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Rostock, Germany

Grienke U.,University of Innsbruck | Grienke U.,University of Vienna | Mair C.E.,University of Innsbruck | Mair C.E.,University of Vienna | And 8 more authors.
Journal of Agricultural and Food Chemistry

Blockage of the human ether-à-go-go related gene (hERG) channel can result in life-threatening ventricular tachyarrhythmia. In an in vitro screening of herbal materials for hERG blockers using an automated two-microelectrode voltage clamp assay on Xenopus oocytes, an alkaloid fraction of Nelumbo nucifera Gaertn. (lotus) leaves induced ∼50% of hERG current inhibition at 100 μg/mL. Chromatographic separation resulted in the isolation and identification of (-)-asimilobine, 1, nuciferine, 2, O-nornuciferine, 3, N-nornuciferine, 4, and liensinine, 5. In agreement with in silico predicted ligand-target interactions, 2, 3, and 4 revealed distinct in vitro hERG blockages measured in HEK293 cells with IC50 values of 2.89, 7.91, and 9.75 μM, respectively. Because lotus leaf dietary weight loss supplements are becoming increasingly popular, the identified hERG-blocking alkaloids were quantitated in five commercially available products. Results showed pronounced differences in the content of hERG-blocking alkaloids ranging up to 992 μg (2) in the daily recommended dose. © 2015 American Chemical Society. Source

Leifert A.,Institute of Inorganic Chemistry | Pan Y.,RWTH Aachen | Kinkeldey A.,RWTH Aachen | Schiefer F.,Institute of Inorganic Chemistry | And 7 more authors.
Proceedings of the National Academy of Sciences of the United States of America

Understanding the mechanism of toxicity of nanomaterials remains a challenge with respect to both mechanisms involved and product regulation. Here we show toxicity of ultrasmall gold nanoparticles (AuNPs). Depending on the ligand chemistry, 1.4-nm-diameter AuNPs failed electrophysiology-based safety testing using human embryonic kidney cell line 293 cells expressing human ether-á-go-go- Related gene (hERG), a Food and Drug Administration- established drug safety test. In patch-clamp experiments, phosphine-stabilized AuNPs irreversibly blocked hERG channels, whereas thiol-stabilized AuNPs of similar size had no effect in vitro, and neither particle blocked the channel in vivo. We conclude that safety regulations may need to be reevaluated and adapted to reflect the fact that the binding modality of surface functional groups becomes a relevant parameter for the design of nanoscale bioactive compounds. Source

Agency: Cordis | Branch: H2020 | Program: ECSEL-IA | Phase: ECSEL-02-2014 | Award Amount: 48.05M | Year: 2015

The goal of the InForMed project is to establish an integrated pilot line for medical devices. The pilot line includes micro-fabrication, assembly and even the fabrication of smart catheters. The heart of this chain is the micro-fabrication and assembly facility of Philips Innovation Services, which will be qualified for small/medium-scale production of medical devices. The pilot facility will be open to other users for pilot production and product validation. It is the aim of the pilot line: to safeguard and consolidate Europes strong position in traditional medical diagnostic equipment, to enable emerging markets - especially in smart minimally invasive instruments and point-of-care diagnostic equipment - and to stimulate the development of entirely new markets, by providing an industrial micro-fabrication and assembly facility where new materials can be processed and assembled. The pilot line will be integrated in a complete innovation value chain from technology concept to high-volume production and system qualification. Protocols will be developed to ensure an efficient technology transfer between the different links in the value chain. Six challenging demonstrators products will be realized that address societal challenges in: Hospital and Heuristic Care and Home care and well-being, and demonstrate the trend towards Smart Health solutions.

Vilums M.,Leiden University | Overman J.,Leiden University | Klaasse E.,Leiden University | Scheel O.,Cytocentrics | And 2 more authors.

Cardiotoxicity is a common side effect of a large variety of drugs that is often caused by off-target human ether-à-go-go-related gene (hERG) potassium channel blockade. In this study, we designed and synthesized a series of derivatives of the classIII antiarrhythmic agent E-4031. These compounds where evaluated in a radioligand binding assay and automated patch clamp assay to establish structure-activity relationships (SAR) for their inhibition of the hERG K + channel. Structural modifications of E-4031 were made by altering the peripheral aromatic moieties with a series of distinct substituents. Additionally, we synthesized several derivatives with a quaternary nitrogen and modified the center of the molecule by introduction of an additional nitrogen and deletion of the carbonyl oxygen. Some modifications caused a great increase in affinity for the hERG K + channel, while other seemingly minor changes led to a strongly diminished affinity. Structures with quaternary amines carrying an additional aromatic moiety were found to be highly active in radioligand binding assay. A decrease in affinity was achieved by introducing an amide functionality in the central scaffold without directly interfering with the pK a of the essential basic amine. The knowledge gained from this study could be used in early stages of drug discovery and drug development to avoid or circumvent hERG K + channel blockade, thereby reducing the risk of cardiotoxicity, related arrhythmias and sudden death. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Kratz J.M.,University of Vienna | Mair C.E.,University of Vienna | Oettl S.K.,University of Innsbruck | Saxena P.,University of Vienna | And 4 more authors.
Planta Medica

Human ether-a-go-go-related gene channel blocking is associated with QT interval prolongation and increased risk of potentially fatal arrhythmias. As natural products keep increasing in popularity, there is an urgent need for studies assessing human ether-a-go-go-related gene channel-related cardiotoxic risks. We selected 49 plant species based on the results of a pharmacophore-based virtual screening campaign, in parallel with a literature data survey concerning highly consumed herbal medicines with reported cardiac liabilities. Lead-like enhanced extracts were prepared, an initial in vitro screening was performed at 100 µg/mL by voltage clamp on Xenopus oocytes, and five human ether-a-go-go-related gene channel blocking extracts were identified. In accordance to the six virtually predicted alkaloids, the root extract of Carapichea ipecacuanha inhibited human ether-a-go-go-related gene channel currents by 32.5?%. A phytochemical workflow resulted in the isolation and identification of five out of the six virtually predicted alkaloids. All isolates blocked human ether-a-go-go-related gene channel currents to different extents. The major ipecac constituents emetine (1) and cephaeline (2) showed IC50 values of 21.4 and 5.3 µM, respectively, measured by whole-cell patch clamp in HEK293 cells. This is the first report on human ether-a-go-go-related gene channel blockers from C. ipecacuanha. Its roots and rhizomes are used to produce different pharmacopeial ipecac preparations that are mainly used as emetics for poisoning treatment. Our findings raise further questions regarding the safety and over-the-counter appropriateness of these herbal products. Copyright © 2016, Georg Thieme Verlag KG. All rights reserved. Source

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