Drug and Alcohol Rehabilitation: First in Vitro and in Vivo Results of an Anti-Human CD133-Antibody Coated Coronary Stent in the Porcine Model.

First in vitro and in vivo results of an anti-human CD133-antibody coated coronary stent in the porcine model.

Filed under: Drug and Alcohol Rehabilitation

Clin Res Cardiol. 2013 Feb 10;
Sedaghat A, Sinning JM, Paul K, Kirfel G, Nickenig G, Werner N

BACKGROUND: Drug-eluting stents successfully reduce restenosis at the cost of delayed re-endothelialization. A novel concept to enhance re-endothelialization is the use of antibody-coated stents which capture circulating progenitor cells. A CD34-positive-cell-capturing stent was recently developed with conflicting clinical results. CD133 is a glycoprotein expressed on circulating hematopoietic and putative endothelial-regenerating cells and may be superior to CD34. OBJECTIVE: The aim of our study was to develop a CD133-cell-capturing bare-metal stent and investigate feasibility, safety, and efficacy of CD133-stents in terms of re-endothelialization and neointima inhibition. METHODS AND RESULTS: Anti-human CD133-antibodies were covalently attached to bare-metal stents. In vitro, binding capacity of CD133-stents was studied, revealing a significantly higher affinity of human CD133-positive cells to CD133-stents compared with mononuclear cells (MNCs). In vivo, 15 landrace pigs received BMS and CD133-stents in either RCX or LAD (n = 30 stents). Re-endothelialization was examined on day 1 (n = 4), 3 (n = 4) and day 7 (n = 4) using scanning electron microscopy. In histology, injury and inflammatory scores, as well as diameter restenosis were evaluated after day 7 (n = 3), 14 (n = 4), and 28 (n = 2). Overall no reduction in re-endothelialization, diameter stenosis or inflammatory score was seen with CD133-stents. CONCLUSION: Stent coating with anti-human CD133-antibodies was successfully achieved with effective binding of CD133-positive cells. However, in vivo, no difference in re-endothelialization or neointima formation was evident with the use of CD133-stents compared with BMS. The low number of circulating CD133-positive cells and an increase in unspecific binding of MNCs over time may account for the observed lack of efficacy.
HubMed – drug

HepG2 cells simultaneously expressing five P450 enzymes for the screening of hepatotoxicity: identification of bioactivable drugs and the potential mechanism of toxicity involved.

Filed under: Drug and Alcohol Rehabilitation

Arch Toxicol. 2013 Feb 9;
Tolosa L, Gómez-Lechón MJ, Pérez-Cataldo G, Castell JV, Donato MT

Use of the HepG2 cell line to assess hepatotoxicity induced by bioactivable compounds is hampered by their low cytochrome P450 expression. To overcome this limitation, we have used adenoviral transfection to develop upgraded HepG2 cells (ADV-HepG2) expressing the major P450 enzymes involved in drug metabolism (CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4) at levels comparable to those of human hepatocytes. The potential utility of this new cell model for the in vitro screening of bioactivable drugs was assessed using a high-content screening assay that we recently developed to simultaneously measure multiple parameters indicative of cell injury. To this end, ADV-HepG2 and HepG2 cells, cultured in 96-well plates, were exposed for 24 h to a wide range of concentrations of 12 bioactivable and 3 non-bioactivable compounds. The cell viability and parameters associated with nuclear morphology, mitochondrial function, intracellular calcium concentration, and oxidative stress indicative of prelethal cytotoxicity and representative of different mechanisms of toxicity were evaluated. Bioactivable compounds showed lower IC(50) values in ADV-HepG2 cells than in HepG2 cells. Moreover, significant differences in the other parameters analyzed were observed between both cell models, while similar effects were observed for non-bioactivable compounds (negative controls). The changes in cell parameters detected in our assay for a given compound are in good agreement with the previously reported toxicity mechanism. Overall, our results indicate that this assay may be a suitable new in vitro approach for early screening of compounds to identify bioactivable hepatotoxins and the mechanism(s) involved in their toxicity.
HubMed – drug

Advances in the evaluation and management of children with portal hypertension.

Filed under: Drug and Alcohol Rehabilitation

Semin Liver Dis. 2012 Nov; 32(4): 288-97
Ling SC

Portal hypertension commonly accompanies advanced liver disease and gives rise to severe and life-threatening complications, including hemorrhage from esophageal varices. Diagnosis of portal hypertension in children currently relies on finding evidence of splenomegaly and the formation of portosystemic collaterals. There is a paucity of pediatric data to support the use of primary prophylaxis against variceal hemorrhage. A combination of vasoactive drug and endoscopic therapy should be used to manage variceal bleeding. Prevention of rebleeding is best achieved by endoscopic variceal ligation. Rex bypass surgery is the optimal therapy for prevention of further bleeding from portal vein thrombosis. Options to manage recurrent bleeding while on preventative therapy include surgical portosystemic shunt, Rex bypass, transjugular intrahepatic portosystemic shunt (TIPS), and liver transplantation. Management of gastric varices may require injection of cyanoacrylate glue or TIPS.
HubMed – drug

ESR statement on the stepwise development of imaging biomarkers.

Filed under: Drug and Alcohol Rehabilitation

Insights Imaging. 2013 Feb 9;

Development of imaging biomarkers is a structured process in which new biomarkers are discovered, verified, validated and qualified against biological processes and clinical end-points. The validation process not only concerns the determination of the sensitivity and specificity but also the measurement of reproducibility. Reproducibility assessments and standardisation of the acquisition and data analysis methods are crucial when imaging biomarkers are used in multicentre trials for assessing response to treatment. Quality control in multicentre trials can be performed with the use of imaging phantoms. The cost-effectiveness of imaging biomarkers also needs to be determined. A lot of imaging biomarkers are being developed, but there are still unmet needs-for example, in the detection of tumour invasiveness. Main Messages • Using imaging biomarkers to streamline drug discovery and disease progression is a huge advancement in healthcare. • The qualification and technical validation of imaging biomarkers pose unique challenges in that the accuracy, methods, standardisations and reproducibility are strictly monitored. • The clinical value of new biomarkers is of the highest priority in terms of patient management, assessing risk factors and disease prognosis.
HubMed – drug

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