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Fluoxetine disposition in patients suffering from chronic hepatitis C treated with interferon alpha

Background and Objectives: Combination therapy with interferon-alpha and ribavirin is considered the treatment of choice for chronic hepatitis C. However, interferon-alpha may induce severe depression It has been suggested that interferon-alpha is able to modify cytochrome P450 (CYP) 1A2 and 2D6 activity. We therefore decided to study the effects of the interferon-alpha-2b pegylated derivative on fluoxetine disposition in patients receiving combination chemotherapy for chronic hepatitis C. Methods: After approval by the institutional ethics committee, 20 adult patients with chronic hepatitis C, but with no history of other liver diseases, were prospectively admitted to the study, which included phenotyping by means of a dextromethorphan test and evaluation of fluoxetine and norfluoxetine pharmacokinetic parameters (the area under the serum concentration-time curve, maximum serum concentration, time to reach the maximum serum concentration and terminal elimination half-life) before and after 2 months of continuous peginterferon-alpha-2b therapy. Results: The only statistically Significant difference we observed was a significant reduction in the terminal elimination half-life of fluoxetine (from 4730 to 33.23 hours; p=0.014) after peginterferon-alpha-2b treatment. Conclusion: These data suggest that interferon-alpha may induce, rather than inhibit, the biotransformation of fluoxetine

Effects of antihypertensive drugs on alcohol-induced functional responses of cultured human endothelial cells.

Alcohol-induced endothelial changes might contribute to an increase in blood pressure in regular alcohol consumers. Some antihypertensive drugs affect oxidative stress and endothelial function and might counteract the effects of alcohol at the cellular level. The aim of this study was to investigate in vitro the effects of three different types of anti hypertensive agents on alcohol-induced endothelial responses and oxidative stress. Cultured human endothelial cells were exposed to increasing concentrations (1, 10, 60 mu mol/L) of zofenoprilat, carvedilol, and lacidipine in the absence and in the presence of ethanol (140 mmol/L). Concentrations of endothelin (ET) and nitric oxide (NO) were measured in the culture media as markers of endothelial function, and malondialdehyde (MDA) and intracellular glutathione (GSHi) were measured as markers of oxidative stress. Exposure to alcohol increased the levels of ET, NO, and MDA, and decreased GSHi. Carvedilol and zofenoprilat were more effective than lacidipine in counteracting the effects of alcohol on ET production. Alcohol-induced NO production was enhanced by carvedilol, whereas zofenoprilat and lacidipine did not have a significant effect. The alcohol-induced increase in MDA concentrations was blunted by all three drugs, but only carvedilol restored a normal response. All three drugs increased GSHi levels, with the effect being greater for carvedilol and lacidipine than zofenoprilat. Carvedilol is more effective than zofenoprilat and lacidipine in counteracting alcohol-induced endothelial responses in vitro and in decreasing oxidative stress. These effects might be particularly beneficial in patients with alcohol-related hypertension

Effects of Monacolin K in Nondiabetic Patients with NAFLD: A Pilot Study

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver condition with significant risk of progression to steatohepatitis and cirrhosis. Therapeutic strategies in NAFLD include lifestyle changes mainly related to dietary interventions and use of drugs or nutritional components that could improve plasma lipid profiles and insulin sensitivity and decrease the local inflammatory response. In this study, we tested the effects of monacolin K, an inhibitor of HMCoA reductase. In a prospective, uncontrolled, open study, we treated 24 patients with NAFLD and mild hypercholesterolemia with 10 mg/day of monacolin K. At baseline and after 26 weeks, we measured in plasma liver tests, lipids, malondialdehyde, and oxidized glutathione, and assessed biochemical steatosis scores, liver elastography, and body composition with bioimpedance analysis. Monacolin K significantly reduced plasma alanine aminotransferase, cholesterol, triglycerides and the homeostatic model assessment (HOMA) index that indicated improved insulin sensitivity. No significant changes were found in body fat mass and visceral fat, nor in liver elastography, while the fatty liver index (FLI) was significantly decreased. Plasma levels of both malondialdehyde and oxidized glutathione were markedly reduced by monacolin K treatment, suggesting a reduction in oxidative stress and lipid peroxidation. In summary, this pilot study suggests possible benefits of monacolin K use in NAFLD patients that could be linked to a reduction in oxidative stress. This hypothesis should be further investigated in future studies

Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance

Context: The recently discovered hormone resistin is linked to the development of insulin resistance, but direct evidence of resistin levels in humans with nonalcoholic fatty liver disease (NAFLD) is lacking. Methods: We conducted this study to assess the relationship between serum resistin and NAFLD. We measured serum resistin and biochemical, hormonal, and histological correlates in 28 NAFLD patients, 33 controls, and 30 obese patients [body mass index (BMI), >30 kg/m2] without NAFLD. Results: Resistin and adiponectin expression were measured in sc adipose tissue by quantitative RT-PCR. Resistin was higher in NAFLD patients compared with controls (5.87 \ub1 0.49 vs. 4.30 \ub1 0.20 ng/ml; P = 0.002) and obese patients (4.37 \ub1 0.27 ng/ml; P = 0.002). Increased resistin mRNA was also found in the adipose tissue of NAFLD patients compared with controls and obese subjects. Conclusions: Both NAFLD and obese patients had lower adiponectin levels, whereas leptin was increased only in the obese group. No correlation was found between resistin and high-sensitivity C-reactive protein, BMI, homeostasis model assessment, insulin, glucose, transaminases, and lipid values. A positive correlation was found between resistin and histological inflammatory score. These data report increased resistin in NAFLD patients that is related to the histological severity of the disease, but do not support a link between resistin and insulin resistance or BMI in these patients. Copyrigh

RELATIONSHIPS BETWEEN NAFLD BIOCHEMICAL SCORES AND LEFT VENTRICULAR GEOMETRIC PATTERN IN NAÏVE ESSENTIAL HYPERTENSIVE PATIENTS

OBJECTIVE: The not alcoholic fatty liver disease (NAFLD) is associated with an increased cardiovascular mortality and morbidity. An hypothesis for this association could be the left ventricular (LV) geometric alteration sometime found in hypertension that is a known prognostic factor for cardiovascular events in hypertension. We searched for a relationship between biochemical scores of NAFLD and left ventricular (LV) hypertrophy (LVH) or LV geometric patterns changes in a large group of never treated essential hypertensive (EH) patients. DESIGN AND METHOD: In 434 naïve (49 ± 14 years, 234 males) we evaluated BMI, waist circumference, liver steatosis at abdominal echography, the biochemical scores of liver steatosis: Liver Fat Score (LFS), Fatty Liver Index (FLI), Hepatic Steatosis Index (NAÏVE), and the fibrosis scores: NAFLD Fibrosis Score (NFS), APRI, FIB-4, parameters of glucose and insulin homeostasis, liver blood tests, lipids, platelets count, glomerular filtration rate (GFR), reactive C protein. LV mass and relative wall thickness was calculated with echocardiography. Patients were classified in 4 groups of LV geometry: 1 = LV normal geometry, 2 = LV concentric remodeling, 3 = concentric LVH, 4 = eccentric LVH. RESULTS: A LVH was present in 17.3% of patients, and these patients had higher LFS (P < 0.001), FLI (P = 0.008), NAÏVE (P = 0.004) and NFS (P = 0.011) scores than patients without LVH. LVH was independently associated with the FLI score but not with fibrosis scores. The steatosis scores (LFS, NAÏVE, FLI) linearly increased across the four LV geometric patterns (P = 0.007, P = 0.001, P = 0.003, respectively). The fibrosis score NFS was significantly higher in subjects with concentric LVH (P = 0.041). The LFS was independently associated with BMI, GAUC, G120, and triglycerides levels. The NFS was independently associated with waist circumference, GFR and weakly with fasting glucose level. Ultrasound steatosis was not different among the four LV geometric patterns. CONCLUSIONS: In naïve EH patients the biochemical steatosis scores show a relationship with LVH and LV geometric changes, while fibrosis is associated with concentric LVH. An accurate investigation to reveal a NAFLD should be done in EH patients with altered LV geometry and to better understanding of mechanisms linking the two conditions