Systemische Anwendung von Ketoconazol (Nizoral®Tabletten) auf dem Prüfstand

Derzeit erfolgt in der EU eine Überprüfung des Nutzen-Risiko-Verhältnisses des Azol-Antimykotikums Ketoconazol in der systemischen Anwendung. Hintergrund sind häufigere und schwerer verlaufende Leberschäden einschließlich Leberversagen im Vergleich zu anderen Antimykotika (zum Beispiel Itraconazol, Terbinafin). Die topische Anwendung von Ketoconazol zum Beispiel in Cremes ist hiervon nicht betroffen. Gerade vor dem Hintergrund der aktuellen Bewertung sollten unbedingt die Vorgaben der Fachinformation hinsichtlich Anwendungsgebieten, Gegenanzeigen und Warnhinweisen beachtet werden. Hierzu zählen insbesondere die Überwachung der Leberfunktion vor und während der Therapie sowie das sofortige Beenden der Behandlung bei Symptomen einer Leberschädigung

CD66b Overexpression and Loss of C5a Receptors as Surface Markers for Staphylococcus aureus-Induced Neutrophil Dysfunction.

Neutrophil granulocytes constitute the main component of innate immunity in the clearance of bacterial infections. However, during systemic inflammation, immunoparalysis may occur resulting in neutrophil dysfunction. This study presents a new in vitro model for analyzing the dysfunction of human peripheral blood neutrophils resulting from the interaction with Staphylococcus aureus components in whole blood. After induction of a massive complement activation by S. aureus supernatant, the neutrophils exhibit a reduced phagocytic capacity resulting in a dramatic reduction of the antibacterial activity similar to that of neutrophils isolated from septic patients. The number of phagocytozing neutrophils is drastically reduced as well as the phagocytic capacity designated by a significantly lower number of ingested microbes. This dysfunction correlates with the loss of complement component 5a receptor 1 from the neutrophil cell surface and can be further characterized by a C5a-induced CD66b overexpression. The presented in vitro model offers a new platform for preclinical testing of immunosuppressive drugs and delivers new information for the understanding of neutrophil dysfunctions under the conditions described

GIS-based scenario calculations for a nationwide German hydrogen pipeline infrastructure

This study assumes a high penetration of hydrogen-fuelled vehicles for Germany in 2050 and investigates the structure of a potential pipeline network for hydrogen transmission and distribution under different scenarios for H2 production and demand. All data are georeferenced for their computation and displayed within a Geographical Information System (GIS) environment.Statistical data describing the current vehicle distribution by type and district are computed to evaluate the geographical distribution of hydrogen demand that can be expected. Assumptions on market penetration for hydrogen-fuelled vehicles are also varied. We identified the majority of the approximately 14,000 existing refuelling stations for conventional fuels and expect hydrogen to be delivered at most of them, selected according to their localisation (along or near main roads, within urban areas, etc.). They form the sinks of the modelled distribution network.On the hydrogen production side, we envisage highly differentiated scenarios: electrolysis using offshore wind-generated electricity associated with onshore wind-generated electricity or with lignite gasification. Then we calculate the preliminary layouts and costs of pipeline networks capable of balancing the proposed demand and supply options. Finally, we compare the different options from an infrastructure planning and support perspective

Instruments of official communication by regulatory authorities on risks of drug use

Active communication of authorities, such as the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI), including maintenance of contacts with health care professionals, as well as press and public relations work, are essential prerequisites for ensuring that information on the risks of using medicinal products reaches both affected patients and healthcare professionals quickly and in a targeted manner. The various instruments of targeted communication describe possible risks and also contain recommendations that help to reduce the risk of using a medicinal product. The supplementary public relations work aims to make the tasks and objectives of the authority known to the public and to experts with the goal of creating and expanding trust in the actions of the authorities. To this end, appropriate communication platforms must be established and accepted so that they are used by both experts and the general public and the authority is perceived and appreciated as a reliable source of risk information. The currently available instruments of targeted risk communication, such as Dear Health Care Professional Communication (DHPC), risk management plans, and educational materials are described in this paper as well as broader communication on official websites or towards the media. Finally, PEI’s risk communication is highlighted with particular reference to COVID-19 vaccines.Die aktive Kommunikation von Behörden, wie dem Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) und dem Paul-Ehrlich-Institut (PEI), einschließlich der Kontaktpflege zu Fachkreisen sowie Presse- und Öffentlichkeitsarbeit sind wesentliche Voraussetzung dafür, dass Informationen zu Anwendungsrisiken von Arzneimitteln sowohl betroffene Patientinnen und Patienten als auch Angehörige der Heilberufe schnell und gezielt erreichen. Die verschiedenen Instrumente der gezielten Kommunikation beschreiben mögliche Risiken und enthalten darüber hinaus auch Empfehlungen, die helfen, das Anwendungsrisiko eines Arzneimittels zu reduzieren. Die ergänzende Öffentlichkeitsarbeit zielt darauf ab, die Aufgaben und Ziele der Behörde in der Bevölkerung und in Fachkreisen bekannt zu machen, um Vertrauen in behördliches Handeln zu schaffen und auszubauen. Dafür müssen entsprechende Kommunikationsplattformen etabliert und akzeptiert sein, die sowohl von Fachkreisen als auch von der Bevölkerung genutzt werden können. Die aktuell verfügbaren Instrumente der gezielten Risikokommunikation, wie Rote-Hand-Briefe (RHB), Risikomanagementpläne und Schulungsmaterial, werden in dieser Publikation ebenso beschrieben wie die breiter angelegte Kommunikation auf den behördlichen Webseiten oder gegenüber den Medien. Schließlich wird die Risikokommunikation des PEI unter besonderer Berücksichtigung der COVID-19-Impfstoffe beleuchtet

Phagocytosis of peripheral blood neutrophils after stimulation with SaS.

