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Pharmaceutical composition for treating or preventing hcv infection

A composition and drug technology, applied in the direction of drug combination, antineoplastic drugs, pharmaceutical formulations, etc.

Inactive Publication Date: 2009-07-22
TOKYO METROPOLITAN INST OF MEDICAL SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The above results show that myriocin exhibits an anti-HCV effect, but it is not yet clear what effect the combined use of myriocin and interferon has on the inhibition of HCV replication

Method used

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  • Pharmaceutical composition for treating or preventing hcv infection
  • Pharmaceutical composition for treating or preventing hcv infection
  • Pharmaceutical composition for treating or preventing hcv infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0296] [Example 1] Anti-HCV effect of SPT inhibitor myriocin

[0297] The present inventors studied the anti-HCV effect and cytotoxicity of myriocin in the HCV subgenome replicon cell FLR3-1.

[0298]First, myriocin (Sigma, St. Louis, MO, USA) was added to HCV subgenomic replicon cells FLR3-1 (genotype 1b, Con-1, Sakamoto, H. et al., Nat Chem Biol, 1, 333-337 (2005)) in the proliferation medium, the final concentration was 0.2, 1.0, 3.9, 15.6 or 62.5 nM. After culturing for 72 hours, the inventors performed a luciferase assay using the Birght-Glo Luciferase Assay Kit (Promega, Madison, Wisconsin, USA).

[0299] In addition, myriocin was added to FLR3-1 cells, cultured for 72 hours, and then the cell viability was measured using Tetra Color One kit (Seikagakukogyo, Tokyo, Japan) according to the manufacturer's instructions.

[0300] The results showed that myriocin had no effect on cell viability ( figure 2 A) or cell proliferation (data not shown) is affected, but the lu...

Embodiment 2

[0304] [Example 2] Correlation between sphingolipid metabolites and HCV replication

[0305] To investigate the correlation of sphingolipid metabolites with HCV replication, the present inventors monitored de novo biosynthesis of sphingolipids in FLR3-1 cells in the presence of myriocins.

[0306] First, FLR3-1 cells were mixed in Opti-MEM (Invitrogen) with [ 14 C] Serine (0.5 μCi / mL) was incubated together for 2 hours. Cells were lysed with 0.1% SDS, and then total lipids were extracted with chloroform / methanol (1:2 v / v). The extract was spotted on a silica gel 60 thin-layer chromatography (TLC) plate (Merck, Darmstadt, Germany) by methyl acetate / 1-propanol / chloroform / methanol / 0.25% KCl (25:25: 25:10:9, v / v) for chromatographic analysis. Radioactive spots were detected by BAS 2000 (Fuji Film, Kanagawa, Japan).

[0307] As a result, the production of ceramide and sphingomyelin was dose-dependently inhibited, while the production of phosphatidylethanolamine and phosphatid...

Embodiment 3

[0311] [Example 3] Infection of HCV in chimeric mice against myriocin and PEG-IFN HCV effect

[0312] The inhibitory capacity of myriocins was studied using chimeric mice with humanized livers infected with HCR6 (genotype 1b). The chimeric mice used were purchased (PhoenixBio Co., Ltd., Hiroshima, Japan).

[0313] Specifically, according to Table 2, myriocin and / or PEG-IFN (Chugai, Tokyo, Japan) were administered to patients infected with HCV genotype 1b (HCR6, accession number) by intraperitoneal or subcutaneous injection. AY045702) mice, blood was collected.

[0314] (Table 2) Dosing schedule for chimeric mice infected with HCV genotype 1b

[0315]

[0316] In Table 2, B, I, and M show that each operation was performed as needed, and that the administration of the reagent was started from day 0. PEG-IFN was injected at 30 μg / kg. The amount of myriocin injected was adjusted according to the body weight of the mice. Dosing starts at 1 mg / kg (M), and when the body w...

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Abstract

The inventors examined an anti-HCV effect of an SPT inhibitor and / or interferon using an HCV subgenomic replicon cell FLR3-1 or an HCV infected chimeric mouse. As a result, it was found that myriocin, an SPT inhibitor, or a compound represented by the formula (III) can be a novel therapeutic agent for HCV infection and that a higher HCV replication inhibitory effect can be obtained by concomitantly using the SPT inhibitor and interferon.

Description

technical field [0001] The invention relates to a pharmaceutical composition containing myriocin and interferon as active ingredients for treating or preventing HCV infection and its application. Background technique [0002] Hepatitis C (HCV) infection usually leads to chronic hepatitis, often leading to cirrhosis or hepatocellular carcinoma. The number of carriers currently rises to about 3% of the world's population (-170 million people). Since HCV evades the host's immune system for unknown reasons, even when infected by adults with developed immune systems, persistent infection often occurs and progresses to chronic hepatitis, liver cirrhosis, and liver cancer. It is known that liver cancer recurs in many patients due to persistent inflammation at non-cancerous sites even after surgical removal. [0003] Currently, the most effective treatment for HCV infection is known to be the combined use of PEGylated interferon (PEG-IFN) and ribavirin (Non-Patent Documents 1 and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/21A61K45/00A61P1/16A61P31/12A61P35/00
CPCA61K38/21A61K45/06A61P1/16A61P31/12A61P31/14A61P35/00A61K31/197
Inventor 小原道法楳原琢哉须藤正幸
Owner TOKYO METROPOLITAN INST OF MEDICAL SCI
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