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- Toepper, Christoph, et al.
(författare)
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Variable Linezolid Exposure in Intensive Care Unit PatientsPossible Role of Drug-Drug Interactions
- 2016
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:5, s. 573-578
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Tidskriftsartikel (refereegranskat)abstract
- Background:Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population.Methods:Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37 degrees C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (C-min) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, C-min 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted.Results:Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated C-min 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and C-min were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or C-min was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC approximate to 60 mg*h/L, C-min <0.4 mg/L). The median unbound fraction in all 20 patients was 90.9%.Conclusions:Drug exposure after standard doses of linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.
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| 2. |
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| 3. |
- Rajeswara, Pannem Rao, et al.
(författare)
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CYLD controls c-MYC expression through the JNK-dependent signaling pathway in hepatocellular carcinoma.
- 2014
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 35:2, s. 461-468
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Tidskriftsartikel (refereegranskat)abstract
- Post-translational modification of different proteins via direct ubiquitin attachment is vital for mediating various cellular processes. CYLD, a deubiquitination enzyme, is able to cleave the polyubiquitin chains from the substrate, and to regulate different signaling pathways. Loss, or reduced expression, of CYLD is observed in different types of human cancer, such as hepatocellular carcinoma (HCC). However, the molecular mechanism by which CYLD affects cancerogenesis has to date not been unveiled. The aim of the present study was to examine how CYLD regulates cellular functions and signaling pathways during hepatocancerogenesis. We found that mice lacking CYLD were highly susceptible to chemically induced liver cancer. The mechanism behind proved to be an elevated proliferation rate of hepatocytes, owing to sustained JNK1-mediated signaling via ubiquitination of TRAF2 and expression of c-MYC. Overexpression of wild type CYLD in an HCC cell lines prevented cell proliferation, without affecting apoptosis, adhesion, and migration. A combined immunohistochemical and tissue microarray analysis of 81 human HCC tissues revealed that CYLD expression is negatively correlated with expression of proliferation marker Ki-67 and c-MYC. To conclude, we found that downregulation of CYLD induces tumor cell proliferation, consequently contributing to the aggressive growth of HCC. Our findings suggest that CYLD holds potential to serve as a marker for HCC progression, and its link to c-MYC via JNK1 may provide the foundation for new therapeutic strategies for HCC-patients.
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| 4. |
- Rajeswara, Pannem Rao, et al.
(författare)
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CYLD regulates HGF expression in hepatic stellate cells via interaction with HDAC7.
- 2014
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 60:3, s. 1066-1081
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Tidskriftsartikel (refereegranskat)abstract
- Hepatic fibrosis is considered as a physiological wound-healing response to liver injury. The process involves several factors, such as the hepatocyte growth factor (HGF), which restrain hepatic injury and facilitate the reversibility of the fibrotic reaction in response to an acute insult. Chronic liver injury and sustained inflammation cause progressive fibrosis and, ultimately, organ dysfunction. The mechanisms tipping the balance from restoration to progressive liver tissue scarring are not well understood. In the present study, we identify a mechanism in which the tumor suppressor gene, cylindromatosis (CYLD), confers protection from hepatocellular injury and fibrosis. Mice lacking CYLD (CYLD(-/-) ) were highly susceptible to hepatocellular damage, inflammation and fibrosis and revealed significantly lower hepatic HGF-levels compared with wild-type animals. Exogenous application of HGF rescued the liver injury phenotype of CYLD(-/-) mice. In the absence of CYLD, gene transcription of HGF in hepatic stellate cells was repressed through the binding of histone deacetylase 7 (HDAC7) to the promoter of HGF. In wildtype cells, CYLD removed HDAC7 from HGF promoter and induced HGF expression. Noteworthy, this interaction occurred independent of deubiquitinating activity of CYLD. Conclusions: Our findings highlight a novel link between CYLD and HDAC7, offering mechanistic insight into the contribution of these proteins to the progression of liver disease. Thus, through the regulation of the HGF level, CYLD ameliorates hepatocellular damage and liver fibrogenesis. (Hepatology 2014).
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