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The aim of our study was to determine the efficacy of rapamycin, everolimus, irbesartan and captopril, alone and in combination, as antifibrotic agents in the<jats:italic>Mdr2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>model of cholestasis both in early injury and established disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>Mdr2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice were treated for 4\u00a0weeks with vehicle, rapamycin (1\u00a0mg\/kg) or everolimus (5\u00a0mg\/kg) every second day or with captopril (30\u00a0mg\/kg\/day), irbesartan (10\u00a0mg\/kg\/day) or vehicle. Further groups of 3\u2010week\u2010old<jats:italic>Mdr2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice were treated with rapamycin and irbesartan in combination (1\u00a0mg\/kg\/day and 10\u00a0mg\/kg\/day) or with rapamycin (2\u00a0mg\/kg\/day) for 4\u00a0weeks. Liver injury and fibrosis were compared between treated and untreated animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There were no significant improvements in liver injury, histology, hepatic hydroxyproline or profibrogenic gene expression following treatment with rapamycin, everolimus, captopril or irbesartan at any time point studied. Likewise, there were no improvements in liver histology or profibrogenic gene expression following combination therapy or high\u2010dose rapamycin treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The antifibrotic effects of rapamycin, everolimus, captopril and irbesartan seen in other models of fibrosis were not replicated in the<jats:italic>Mdr2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>model in this study. This highlights the clear need to test specific antifibrotic agents in a number of different animal models. We believe this animal model is ideal to study usefulness of antifibrotic agents in cholestatic liver disease because of the similarity in genetics and hepatic histopathology to human cholestatic liver disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.12494","type":"journal-article","created":{"date-parts":[[2014,2,12]],"date-time":"2014-02-12T11:19:01Z","timestamp":1392203941000},"page":"1451-1463","source":"Crossref","is-referenced-by-count":5,"title":["Lack of efficacy of m<scp>TOR<\/scp>inhibitors and<scp>ACE<\/scp>pathway inhibitors as antifibrotic agents in evolving and established fibrosis in<i>Mdr2<\/i><sup><i>\u2212\/\u2212<\/i><\/sup>mice"],"prefix":"10.1111","volume":"35","author":[{"given":"Kim R.","family":"Bridle","sequence":"first","affiliation":[{"name":"The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation Greenslopes Private Hospital Envoi Specialist Pathologists and The Queensland Institute of Medical Research Brisbane Qld Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy L.","family":"Sobbe","sequence":"additional","affiliation":[{"name":"The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation Greenslopes Private Hospital Envoi Specialist Pathologists and The Queensland Institute of Medical Research Brisbane Qld Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. Erika","family":"de Guzman","sequence":"additional","affiliation":[{"name":"The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation Greenslopes Private Hospital Envoi Specialist Pathologists and The Queensland Institute of Medical Research Brisbane Qld Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nishreen","family":"Santrampurwala","sequence":"additional","affiliation":[{"name":"The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation Greenslopes Private Hospital Envoi Specialist Pathologists and The Queensland Institute of Medical Research Brisbane Qld Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lesley A.","family":"Jaskowski","sequence":"additional","affiliation":[{"name":"The University of Queensland School of Medicine and the Gallipoli Medical Research Foundation Greenslopes Private Hospital Envoi Specialist Pathologists and The Queensland 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