Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity
Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the e...
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| Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2006-03, Vol.43 (3), p.581-591 |
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| creator | LEVY, Gary A ADAMSON, Gord LEVY, Adam KOSCIK, Cheryl HE, William GORCZYNSKI, Reginald BROOKES, Steve WOODS, Caroline MCGILVRAY, Ian D BELL, David PHILLIPS, M. James SCROCCHI, Louise A FUNG, Laisum BIESSELS, Pieter NG, Nancy F GHANEKAR, Anand ROWE, Andrea XUEZHONG MA, Max |
| description | Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis ( |
| doi_str_mv | 10.1002/hep.21072 |
| format | Article |
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James ; SCROCCHI, Louise A ; FUNG, Laisum ; BIESSELS, Pieter ; NG, Nancy F ; GHANEKAR, Anand ; ROWE, Andrea ; XUEZHONG MA, Max</creator><creatorcontrib>LEVY, Gary A ; ADAMSON, Gord ; LEVY, Adam ; KOSCIK, Cheryl ; HE, William ; GORCZYNSKI, Reginald ; BROOKES, Steve ; WOODS, Caroline ; MCGILVRAY, Ian D ; BELL, David ; PHILLIPS, M. James ; SCROCCHI, Louise A ; FUNG, Laisum ; BIESSELS, Pieter ; NG, Nancy F ; GHANEKAR, Anand ; ROWE, Andrea ; XUEZHONG MA, Max</creatorcontrib><description>Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203-treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro.</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.21072</identifier><identifier>PMID: 16496340</identifier><identifier>CODEN: HPTLD9</identifier><language>eng</language><publisher>Hoboken, NJ: Wiley</publisher><subject>Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - administration & dosage ; Biological and medical sciences ; Coronavirus Infections - complications ; Coronavirus Infections - drug therapy ; Drug Delivery Systems ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Hepatitis, Viral, Animal - complications ; Hepatitis, Viral, Animal - drug therapy ; Hepatocytes - drug effects ; Hepatocytes - virology ; Human viral diseases ; Infectious diseases ; Liver Failure, Acute - virology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Macrophages - drug effects ; Macrophages - virology ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Murine hepatitis virus ; Other diseases. Semiology ; Outcome Assessment, Health Care ; Pharmacology. Drug treatments ; Ribavirin - administration & dosage ; Viral diseases ; Viral Hepatitis ; Virus Replication</subject><ispartof>Hepatology (Baltimore, Md.), 2006-03, Vol.43 (3), p.581-591</ispartof><rights>2006 INIST-CNRS</rights><rights>Copyright © 2006 American Association for the Study of Liver Diseases</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c469t-d624b01a45e6f7579d84c30209c98ecea6f5fc5f4086477b94a2c121934e56923</citedby><cites>FETCH-LOGICAL-c469t-d624b01a45e6f7579d84c30209c98ecea6f5fc5f4086477b94a2c121934e56923</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17595008$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16496340$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LEVY, Gary A</creatorcontrib><creatorcontrib>ADAMSON, Gord</creatorcontrib><creatorcontrib>LEVY, Adam</creatorcontrib><creatorcontrib>KOSCIK, Cheryl</creatorcontrib><creatorcontrib>HE, William</creatorcontrib><creatorcontrib>GORCZYNSKI, Reginald</creatorcontrib><creatorcontrib>BROOKES, Steve</creatorcontrib><creatorcontrib>WOODS, Caroline</creatorcontrib><creatorcontrib>MCGILVRAY, Ian D</creatorcontrib><creatorcontrib>BELL, David</creatorcontrib><creatorcontrib>PHILLIPS, M. James</creatorcontrib><creatorcontrib>SCROCCHI, Louise A</creatorcontrib><creatorcontrib>FUNG, Laisum</creatorcontrib><creatorcontrib>BIESSELS, Pieter</creatorcontrib><creatorcontrib>NG, Nancy F</creatorcontrib><creatorcontrib>GHANEKAR, Anand</creatorcontrib><creatorcontrib>ROWE, Andrea</creatorcontrib><creatorcontrib>XUEZHONG MA, Max</creatorcontrib><title>Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203-treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro.