1. Volume 133, Issue 4, Pages 1144-1155 (October 2007)
Ultra-Rapid Cardiotoxicity of the Hepatitis C Virus Protease Inhibitor BILN 2061 in the Urokinase-Type Plasminogen Activator Mouse 
Thomas Vanwolleghem, Philip Meuleman, Louis Libbrecht, Tania Roskams, Rita De Vos, Geert Leroux–Roels 
Gastroenterology 
Volume 133, Issue 4, Pages (October 2007)
DOI: /j.gastro
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2. Figure 1
Evolution of human albumin and HCV RNA levels in plasma of human liver-uPA+/+SCID mice treated with BILN 2061 or PBS. Viral loads (■—■) and human albumin levels (▴---▴) were quantified in the plasma from infected mice treated twice daily with (A) 10 mg/kg of BILN 2061 for 4 days and (B) PBS for 8 days. The detection limit (det limit) of viral load (315 IU/mL) is set at the origin of the y axis. (C) Mean log10 change in HCV RNA levels after 7 or 8 oral doses of BILN 2061 or 8 doses of PBS administered twice daily (day 4). Error bars indicate SD (n = 3 in each treatment group).
Gastroenterology  , DOI: ( /j.gastro )
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3. Figure 2
Ultrastructural morphology of the heart of uPA-transgenic animals after dosing with BILN 2061 (A, B), with compound vehicle (C, D) or without treatment (E, F). (A) Diffuse lipid accumulation (*), aberrant swollen mitochondria (open arrows), and relative abundance of mitochondria in the myocard of an HCV-infected chimeric animal treated with BILN 2061 (see Methods). (B) Magnification of the sarcoplasm of 2 adjacent myocytes from (A) showing mitochondria with a pale matrix, disrupted cristae, and lipid inclusions (*). (C–F) Normal ultrastructure of the heart. (C, E) Mitochondria are round to elongated, regularly dispersed, and normally matched to sarcomeric units in an uninfected chimeric animal (C) and a uPA+/+SCID mouse (E). (D, F) Higher magnifications showing densely packed mitochondria with closely arranged parallel membranous cristae in an HCV-infected chimeric animal (D) and a uPA+/−SCID mouse (F). Scale bars indicate 2.5 μm (A, C, E) and 1 μm (B, D, F).
Gastroenterology  , DOI: ( /j.gastro )
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4. Figure 3
BILN 2061 dosing induces mitochondrial deformation in cardiomyocytes of uPA-transgenic animals, but not in skeletal muscle. Nontransgenic SCID (A, B), uPA+/−SCID (C, D) and uninfected chimeric mice (E, F) received a 4-day BILN 2061 treatment (see Materials and Methods) after which heart (A, C, E) and skeletal muscle (B, D, F) were examined by electron microscopy. Normal ultrastructural morphology of the heart (A) and skeletal muscle (B) was found in SCID mice. (C) Sarcoplasm of 2 adjacent cardiomyocytes from a uPA+/−SCID mouse showing mitochondrial swelling, disruption of cristae, and complete loss of mitochondrial morphology (open arrow). Note the intercalated discs. (D) Skeletal muscle of the same animal as in (C) with a normal ultrastructure. (E) Aberrant swollen mitochondria with disarranged cristae and lipid inclusions (*) in the cardiomyocytes, but not in skeletal muscle (F), of an uninfected chimeric animal. Scale bars indicate 1 μm.
Gastroenterology  , DOI: ( /j.gastro )
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5. Figure 4
BILN 2061 plasma trough levels in human liver- (hu liv-) uPA+/+SCID, uPA+/−SCID and SCID, mice after 8 oral doses at 10 mg/kg. Mean BILN 2061 plasma levels (indicated by the line) are not significantly different (P = .13).
Gastroenterology  , DOI: ( /j.gastro )
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6. Figure 5
Liver function of uPA+/−SCID mice depends on the number of red nodules in the liver parenchyme. (A) Morphologic quantification of healthy hepatocytes forming red nodules in the liver parenchyma of 5-week-old uPA+/−SCID mice shows a linear correlation with body weight (n = 15; P < .0001; r2 = ). (B) Enrichment of 13CO2 in breath samples after IP injection of 13C-aminopyrine in low weight (▴---▴) and higher weight uPA+/−SCID mice (■---■) and SCID mice of the same age (●—●). PBS was injected in controls (SCID, ○; uPA+/−SCID, □). APE 13C/min is the atom percent excess 13C above baseline, exhaled per minute over a 5-minute sampling period. Error bars indicate SD (n = 3 or 6 for 13C-aminopyrine–injected animals). (C) Peak enrichment of 13CO2 in breath samples after IP injection of 13C-aminopyrine in uPA+/−SCID mice shows a linear correlation with the amount of red nodules in the liver parenchyma. APEmax is the peak APE 13C/min measured over the 90-minute sampling period as indicated in Figure 5B. (n = 9; P = .0001; r2 = ).
Gastroenterology  , DOI: ( /j.gastro )
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7. Figure 6
Total mouse uPA antigen levels in plasma of SCID and uPA+/−SCID mice. Total mouse uPA antigen levels in the plasma of uPA+/−SCID mice were grouped into 3 categories according to the amount of red nodules in the liver parenchyma (% red nodules on the x axis) and compared with those of SCID mice of the same age. The mean is indicated by the line.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2007 AGA Institute Terms and Conditions