressive it often
culminates in prolonged hospitalization and death from hepatic failure
and co-morbid infections. In the more common form there is also an
underlying chronic liver disease bordering on cirrhosis, which retards
spontaneous healing and regeneration. The two studies quoted below
exposes the exciting and new treatment option for a difficult clinical
problem. However caution must be expressed until studies of large scale
clinical studies are published.
Increased concentration of plasma tumor necrosis factor-alpha,
correlates with the clinical coarse of alcoholic liver disease. The
protein -hepatic RANTES (A pro-inflamatory chemokine), which mobilizes
CD4 T lymphocytes to the liver, is also increased in this condition. In
an elegant invitro scientific experiment using hepatoma cell lines, it
has been shown that TNF-Alpha clearly up-regulated RANTES gene
expression in a time dependant fashion and induced DNA-binding activity
of NF-kappaB (a protein kinase). These findings allows them conclude
that TNF-alpha induced expression of RANTES plays important roles in
cell mediated liver injury in alcoholic liver disease.
- Hirano F et al, Department of Internal medicine, Asahikawa medical
college, Midorigaoka-higashi, Asahikawa, Japan. J Hepatol 2003
Severe forms of alcoholic hepatitis is associated with high mortality.
In a small clinical study where 12 patients with biopsy proven AH were
treated with a single infusion of Infliximab (monoclonal antibody to TNF-alpha)
at adose of 5mg/Kg body weight. Subsequently serial measurement were
made of various pro-inflamatory cytokines by ELISA technique. Ten out of
twelve patients were alive at a median of 15 months. Two patients died
within 30 days from septicemia. The serum bilurubin levels, Maddrey
score, neutrophil count and C-reactive protein fell significantly within
the first month. The mRNA expression of IL-8 was almost absent after 4
-Tilg H, Jalan R etal. Dept. of medicine, University hospital
Innsbruk, Anichstrasse, Innsbruk, Austria. J Hepatol 2003
Current research in liver disease
The scientific community is in search for alternative forms of effective
therapy for various incurable liver diseases and cancers. Hepatocyte
transplantation is increasingly being projected as
cure for different disease conditions. It is now being considered for
gene therapy because hepatocytes can maintain many genes at high levels.
Particularly in treatment of the conditions that arise from metabolic
dysfunction of cells resulting in deficiency of several liver specific
proteins. Total liver replacement for such conditions is considered a
drastic approach. Current research has also progressed in the field of
treatment of viral
The new drugs with added cure rates are being evaluated.
Liver directed gene therapy using
The important research objectives to achieve this goal are- to
immortalize liver cells in culture under laboratory conditions, to
abrogate the host rejection response by modulating recipient immune
responses by gene transfer and to achieve preferential proliferation of
transplanted hepatocytes to achieve re-population of the host liver.
Recently this work has been translated into the first successful
hepatocyte allotransplantation in humans for Crigler-Najar
Strategies for gene therapy: The various strategies for gene
therapy include- Gene augmentation, Gene delivery using recombinant
viral vectors, gene repair with oligonucleotide therapy and polymer
based gene carriers. Recombinant retro viruses require a proliferating
hepatocyte for integration. While adenoviral vectors can affectively
transfer genes their use is limited due to strong host immune responses.
The SV-40 virus holds a better prospect as a gene delivery system. One
of the newest techniques in liver directed gene therapy is
oligonucleotide-mediated-site-directed gene repair. Here a molecule is
prepared composed of both DNA and RNA domains forming a chimeric RNA/DNA
oligonucleotide. This is designed to be perfectly complimentary to the
targeted gene except for a single base mismatch. This mismatch seems to
trigger the cell's DNA repair mechanism. Viral enzyme pro-drug therapy
is a strategy developed to treat liver cancer. Here the tumour cells are
transduced with a non-mammalian suicide gene which can convert a non
toxic prodrug to a chemotherapeutic agent within the target malignant
cells. This ensures reduction of systemic toxicity of chemotherapy. Non
viral polymer-gene carriers are the latest in gene delivery sytems. The
lipid based or polymer based cationic carriers have been explored for
this purpose. The choice of carrier depends on the desired affinity to
receptors of the target organ. This system if efficient will overcome
the teething problems of biological vectors for gene delivery.
