| Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. | |
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MedLine Citation:
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PMID: 19137587 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs. CONCLUSION: Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension. |
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Authors:
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Marc Mejias; Ester Garcia-Pras; Carolina Tiani; Rosa Miquel; Jaime Bosch; Mercedes Fernandez |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 49 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-04-06 Completed Date: 2009-05-08 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 1245-56 Citation Subset: IM |
Affiliation:
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Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Ciberehd, Barcelona, Spain. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Benzenesulfonates / pharmacology, therapeutic use* Collateral Circulation / drug effects Enteritis / drug therapy, etiology Heme Oxygenase-1 / metabolism Hepatitis / drug therapy, etiology Hypertension, Portal / drug therapy*, etiology Liver / metabolism Liver Cirrhosis / complications, drug therapy* Male Neovascularization, Physiologic / drug effects Nitric Oxide Synthase Type III / metabolism Protein Kinase Inhibitors / pharmacology, therapeutic use* Pyridines / pharmacology, therapeutic use* Rats Rats, Sprague-Dawley Splanchnic Circulation / drug effects* |
| Chemical | |
Reg. No./Substance:
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0/Benzenesulfonates; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/sorafenib; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.99.3/Heme Oxygenase-1 |
| Comments/Corrections | |
Comment In:
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Hepatology. 2009 Apr;49(4):1066-8
[PMID:
19330868
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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