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Untersuchung von Lungentoxizität in vitro mittels verschiedener Alternativmethoden und einer auf dem Cultex®-Modul basierenden In-Vitro-Aerosol-Testapparatur

Untersuchung von Lungentoxizität in vitro mittels verschiedener Alternativmethoden und einer auf dem Cultex®-Modul basierenden In-Vitro-Aerosol-Testapparatur

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Prüfsumme: MD5:91ea9118645fb8dc528bef6b91ca1917

MATT, Florian, 2008. Untersuchung von Lungentoxizität in vitro mittels verschiedener Alternativmethoden und einer auf dem Cultex®-Modul basierenden In-Vitro-Aerosol-Testapparatur [Master thesis]

@mastersthesis{Matt2008Unter-8390, title={Untersuchung von Lungentoxizität in vitro mittels verschiedener Alternativmethoden und einer auf dem Cultex®-Modul basierenden In-Vitro-Aerosol-Testapparatur}, year={2008}, author={Matt, Florian} }

Untersuchung von Lungentoxizität in vitro mittels verschiedener Alternativmethoden und einer auf dem Cultex®-Modul basierenden In-Vitro-Aerosol-Testapparatur The aim of this work was to establish and evaluate various in vitro methods to examine lung toxicity. The methods differed in the used cell type, the chosen culture conditions, the kind of compound exposure and the measured endpoint. The methods were employed to quantify the toxicity of the two NK1 receptor antagonists BIIF 1149 and BIIM 1310, which have been intended for the indication COPD. However, the development of the compounds was stopped due to safety issues. In an in vivo toxicity study the two compounds showed a different toxicity profile. In contrast to the administration of BIIF 1149, the administration of BIIM 1310 led to local irritative effects in the lung. In addition, the toxicity of terbutaline, a beta2-adrenergic receptor agonist, which is actually used for the pulmonary pharmacotherapy of COPD and Asthma, was assessed.<br />Under submerged culture conditions the compounds were dissolved in the culture medium. The human epithelial lung cell line A549 was used to investigate the cytotoxicity of the compounds via MTT, XTT, WST-1, SRB, Alamar Blue, ATP, enzyme leakage and multiparameter assay. In addition, the human epithelial lung cell line 16HBE14o- was used to assess the effect of the compounds on the TEER of 16HBE14o- monolayers.<br />Amongst other things, the methods differed in terms of sensitivity, variability, linearity, labour costs, financial expense and automatability. Unlike terbutaline, the two NK1 receptor antagonists showed a dose-dependent toxicity in all assays. On the basis of the IC50 values, all assays led to the same toxicity ranking, which was BIIF 1149 smaller than BIIM 1310 much smaller than terbutaline. Already established in vitro toxicity assays with primary hepataocytes and U-937 cells respectively, led to the same ranking and comparable IC50 values. Therefore the toxicity of the two NK1 receptor antagonists can be classified as basal toxicity. The in vivo difference in lung toxicity for the two compounds couldn t be reproduced with the in vitro methods which used submerged culture conditions.<br />The direct exposure via IVAT made it possible to examine the aerosols of the compounds appropriately. The direct exposure of air-liquid cultured A549 cells also showed a dose-dependency of toxic effects of the two NK1 receptor antagonists. However, in contrast to the methods with submerged culture conditions, the direct exposure led to an inverse toxicity ranking of the two NK1 receptor antagonists. This ranking better depicts the observed in vivo lung toxicity of the compounds. However, it s not clear, whether the inverse toxicity ranking is actually due to the better representation of the in vivo situation via the direct exposure or if it s due to a different particle size distribution of the aerosols at the exposure moment and therefore due to a different deposition efficiency of the aerosols. Because of that, the input conditions of the direct exposure method would have to be optimized, so that the actual dose of an aerosol is known, which allows one to make a reasonable toxicity ranking. application/pdf Matt, Florian deposit-license 2011-03-24T17:43:14Z Examination of lung toxicity in vitro via various alternative methods and a Cultex®-module based In-Vitro-Aerosol-Device 2008 deu Matt, Florian 2011-03-24T17:43:14Z

Dateiabrufe seit 01.10.2014 (Informationen über die Zugriffsstatistik)

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