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Alimentary Pharmacology & Therapeutics 11/2012; 36(10):994-5. · 3.77 Impact Factor
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ABSTRACT: Increased intrahepatic vascular resistance and hyperperfusion in the splanchnic circulation are the principal mechanisms leading to portal hypertension in cirrhosis. Several preclinical studies have demonstrated a beneficial effect of the multikinase inhibitor sorafenib on the portal hypertensive syndrome.
To investigate the effect of sorafenib on hepatic venous pressure gradient (HVPG), systemic hemodynamics and intrahepatic mRNA expression of proangiogenic, profibrogenic and proinflammatory genes.
Patients with liver fibrosis/cirrhosis and hepatocellular carcinoma were treated with sorafenib 400 mg b.d. HVPG measurement and transjugular liver biopsy were performed at baseline and at week 2. Changes in HVPG and intrahepatic mRNA expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), RhoA, tumour necrosis factor-alpha (TNF-α) and placental growth factor (PlGF) were evaluated.
Thirteen patients (m/f = 12/1; Child-Pugh class A/B = 10/3) were included. The most common aetiology of liver disease was alcohol consumption (n = 7). Eleven patients had an elevated portal pressure, including eight patients with clinically significant portal hypertension. A significant decrease of HVPG (≥ 20% from baseline) was observed in four subjects. In HVPG responders, we observed mRNA downregulation of VEGF, PDGF, PlGF, RhoA kinase and TNF-α, while no substantial mRNA decrease was found in nonresponders in any of the five genes. In two of the four HVPG responders we observed a dramatic (43-85%) mRNA decrease of all five investigated genes.
Larger controlled clinical trials are needed to demonstrate any potential beneficial effect of sorafenib on portal hypertension in patients with cirrhosis.
Alimentary Pharmacology & Therapeutics 01/2012; 35(1):83-91. · 3.77 Impact Factor
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Alimentary Pharmacology & Therapeutics 12/2011; 34(11-12):1348-1349. · 3.77 Impact Factor
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M Pinter, W Sieghart,
F Hucke,
I Graziadei,
W Vogel,
A Maieron,
R Königsberg,
A Weissmann,
G Kornek,
J Matejka,
R Stauber,
R Buder,
B Grünberger,
M Schöniger-Hekele,
C Müller,
M Peck-Radosavljevic
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ABSTRACT: Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC).
To identify prognostic factors in sorafenib-treated HCC patients and to evaluate outcomes with respect to liver function.
In this retrospective study, 148 HCC patients received sorafenib 400 mg b.d. across 11 Austrian institutions. Seventy-eight HCC patients who received best supportive care (BSC) in the pre-sorafenib era served as a control.
In sorafenib-treated patients, low baseline α-fetoprotein, low Child-Pugh (CP) score, compensated cirrhosis, and low baseline aspartate aminotransferase (AST) were associated with significantly longer overall survival (OS) on univariate analysis. CP score and baseline AST remained independent prognostic factors on multivariate analysis. In patients with Barcelona Clinic liver Cancer (BCLC) stage B or C HCC (sorafenib: n = 139; BSC: n = 39), CP-A patients had a median OS of 11.3 (sorafenib [n = 76]) vs. 6.4 (BSC [n = 17]) months (P = 0.010), and CP-B patients had a median OS of 5.5 (sorafenib [n = 55]) vs. 1.9 (BSC [n = 22]) months (P = 0.021). In the sorafenib group, median OS according to baseline AST was 11.8 (<100 U/L [n = 58]) vs. 3.9 (≥100 U/L [n = 15]) months for CP-A patients (P = 0.127), and 6.5 (<100 U/L [n = 33]) vs. 2.1 (≥100 U/L [n = 21]) months for CP-B patients (P = 0.011). There was no survival difference between sorafenib and BSC in patients with BCLC stage D HCC (1.5 vs. 1.4 months; P = 0.116).
Sorafenib was associated with improved survival in both CP-A and CP-B patients. In CP-B patients, baseline AST may be helpful in determining which patients are most likely to benefit from sorafenib.