</description><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - administration & dosage</subject><subject>Biological and medical sciences</subject><subject>Coronavirus Infections - complications</subject><subject>Coronavirus Infections - drug therapy</subject><subject>Drug Delivery Systems</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Hepatitis, Viral, Animal - complications</subject><subject>Hepatitis, Viral, Animal - drug therapy</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - virology</subject><subject>Human viral diseases</subject><subject>Infectious diseases</subject><subject>Liver Failure, Acute - virology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - virology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Murine hepatitis virus</subject><subject>Other diseases. Semiology</subject><subject>Outcome Assessment, Health Care</subject><subject>Pharmacology. Drug treatments</subject><subject>Ribavirin - administration & dosage</subject><subject>Viral diseases</subject><subject>Viral Hepatitis</subject><subject>Virus Replication</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkE1rGzEQhkVoaBynh_yBoksPPWw60upjdSkU06SFQC_OeZG1o1hlP4wkL_jfR45N0p7m8Dx6Z_QScsvgjgHwb1vc3XEGml-QBZNcV3Ut4QNZANdQGVabK3Kd0l8AMII3H8kVU8KoWsCC5LWNz5ixox32YcZ4oJOnMWzsHGIYaRh2cZox0Wmf3TTgkQ77QpAWwfbU7_shjHbMtFxhc8ghFWIpjls7upJbUKhOrnU5zCEfbsilt33CT-e5JE_3P9erX9Xjn4ffqx-PlRPK5KpTXGyAWSFReS216RrhauBgnGnQoVVeeie9gEYJrTdGWO4YZ6YWKJXh9ZJ8P-Xu9psBO4djLme0uxgGGw_tZEP7PxnDtn2e5lYzJUVjSsDXU4CLU0oR_dtbBu2x-rZ8un2tvrif_132bp67LsKXs2CTs72PpZ-Q3j0tjQRo6hftS4-D</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>LEVY, Gary A</creator><creator>ADAMSON, Gord</creator><creator>LEVY, Adam</creator><creator>KOSCIK, Cheryl</creator><creator>HE, William</creator><creator>GORCZYNSKI, Reginald</creator><creator>BROOKES, Steve</creator><creator>WOODS, Caroline</creator><creator>MCGILVRAY, Ian D</creator><creator>BELL, David</creator><creator>PHILLIPS, M. 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Abdomen</topic><topic>Hepatitis, Viral, Animal - complications</topic><topic>Hepatitis, Viral, Animal - drug therapy</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - virology</topic><topic>Human viral diseases</topic><topic>Infectious diseases</topic><topic>Liver Failure, Acute - virology</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - virology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Murine hepatitis virus</topic><topic>Other diseases. Semiology</topic><topic>Outcome Assessment, Health Care</topic><topic>Pharmacology. Drug treatments</topic><topic>Ribavirin - administration & dosage</topic><topic>Viral diseases</topic><topic>Viral Hepatitis</topic><topic>Virus Replication</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LEVY, Gary A</creatorcontrib><creatorcontrib>ADAMSON, Gord</creatorcontrib><creatorcontrib>LEVY, Adam</creatorcontrib><creatorcontrib>KOSCIK, Cheryl</creatorcontrib><creatorcontrib>HE, William</creatorcontrib><creatorcontrib>GORCZYNSKI, Reginald</creatorcontrib><creatorcontrib>BROOKES, Steve</creatorcontrib><creatorcontrib>WOODS, Caroline</creatorcontrib><creatorcontrib>MCGILVRAY, Ian D</creatorcontrib><creatorcontrib>BELL, David</creatorcontrib><creatorcontrib>PHILLIPS, M. 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James</au><au>SCROCCHI, Louise A</au><au>FUNG, Laisum</au><au>BIESSELS, Pieter</au><au>NG, Nancy F</au><au>GHANEKAR, Anand</au><au>ROWE, Andrea</au><au>XUEZHONG MA, Max</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2006-03-01</date><risdate>2006</risdate><volume>43</volume><issue>3</issue><spage>581</spage><epage>591</epage><pages>581-591</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><abstract>Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203-treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro.</abstract><cop>Hoboken, NJ</cop><pub>Wiley</pub><pmid>16496340</pmid><doi>10.1002/hep.21072</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Hepatology (Baltimore, Md.), 2006-03, Vol.43 (3), p.581-591 |
| issn | 0270-9139 1527-3350 |
| language | eng |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - administration & dosage Biological and medical sciences Coronavirus Infections - complications Coronavirus Infections - drug therapy Drug Delivery Systems Female Gastroenterology. Liver. Pancreas. Abdomen Hepatitis, Viral, Animal - complications Hepatitis, Viral, Animal - drug therapy Hepatocytes - drug effects Hepatocytes - virology Human viral diseases Infectious diseases Liver Failure, Acute - virology Liver. Biliary tract. Portal circulation. Exocrine pancreas Macrophages - drug effects Macrophages - virology Medical sciences Mice Mice, Inbred BALB C Murine hepatitis virus Other diseases. Semiology Outcome Assessment, Health Care Pharmacology. Drug treatments Ribavirin - administration & dosage Viral diseases Viral Hepatitis Virus Replication |
| title | Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity |
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