Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats.

BACKGROUND/AIMS: Angiogenesis plays a key role in development of portal hypertension (PHT) and represents a potential therapeutic target. We aimed to evaluate the molecular effects of sorafenib, a multiple tyrosine kinase inhibitor, on splanchnic hemodynamics in rats with partial portal vein ligation (PPVL). METHODS: The following four groups of rats were treated orally with sorafenib (10mg/kg per day; SORA group) or placebo (PLAC group) for 7 days, beginning at the day of PPVL or sham operation (SO): (1) PPVL-SORA, (2) PPVL-PLAC, (3) SO-SORA and (4) SO-PLAC. Measurements of mean arterial pressure (MAP), portal pressure (PP), and superior mesenterial artery blood flow (SMABF) were performed. Portosystemic collateral blood flow (PSCBF) was determined by radioactive microspheres. Splanchnic protein expression of CD31, alpha-smooth muscle actin (alphaSMA), phospho-extracellular signal-regulated kinase (pERK), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNFalpha), and endothelial nitric oxide synthetase (eNOS) was assessed by Western blot. Gene expression was studied by angiogenesis-focused real-time reverse transcription polymerase chain reaction microarray. RESULTS: PP, SMABF, and PSCBF were significantly higher in PPVL rats than in SO rats. MAP and heart rate were similar in all groups. Treatment with sorafenib resulted in a significant decrease of PP (p<0.001) and SMABF (p<0.05) in PPVL-SORA rats compared to PPVL-PLAC rats. PPVL-SORA rats had markedly less PSCBF than PPVL-PLAC rats (p<0.001). Superior mesenteric artery resistance (SMAR) was significantly lower in both PPVL groups compared to both SO groups, but PPVL-SORA rats showed significantly higher SMAR than PPVL-PLAC rats (p<0.05). The increased protein expression of CD31, alphaSMA, pERK, VEGF, PDGF, TNFalpha, and eNOS in rats with PHT was markedly decreased by sorafenib treatment. Sorafenib decreased mRNA levels of TNFalpha, VEGF receptor 2, VEGF receptor 1, transforming growth factor beta, cyclooxygenase 1, and expression of various genes that are involved in pathways of cellular proliferation, fibrogenesis, tissue remodeling, inflammation, and angiogenesis. CONCLUSIONS: Treatment with sorafenib reduced PP, SMABF, and PSCBF in noncirrhotic rats with prehepatic PHT, without affecting systemic hemodynamics. Additional antiproliferative, anti-inflammatory, and antiangiogenic effects of sorafenib were identified.

Impact of high-dose interferon induction and ribavirin therapy in patients with chronic hepatitis C relapsing after or not responding to interferon monotherapy.

BACKGROUND/AIMS: Initial high-dose interferon-alpha induction therapy in combination with ribavirin improves sustained response rates in treatment-naïve patients. This prospective, randomized, controlled study tested whether non-responders or relapsers to interferon monotherapy also benefit from induction therapy. METHODS: Patients with chronic hepatitis C who had not responded to (n=75) or relapsed (n=80) after previous interferon therapy were randomized to receive three different interferon doses during the first 14 weeks of therapy (A: 10 MU IntronA/day for 2 weeks, followed by 10 MU/2 days for 12 weeks; B:5 MU/d for 14 weeks; C: 5 MU/2 days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. All patients received 1-1.2 g ribavirin/day throughout the whole study. RESULTS: The rates of viral clearance at any time on treatment were similar in all groups. Sustained response rates were also not different among the groups in interferon nonresponders (A 32%, B 29%, C 31%) and relapsers (A 64%, B 68%, C 71%), respectively, as well as in patients with different genotypes. As expected, sustained response rates were higher in patients with genotype non-1 than in those with genotype 1. CONCLUSION: High-dose induction therapy does not improve the outcome of interferon/ribavirin therapy in interferon nonresponders or relapsers.

Chemoembolization with cisplatin, lipiodol and Gelfoam and subsequent systemic chemotherapy with cisplatin and interferon in patients with hepatocellular carcinoma: a non-randomized prospective study.

Arterial chemoembolization with subsequent systemic chemotherapy was assessed prospectively. Of 94 consecutive patients with HCC, 31 patients were considered to have inoperable disease and were selected for chemoembolization. Twenty-two of the 31 patients underwent chemoembolization. In eight patients, technical problems with catheterization prevented the application of therapy, and one patient rejected further treatment. Regimen: Three monthly cycles of chemoembolization with cisplatin 20 mg/m(2) mixed with lipiodol delivered intraarterially with Gelfoam or collagen on day 1, followed by intravenous chemotherapy with cisplatin 60 mg/m(2) on day 2; interferon alpha-2c 30 microg (10 M IU) subcutaneously on days 2, 5, 9, and 12. Three percent of the patients (1/31) (CI 95% 0.08; 16.7) experienced a partial clinical response, in 53% alpha-fetoprotein levels decreased by more than 50%. On univariate analysis, performance status, Child score, Okuda stage, albumin levels, and lactate dehydrogenase were found to have an effect on survival. Postchemoembolization syndrome occurred in 68% of the patients, nausea/vomiting grades 3/4 (according to the World Health Organization WHO) in six patients, anemia grade 3 in three patients, leukopenia grade 3 in one patient and thrombocytopenia grade 3 in one patient. This treatment regimen is a very selective procedure. Because of the low response rate it is not recommended for routine clinical use.

Novel variants of the IL-10 receptor 1 affect inhibition of monocyte TNF-alpha production.

IL-10-deficient mice exhibit spontaneous enterocolitis and other symptoms akin to Crohn's disease, indicating that IL-10 might regulate normal physiology in the gut. However, clinical trials with IL-10 in Crohn's disease were disappointing, although some patients showed healing of intestinal mucosa. This study searched for genetic polymorphisms within the IL-10 pathway. We decided to screen for mutations of the IL-10R1 cDNA in healthy volunteers and Crohn's disease patients and identified two novel variants: a serine 138-to-glycine (S138G) and a glycine 330-to-arginine (G330R) substitution. The allelic frequency in a European cohort was relatively high (16% for the S138G and 33% for the G330R), and S138G was in strong linkage disequilibrium with G330R. A similar allele frequency was found in a group of Crohn's patients. In IL-10R1 G330R-expressing monocytes, the inhibitory effect of IL-10 on TNF-alpha production was diminished, indicating that this variant may be a loss-of-function allele. No such difference was observed between haplotypes 4 (G330R only) and 7 (S138G and G330R). In addition, these IL-10R1 variants had no influence on the IL-10R1 expression density. Structural analysis of the S138G variant revealed that the substitution of S138G may interfere with binding of IL-10 to IL-10R1.