Alimentary Pharmacology & Therapeutics 08/2011; 34(8):949-59. · 3.77 Impact Factor
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M Pinter, W Sieghart,
F Hucke,
I Graziadei,
W Vogel,
A Maieron,
R Königsberg,
A Weissmann,
G Kornek,
J Matejka,
R Stauber,
R Buder,
B Grünberger,
M Schöniger-Hekele,
C Müller,
M Peck-Radosavljevic
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ABSTRACT: Background Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC). Aim To identify prognostic factors in sorafenib-treated HCC patients and to evaluate outcomes with respect to liver function. Methods In this retrospective study, 148 HCC patients received sorafenib 400 mg b.d. across 11 Austrian institutions. Seventy-eight HCC patients who received best supportive care (BSC) in the pre-sorafenib era served as a control. Results In sorafenib-treated patients, low baseline α-fetoprotein, low Child-Pugh (CP) score, compensated cirrhosis, and low baseline aspartate aminotransferase (AST) were associated with significantly longer overall survival (OS) on univariate analysis. CP score and baseline AST remained independent prognostic factors on multivariate analysis. In patients with Barcelona Clinic liver Cancer (BCLC) stage B or C HCC (sorafenib: n = 139; BSC: n = 39), CP-A patients had a median OS of 11.3 (sorafenib [n = 76]) vs. 6.4 (BSC [n = 17]) months (P = 0.010), and CP-B patients had a median OS of 5.5 (sorafenib [n = 55]) vs. 1.9 (BSC [n = 22]) months (P = 0.021). In the sorafenib group, median OS according to baseline AST was 11.8 (<100 U/L [n = 58]) vs. 3.9 (≥100 U/L [n = 15]) months for CP-A patients (P = 0.127), and 6.5 (<100 U/L [n = 33]) vs. 2.1 (≥100 U/L [n = 21]) months for CP-B patients (P = 0.011). There was no survival difference between sorafenib and BSC in patients with BCLC stage D HCC (1.5 vs. 1.4 months; P = 0.116). Conclusions Sorafenib was associated with improved survival in both CP-A and CP-B patients. In CP-B patients, baseline AST may be helpful in determining which patients are most likely to benefit from sorafenib
Alimentary pharmacology & therapeutics. 01/2011;
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ABSTRACT: Patients co-infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV-HCV co-infection. Data of 74 interferon-naïve HIV-HCV co-infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV-HCV patients had rapid progression of fibrosis [0.201 +/- 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 +/- 13 years), high HCV viral loads (4.83 x 10(6) IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC-2 = 0.177 FU/y; CDC-3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC-1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression (R = -0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC-3 patients. Patients treated with highly active anti-retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV-HCV co-infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/microL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV-HCV co-infection and largely preserved CD4+ cell counts.
Journal of Viral Hepatitis 09/2009; 17(6):400-9. · 4.09 Impact Factor
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ABSTRACT: Circulating endothelial progenitor cells have a negative prognostic impact in patients with hepatocellular carcinoma, but may play a different role in portal hypertension according to preclinical data. Here, we address this issue for the first time in cirrhotic patients+/-hepatocellular carcinoma.
Portal hypertension in cirrhotic and hepatocellular carcinoma patients was determined by hepatic venous pressure gradient. Blood cells staining positive for CD34/KDR/AC133 using flow cytometry were characterised as endothelial progenitor cells. Vascular endothelial growth factor levels were determined by ELISA.
Endothelial progenitor cells levels in peripheral blood were elevated in cirrhotic (n=23) (mean: 0.12+/-0.06% S.D.) and in hepatocellular carcinoma patients (n=24) (0.14+/-0.09% S.D.) relative to healthy controls (H-group, n=15) (0.06+/-0.04% S.D.) (P=0.056 and P=0.02, respectively). There were higher vascular endothelial growth factor levels in hepatocellular carcinoma patients compared to cirrhotics (P=0.047) and HC (P=0.037). Notably, hepatic venous pressure gradient was positively correlated with vascular endothelial growth factor (r=0.5, P=0.046) but negatively with endothelial progenitor cells levels (r=-0.51, P=0.02) in cirrhotics, but not hepatocellular carcinoma patients.
