By Liz Highleyman

Given that current standard therapy for chronic hepatitis C (pegylated interferon alpha plus ribavirin) does not cure about half of all patients, and that there are no proven effective treatments for liver fibrosis, researchers have explored a wide range of complementary and alternative ( CAM) therapies for management of the disease.

Two studies presented at the recent 58th Annual Meeting of the American Association for the Study of Liver Diseases in Boston (November 2-6, 2007) looked at botanical therapies for patients with hepatitis C.

Glycyrrhizin

Glycyrrhizin, derived from licorice root (Glychyrrhiza glabra), has long been used in traditional Asian medicine to treat liver conditions. In Japan, it has been used as a treatment for hepatitis C for more than 20 years. However, there is less data on the use of glycyrrhizin in non-Asian patients.

M.P. Manns and colleagues conducted a study to assess the safety and efficacy of glycyrrhizin in chronic hepatitis C patients in Western and Eastern Europe who did not achieve sustained response to standard combination anti-HCV therapy. Efficacy was defined in terms of biochemical response (ALT reduction) and histological response (improvement of necroinflammation), not virological response (HCV viral load reduction).

All 374 participants were non-responders or relapsers to prior treatment with conventional or pegylated interferon plus ribavirin. At baseline, they had detectable HCV RNA and abnormal ALT (mean 77 IU/L); 73% had HCV genotype 1. The mean necroinflammation score was 7.6 and the mean fibrosis score was 3.1. Liver biopsy results were available at study entry or performed within 6 months.

The trial consisted of 2 phases. Phase 1 was a randomized, double-blind, placebo-controlled comparison of intravenous injections of 200 mg glycyrrhizic acid 5 or 3 times per week, or placebo 5 times per week, for 12 weeks. The following Phase 2 was a randomized, open-label comparison of 200 mg glycyrrhizin administered 5 or 3 times per week for an additional 40 weeks, with no placebo arm.

Results

• 30% of patients in the 5 times weekly glycyrrhizin arm and 32% in the 3 times weekly glycyrrhizin arm had ≥50% ALT reduction after 12 weeks, significantly higher than the 6% in the placebo arm.

• Based on evaluable biopsies taken before and at the end of treatment (n=249), 45% of patients experienced histological improvement (defined as at least 1 point difference in necroinflammation score) and 17% had stable histology (that is, 62% had no histological worsening).

• About 4% of patients discontinued therapy due to treatment-related adverse events.

• Favorable results were also seen in secondary endpoints, including quality of life.

The investigators concluded that, “Glycyrrhizin appears to be effective and well tolerated in the treatment of chronic hepatitis C [patients] not responding to interferon alpha or pegylated interferon plus ribavirin therapy.”

CEE, PharmaPart AG, Thalwil, Zurich, Switzerland; Hannover Medical School, Hanover, Germany; Military Therapy, Moscow City Hospital No. 29, Moscow, Russian Federation; Moscow Hepatology Center, Moscow Clinical Hospital for Infectious Diseases No. 1, Moscow, Russian Federation; Lugansk Medical University, Lugansk, Ukraine; University Hospitals Leuven, Belgium; University Hospital of Cologne, Germany; Minophagen Pharmaceutical Co., Ltd, Tokyo, Japan; PharmaPart AG, Thalwil, Zurich, Switzerland.

Silymarin and Sho-saiko-to

In the second study, S.J. Polyak and colleagues examined the mechanism of action of 2 botanical therapies widely used for liver conditions, silymarin (derived from milk thistle, Silybum marianum) and sho-saiko-to, a combination of several herbs based on a traditional Chinese medicine formula.

The activity of the 2 therapies was studied in the laboratory in human hepatoma liver cell lines (Huh 7 and Huh 7.5.1) infected with JFH-1, a genotype 2a strain of HCV that can replicate in vitro.

Results

•Silymarin inhibited expression of TNF-alpha in anti-CD3 stimulated human peripheral blood mononuclear cells and NF-kappa-B dependent transcription in Huh7 cells.

• Both silymarin and sho-saiko-to inhibited infection of Huh7 and Huh7.5.1 cells by JFH-1 virus in a dose-dependent manner.

• Both compounds also displayed prophylactic and therapeutic effects against JFH-1 infection.

• When combined with interferon alpha, both silymarin and sho-saiko-to inhibited HCV replication more than interferon alone.

• The antiviral effects induced by silymarin involved both JAK-STAT pathway dependent and independent signaling.

• Sho-saiko-to enhanced interferon-stimulated response element (ISRE) transcription via p38 MAP kinase activation.

• High performance liquid chromatography fractionation of the herbal preparations permitted identification of specific components eliciting antiviral actions.

“The data demonstrate that standardized silymarin and sho-saiko-to have antiviral action against in vitro HCV infection, and that silymarin has immunomodulatory and anti-inflammatory actions,” the researchers concluded. “Therefore, CAM-based approaches may assist in the management patients with chronic hepatitis C.”

Laboratory of Medicine, University of Washington, Seattle, WA; Harvard University, Cambridge, MA.

12/04/07

References

MP Manns, IG Bakulin, NP Blokhina, and others. A 52 week multi-centre, randomized, double-blind placebo-controlled trial evaluating the efficacy and safety of glycyrrhizin in patients with chronic hepatitis C not responding to IFN alpha or PEG-IFN plus ribavirin therapy. 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007). Boston, MA, November 2-6, 2007. Abstract 1326.

SJ Polyak, J Wagoner, O Kane, and others. Botanical Medicines for Hepatitis C. AASLD 2007. Abstract 1383.

http://www.hivandhepatitis.com/2007icr/aasld/docs/120407_b.html 

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