Back to Search
Start Over
Ultra-Rapid Cardiotoxicity of the Hepatitis C Virus Protease Inhibitor BILN 2061 in the Urokinase-Type Plasminogen Activator Mouse.
- Source :
- Gastroenterology (00165085); Oct2007, Vol. 133 Issue 4, p1144-1155, 12p
- Publication Year :
- 2007
-
Abstract
- Background & Aims: Because current therapies for chronic hepatitis C virus (HCV) infections are suboptimal and associated with severe side effects, novel treatment options are needed. A small animal model has recently been developed to study HCV infections. To examine the usefulness of this human liver–urokinase-type plasminogen activator (uPA)<superscript>+/+</superscript> severe combined immune deficient (SCID) mouse for the development of HCV-targeted drugs, we evaluated the antiviral efficacy and safety of an HCV NS3-protease inhibitor, BILN 2061. Methods: BILN 2061 was orally administered at clinical range doses for 4 days to SCID mice that differed in the presence of HCV infection, human hepatocyte grafts, and uPA zygosity. Treatment outcome was evaluated clinically, virologically, and morphologically. Using standard high-performance liquid chromatography–ultraviolet (HPLC-UV) methods and mass spectrometry, single-dose pharmacokinetics and multiple-dose drug exposures were analyzed. The <superscript>13</superscript>C-aminopyrine breath test was applied to compare in vivo liver function. Results: A 4-day treatment with BILN 2061 of HCV genotype-1b infected chimeric animals reduced the viral load by >100-fold, but concomitant clinical and ultrastructural signs of cardiotoxicity appeared. BILN 2061 administration to uPA-transgenic mice induced mitochondrial swelling with aberrant cristae in cardiomyocytes, but not in skeletal muscle. Because both drug accumulation and liver function were identical in affected uPA-transgenic and nontransgenic SCID mice without cardiac involvement, the urokinase plasminogen activator transgene itself appears to be implicated. Conclusions: The human liver-uPA<superscript>+/+</superscript>SCID mouse is an interesting small animal model to evaluate the preclinical safety and efficacy of new antiviral compounds against HCV. The uPA-transgene increases the susceptibility of mice to BILN 2061-induced cardiotoxicity. [Copyright &y& Elsevier]
- Subjects :
- HEPATITIS C
FLAVIVIRAL diseases
VIRAL hepatitis
DRUG side effects
Subjects
Details
- Language :
- English
- ISSN :
- 00165085
- Volume :
- 133
- Issue :
- 4
- Database :
- Supplemental Index
- Journal :
- Gastroenterology (00165085)
- Publication Type :
- Academic Journal
- Accession number :
- 27015953
- Full Text :
- https://doi.org/10.1053/j.gastro.2007.07.007