Abstract
Hepatitis B virus (HBV) infectious diseases currently remain incurable due to limitations of conventional antivirals such as incapability of eradicating HBV DNA, prolonged use, drug resistance, and virological relapse. KCT-01, a 30% ethanol extract consisting of Artemisia capillaris, Sanguisorba officinalis, and Curcuma longa, was newly developed. The objective of this study was to investigate pharmacological activities of KCT-01 against HBV using HepG2.2.15 cells and a hydrodynamic injection model. KCT-01 significantly lowered antigen secretion, virion production, and pgRNA synthesis in HepG2.2.15 cells without affecting cell viability. KCT-01 administration also resulted in significant decrease of serum virion production, liver covalently closed circular (ccc) DNA levels, and mRNA synthesis of cytokines in the liver of mice injected with HBV DNA hydrodynamically. Interestingly, coadministration of KCT-01 with entecavir enhanced its in vitro and in vivo antiviral activities. Moreover, safety of KCT-01 was assured up to 5000 mg/kg in rats in both single and repeated-dose preclinical studies. Taken together, our findings demonstrate that KCT-01 is capable of suppressing HBV replication and inflammatory cytokine production in in vitro and in vivo models without showing toxicity, suggesting the potential of using KCT-01 alone or in combination with entecavir as antiviral agent.
Highlights
Hepatitis B virus (HBV), a major pathogen that causes chronic infection of the liver, is a serious global health burden [1]
To set criteria for contents of three major reference constituents (6,7dimethylesculetin, ziyuglycoside I, and curcumin) from 1 g of KCT-01, dry material of KCT-01 manufactured in three LOTs (16001, 16002, and 16003) was repeatedly tested to obtain the content of each index component in a Korea Good Manufacturing Practice (KGMP) certified company
These results demonstrate that KCT-01 can inhibit the production of HBV antigens from HBV genomes existing in cells
Summary
Hepatitis B virus (HBV), a major pathogen that causes chronic infection of the liver, is a serious global health burden [1]. Current treatment of CHB depends on several oral nucleos(t)ide analogs (lamivudine, adefovir, telbivudine, entecavir (ETV), and tenofovir) and interferon therapy [4] These therapeutic strategies over the past decade have been very potent in suppressing viral replication, 30-76% of patients treated with lamivudine or adefovir have shown drug resistance and virological breakthrough due to viral mutation after long-term use for 5 years or more. ETV or tenofovir has yet to be definitely investigated on its relevance with renal toxicity or undesirable side effects after long-term oral administration [5] These shortcomings of current conventional anti-HBV agents expose patients with CHB to a high risk of developing liver cirrhotic or hepatocarcinogenic change [6]
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