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

Thomas Vanwolleghem, Philip Meuleman UGent, Louis Libbrecht UGent, Tania Roskams, Rita De Vos and Geert Leroux-Roels UGent (2007) GASTROENTEROLOGY. 133(4). p.1144-1155
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ANTIVIRAL EFFICACY, MATRIX METALLOPROTEINASES, TRANSGENIC MICE, BREATH ANALYSIS, LIVER, UPA, DEMETHYLATION, FIALURIDINE, INFECTION, DYSFUNCTION
journal title
GASTROENTEROLOGY
Gastroenterology
volume
133
issue
4
pages
1144 - 1155
Web of Science type
Article
Web of Science id
000250036200012
JCR category
GASTROENTEROLOGY & HEPATOLOGY
JCR impact factor
11.673 (2007)
JCR rank
1/50 (2007)
JCR quartile
1 (2007)
ISSN
0016-5085
DOI
10.1053/j.gastro.2007.07.007
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
426755
handle
http://hdl.handle.net/1854/LU-426755
date created
2008-07-07 15:51:00
date last changed
2013-04-18 17:37:13
@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},
}

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.