Science

Sorafenib effective in animal models of portal hypertension

Last Updated: 2009-04-07 15:50:22 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Sorafenib, an orally active multikinase inhibitor, has beneficial effects on circulation in two rat models of portal hypertension and cirrhosis, according to a report in the April issue of Hepatology.

Angiogenesis is a pathological hallmark of portal hypertension, the authors explain, and sorafenib is a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases.

Dr. Mercedes Fernandez from Hepatic Hemodynamics Laboratory, Barcelona, Spain, and colleagues investigated the effects of sorafenib on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations.

Sorafenib substantially inhibited splanchnic neovascularization, the authors report, with marked attenuation of the hyperdynamic splanchnic circulation.

Sorafenib reduced the portosystemic collateralization by 18% in both models of portal hypertension and reduced intrahepatic neovascularization by 59%.

Intrahepatic fibrosis and inflammation were both reduced significantly in response to sorafenib, the researchers note, as was intestinal inflammation.

Expression of intrahepatic endothelial nitric oxide synthase and heme oxygenase-1 did not change, the investigators say, indicating that the sorafenib-mediated reduction in intrahepatic vascular resistance is unlikely to be due to nitric oxide and/or carbon monoxide overproduction.

"Keeping in mind the limitations of translating results in animal models into clinical practice," the authors conclude, "we believe that our findings will be stimulating for consideration of this therapeutic approach in patients suffering from advanced portal hypertension, and we predict accelerated progress in this field of research."

In a related editorial, Dr. Vijay H. Shah from Mayo Clinic, Rochester, Minnesota, and Dr. Jordi Bruix from University of Barcelona, Spain, write, "As a whole, it is obvious that a new avenue for pharmacologic intervention in patients with cirrhosis has emerged."

With regard to cirrhosis and liver cancer, the editorialists add, "it may be that the same agent or family of agents will be used for the prevention of fibrosis progression leading to cirrhosis, which at a point is the main risk factor for liver cancer development, and for the treatment of liver cancer itself, when this unfortunate development takes place."

Hepatology 2009;49:1245-1256,1066-1068.