Circulating endothelial progenitor cells are increased in patients with portal hypertension+/-hepatocellular carcinoma. The negative correlation of endothelial progenitor cells with hepatic venous pressure gradient suggests a protective role of endothelial progenitor cells in liver cirrhosis whilst vascular endothelial growth factor is associated with high hepatic venous pressure gradient. In contrast, increased endothelial progenitor cells in hepatocellular carcinoma rather reflect tumour specific endothelial progenitor cells mobilisation.
Digestive and Liver Disease 07/2009; 41(12):902-6. · 3.05 Impact Factor
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ABSTRACT: Gamma-aminobutyric acid (GABA) is the most important inhibitory transmitter in the central nervous system. Most of the actions of GABA are mediated by GABAA receptors. These are choride ion channels that can be opened by GABA and can be modulated by a variety of pharmacologically and clinically important drugs. GABAA receptors are composed of five subunits that can belong to different subunit classes. So far, 19 different subunits have been identified in mammalian brain, exhibiting a distinct but overlapping regional and cellular distribution and giving rise to an enormous heterogeneity of GABAA receptors. Depending on the subunit composition these receptors exhibit distinct electrophysiological and pharmacological properties. Drugs in clinical use are only weakly receptor subtype selective, explaining their similar and broad pharmacological effects. Investigations of mice with a point mutation in a GABAA receptor subunit that eliminates the actions of drugs on certain receptors, only, have indicated that different receptor subtypes mediate distinct actions of GABAergic drugs. This conclusion was supported by experiments with newly developed compounds exhibiting a significantly increased receptor subtype selectivity, suggesting a tremendous clinical potential of drugs with high selectivity for certain receptor subtypes. In addition, the recent availability of structural information on GABAA receptors from homology modeling studies will stimulate experiments leading to the identification of the binding sites of the various GABAA receptor ligands. Accumulating structural information on receptor subtypes will finally lead to more precise pharmacophore models that will provide the basis for a more rational drug design.
Current Medicinal Chemistry - Central Nervous System Agents 08/2005; 5(3):217-242.
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ABSTRACT: GABAA receptors are the major inhibitory transmitter receptors in the central nervous system. The majority of these receptors is composed of two α, two β and one γ subunit that assemble around an aqueous pore and form an intrinsic chloride ion channel. Using full-length or truncated chimeric subunits it was demonstrated that homologous sequences from different subunit classes, α1(54–68), β3(52–66), and γ2(67–81), are important for assembly of GABAA receptors composed of α1, β3, and γ2 subunits. In addition, evidence was provided that these sequences all are located in topologically homologous regions of the different subunits. Finally, it was demonstrated that the sequences investigated cause a selective assembly with certain subunits only and thus influence subunit arrangement within GABAA receptors.
Neuropharmacology.
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ABSTRACT: Kainic acid-induced seizures in rats represent an established animal model for human temporal lobe epilepsy. The neuropathological sequelae include acute status epilepticus followed by neurodegeneration in the CA1 and CA3 sector of the Ammon's horn and of interneurons in the hilus of the dentate gyrus. After about three weeks spontaneous recurrent seizures become manifest. We investigated changes in messenger RNA expression of 13 GABAA receptor subunits in the hippocampus of rats in the initial phase (6 h, 12 h and 24 h) after acute kainic acid-induced status epilepticus and seizure-related neuronal cell damage during and after acquisition of spontaneous recurrent seizures (seven and 30 days after kainic acid injection). In the granule cell layer, initial (after 6 to 12 h) decreases in (α2, α3, α5, β1, β3, γ2 and δ messenger RNAs (by about 25 to 50%) were accompanied by increases (by about 50%) in α1, α4, and β2 messages. At later intervals (after seven to 30 days), expression of α2, α4, β3 and γ2 messenger RNAs recovered to control values, with α5 and δ messenger RNA still being reduced (by 15 and 40% below control levels, respectively). Concentrations of the transcripts encoding for α1, α3, β1, β2, became markedly enhanced (between 20 and 50% of controls). Within the pyramidal cell layers CA1 and CA3, decreases in α2, α4, α5, β1–3 and γ2 messenger RNAs were detected after seven to 30 days, reflecting pronounced neurodegeneration in these areas. The α1 transcript was decreased in CA3 after 24 h and increased to control levels indicating compensatory up-regulation of this message after seven days. Messenger RNAs encoding for α3-, γ1-, and γ3-subunits were detected at rather low levels, α6 was not present in the hippocampus.Our data suggest a fast but transient change in the expression of messenger RNAs encoding for different subunits of the GABAA receptor in the granule cell layer of the dentate gyrus. This is followed by a lasting augmentation of messenger RNAs encoding different GABAA receptor subunits in the same cell layer indicating long-lasting GABAergic inhibition. Changes within the pyramidal cell layer are mostly determined by concomitant neurodegenerative processes.
