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Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse

(2007) GASTROENTEROLOGY. 133(4). p.1144-1155
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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)(+/+) 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 13 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 non-transgenic SCID mice without cardiac involvement, the urokinase plasminogen activator transgene itself appears to be implicated. Conclusions: The human liver-uPA(+/+)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.
Keywords
ANTIVIRAL EFFICACY, MATRIX METALLOPROTEINASES, TRANSGENIC MICE, BREATH ANALYSIS, LIVER, UPA, DEMETHYLATION, FIALURIDINE, INFECTION, DYSFUNCTION

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Chicago
Vanwolleghem, Thomas, Philip Meuleman, Louis Libbrecht, Tania Roskams, Rita De Vos, and Geert Leroux-Roels. 2007. “Ultra-rapid Cardiotoxicity of the Hepatitis C Virus Protease Inhibitor BILN 2061 in the Urokinase-type Plasminogen Activator Mouse.” Gastroenterology 133 (4): 1144–1155.
APA
Vanwolleghem, T., Meuleman, P., Libbrecht, L., Roskams, T., De Vos, R., & Leroux-Roels, G. (2007). Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse. GASTROENTEROLOGY, 133(4), 1144–1155.
Vancouver
1.
Vanwolleghem T, Meuleman P, Libbrecht L, Roskams T, De Vos R, Leroux-Roels G. Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse. GASTROENTEROLOGY. 2007;133(4):1144–55.
MLA
Vanwolleghem, Thomas, Philip Meuleman, Louis Libbrecht, et al. “Ultra-rapid Cardiotoxicity of the Hepatitis C Virus Protease Inhibitor BILN 2061 in the Urokinase-type Plasminogen Activator Mouse.” GASTROENTEROLOGY 133.4 (2007): 1144–1155. Print.
@article{426755,
  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)(+/+) 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 13 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 {\textrangle} 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 non-transgenic SCID mice without cardiac involvement, the urokinase plasminogen activator transgene itself appears to be implicated.
Conclusions: The human liver-uPA(+/+)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.},
  author       = {VANWOLLEGHEM, THOMAS and Meuleman, Philip and Libbrecht, Louis and Roskams, Tania and De Vos, Rita and Leroux-Roels, Geert},
  issn         = {0016-5085},
  journal      = {GASTROENTEROLOGY},
  keyword      = {ANTIVIRAL EFFICACY,MATRIX METALLOPROTEINASES,TRANSGENIC MICE,BREATH ANALYSIS,LIVER,UPA,DEMETHYLATION,FIALURIDINE,INFECTION,DYSFUNCTION},
  language     = {eng},
  number       = {4},
  pages        = {1144--1155},
  title        = {Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse},
  url          = {http://dx.doi.org/10.1053/j.gastro.2007.07.007},
  volume       = {133},
  year         = {2007},
}

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