Experimental gene therapy:
Gene therapy for
liver cirrhosis: Repetitive gene transfer of
hepatocyte growth factor(HGF) gene into skeletal muscle of cirrhotic
rats is shown to produce marked suppression of the expression of
TGF(transforming growth factor) gene which is a major factor which
promotes fibrosis in the liver and apoptosis of hepatocytes. It has also
been shown that HGF stimulated hepatocyte mitosis and the histology
revealed disappearance of liver fibrosis and liver cirrhosis related
mortality was completely abrogated.
Therapy for Familial Hypercholestrolemia(FH): Human trials with
five patients who were homozygous for FH gene underwent ex-vivo
replacement of the faulty gene. This was achieved by using hepatocytes
cultured from segmental liver resection which was transduced with
recombinant retrovirus encoding the gene for human LDL receptor. These
cells were transplanted into the liver through the portal vein.
Prolonged reductions in LDL cholesterol were seen in three of the five
patients. Investigators have also achieved successful transduction of a
functional rabbit LDL gene into target hepatocytes with 30-40% reduction
in serum cholesterol.
New drugs under trial for viral
Entecavir: A new drug promoted by Bristol-Myers Squibb, is an
once daily oral antiviral agent for adults with chronic hepatitis-B
infection. Studies are being carried out in more than 100 centers
worldwide. The hope is that it will prove useful when there is emergence
of resistance to the standard therapy with lamuvudine.
Adefovir: Adefovir Dipivoxil (Hepsera) is now a FDA approved drug
for treatment of histologically active chronic hepatitis B. Hepsera
slows the progression of chronic hepatitis B by interfering with viral
replication and causing DNA chain termination. FDA based its approval on
the results of two controlled trials where at week 48 of the studies 53%
and 64% of patients receiving Hepsera showed significant improvement in
the liver inflammation as compared to 25% and 35% of patients on placebo
respectively. Further there is clinical evidence that it may be useful
in treating HBV infection resistant to Lamuvudine therapy. Patients with
underlying kidney dysfunction may develop kidney failure on Hepsera
Thymosin-alpha-1: The injectable anti-viral agent promoted by
SciClone pharmaceuticals, is undergoing extensive phase -III trials in
Taiwan for resistant chronic hepatitis-B. Given at 1.6 mg twice weekly
regimen for 26 weeks to 98 Asian patients with hepatitis-B, as published
in Hepatology(May-1998) is effective and safe for chronic hepatitis-B.
There was statistically significant increase in conversion of both
hepatitis-B positive to negative and HBe-antigen positive to negative.
Ribozymes: Ribozymes are an emerging technology that appears to
be capable of disrupting the life cycle of hepatitis-B and C viruses by
cleaving RNA transcripts and pregenomic RNA. One of the published
experimental study explored the use of ribozymes targeting the highly
conserved region of the HBV DNA (HepBZyme) in the treatment of chronic
HBV infection. Invitro tests exploring the use of combination of
ribozyme with either Interferron-alpha 2B or Lamuvudine on HepG2 cells
transfected with a replication component HBcDNA showed that this
combination resulted in additive down regulation of HbsAg expression.
(Findings were presented at the 52nd AASLD meeting in Dallas, Texas) A
similar Ribozyme called Heptazyme (The ribozyme targeting site 195 of
the plus strand of HCV virus) can cause inhibition of HCV replication in
cells. This alone or in combination with synthetic stabilized ribozymes
directed against the HCV minus strand RNA have the potential to be
effective therapeutic agents for treatment of chronic HCV infection.