Neuroscience.
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ABSTRACT: The GABAA receptor is a ligand-operated chloride channel. It has a pentameric structure. In mammalian brain different subunits are recruited from four gene subfamilies. Using immunocytochemistry, we investigated the distribution of the 13 GABAA receptor subunits in the hippocampus of the rat. GABAA receptor subunits were heterogeneously distributed within different hippocampal subfields. High concentrations of α1-, α2-, α4-, β3-, γ2- and δ-immunoreactivities were observed within the molecular layer of the dentate gyrus, representing the dendritic area of the granule cells. In the hippocampus proper, the predominant GABAA receptor subunits were α1, α2, α5, β3 and γ2 that were located throughout the strata radiatum and oriens of CA1 to CA3. Immunocytochemical staining was there less prominent for α4-, β1-, β2-, γ3- and δ- subunits. In the hippocampus proper, the β1 subunit was preferentially located in CA2. The α4- and δ-subunits were somewhat more abundant in CA1 than in CA3. Numerous local circuit neurons in the hippocampus proper and the hilus of the dentate gyrus contained α1-, β2-, γ2- and/or δ-subunits. α3 and γ1 were present only in minute amounts and no α6-IR was detected in the hippocampal formation.The distribution of the GABAA receptor subunits indicates the existence of heterogenously constituted GABAA receptor complexes within various hippocampal subfields, which may exert different physiological or pharmacological properties upon stimulation by GABA or its agonists.
Neuroscience.
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ABSTRACT: Prolonged flurazepam exposure regulates the expression of selected (α1, β2, β3) GABAA receptor subunit messenger RNAs in specific regions of the hippocampus and cortex with a time-course consistent with benzodiazepine tolerance both in vivo and in vitro. In this report, the immunostaining density of six specific GABAA receptor subunit (α1, α2, β1–3 and γ2) antibodies was measured in the hippocampus and cortex, among other brain areas, in slide-mounted brain sections from flurazepam-treated and control rats using quantitative computer-assisted image analysis techniques. In parallel with the localized reduction in α1 and β3 subunit messenger RNA expression detected in a previous study, relative α1 and β3 subunit antibody immunostaining density was significantly decreased in flurazepam-treated rat hippocampal CA1, CA3 and dentate dendritic regions, and in specific cortical layers. Quantitative western blot analysis showed that β3 subunit protein levels in crude homogenates of the hippocampal dentate region from flurazepam-treated rats, an area which showed fairly uniform decreases in β3 subunit immunostaining (16–21%), were reduced to a similar degree (18%). The latter findings provide independent support that relative immunostaining density may provide an accurate estimate of protein levels. Consistent with the absence of the regulation of their respective messenger RNAs immediately after ending flurazepam administration, no changes in the density of α2, β1 or β2 subunit antibody immunostaining were found in any brain region. γ2 subunit antibody staining was changed only in the dentate molecular layer.The selective changes in GABAA receptor subunit antibody immunostaining density in the hippocampus suggested that a change in the composition of GABAA receptors involving specific subunits (α1 and β3) may be one mechanism underlying benzodiazepine anticonvulsant tolerance.
Neuroscience.
