Chinese Herbal Cure for Hepatitis-B

http://www.liverindia.com/research.htm

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 Apr;38(4): 483-9.

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 weeks.
-Tilg H, Jalan R etal. Dept. of medicine, University hospital Innsbruk, Anichstrasse, Innsbruk, Austria. J Hepatol 2003 Apr;38(4):419-25.

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 liver 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 hepatitis. The new drugs with added cure rates are being evaluated.

 

Liver directed gene therapy using hepatocytes:

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 Syndrome-Type-I.

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 hepatitis

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 treatment.

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.