<p>A 15 min preincubation with M (media control), fMLF (2 x 10^-8M) or SaS A-C (1%) was performed prior the functional studies. (A) Phagocytosis of BCECF-labelled ATCC52359. Analyzed timepoint: 30 min. X-axis is presenting the BCECF intensity (absolute values), y-axis is presenting the CD66b expression (absolute values). (B) Number of phagocytozing cells (% of whole cell population). Analyzed timepoints: 3, 6, 10, 15, 30 min (experimental series 1; n = 6) and 60, 120, 180 min (experimental series 2; n = 7). (C) BCECF-fluorescence intensity of the BCECF-positive cell populations. Analyzed timepoints: 3, 6, 10, 15, 30 min (experimental series A; n = 6) and 60, 120, 180 min (experimental series B; n = 7). Values are presented as the relative mean of fluorescence in comparison with the negative control. (D) Number of phagocytozed bacteria of single cells and cell doublets. Analyzed timepoint: 30 min. The number of ingested bacteria was calculated per cell which means that values obtained for doublets were divided by 2. Analysis was done by using Image Stream^x (Amnis, Seattle, WA, USA) in combination with the Spot-Count-function of the IDEAS-software (for more detail information see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132703#sec002" target="_blank">Material and Methods</a>). n = 6. (E) Image selection of neutrophil single cells after phagocytosis (30 min) and preincubation with M, fMLF or SaS. All photos were taken with a 40 x objective (Image Stream^x, Amnis, Seattle, WA, USA), analyzed by IDEAS software (Amnis, Seattle, WA, USA) and illustrated in a channel series, including the BF (bright field) mode; the fluorescence channels imaging the staining for ATCC52359 (BCECF / Channel 2), CD11b (PE / channel 3) and an overlay of channel 2 and channel 3. Error bars indicate ± SD *<i>P</i> < 0.05 **<i>P</i> < 0.01 compared to fMLF.</p

Impact of C5aR1 antagonist W-54011 on CD66b:CD11b expression and phagocytosis.

<p>A 15 min preincubation with M (media control) or SaS A (1%) was performed prior the functional studies. The timepoint after 15 min of incubation is defined as A 0 min. (A) Impact of W-54011 (= C5a RA) on the CD66b:CD11b expression. Analyzed timepoint: A 0 min. Values are presented as the relative mean of fluorescence in comparison with the negative control. C5a RA n = 5; SaS A, SaS A + C5a RA n = 7. Error bars indicate ± SD *<i>P</i> < 0.05 ***<i>P</i> < <0.001 compared so SaS A. (B) Impact of W-54011 (C5a RA) on phagocytosis. “% Phagocytosis”—number of phagocytozing cells compared to whole population, “mean fluorescence BCECF”–mean fluorescence intensity of BCECF-positive cell population (phagocytic capacity). Values are presented as the relative mean of fluorescence in comparison with the negative control. %Phagocytosis: n = 8; Mean Fluorescence BCECF: n = 11. Abbr: C5a RA = C5aR1 antagonist W-54011.</p

CD66b and CD11b expression, and aggregate formation.

<p>A 15 min preincubation with M (media control), fMLF (2 x 10^-8M) or SaS A-C (1%) was performed prior the functional studies. The timepoint after 15 min of incubation is defined as A 0 min. (A) CD66b and CD11b expression of human neutrophils after incubation with fMLF and SaS A-C. Analyzed timepoint: A 0min. Values are presented as the relative mean of fluorescence in comparison with the negative control (n = 20). (B) Correlation of SaS A stimulation-induced CD66b expression at timepoint A 0 min and resulting %phagocytosis after 30 min incubation with bacteria. (C) CD66b expression on human neutrophils. Analyzed cell population / timepoint: whole cell population / A 0 min (M, fMLF, SaS A); phagocytosis assay—cells with ingested bacteria / 30 min (M, fMLF, SaS A). Values are presented as the relative mean of fluorescence in comparison with the negative control. n = 13. (D) CD11b expression on human neutrophils. Analyzed cell population / timepoint: whole cell population / A 0 min (M, fMLF, SaS A); phagocytosis assay—cells with ingested bacteria / 30 min (M, fMLF, SaS A). Values are presented as the relative mean of fluorescence in comparison with the negative control. n = 13. Error bars indicate ± SD ***<i>P</i> < 0.001 compared to A 0 min. (E) Aggregate formation of human neutrophils. Analyzed timepoints: A 0 min, 30 min / after addition of bacteria. Values are presented as the percentage of whole neutrophil population. n = 6. Error bars indicate ± SD *<i>P</i> < 0.05 compared to fMLF.</p

Oxidative burst in human neutrophils and whole blood bactericidal assay after stimulation.

<p>A 15 min preincubation with M (media control), fMLF (2 x 10^-8M) or SaS A-C (1%) was performed prior the functional studies. (A) The oxidative burst was determined at timepoint A 0 min and after 30 min. (B) Values are presented as the relative mean of fluorescence in comparison with the negative control after 30 min. Error bars indicate ± SD *<i>P</i> < 0.05 compared to fMLF. (C) Whole blood bactericidal assay after stimulation. 15 min preincubation with M (media control), fMLF (2 x 10^-8M) or SaS A-C (1%) was performed prior the functional studies. ATCC52953 was incubated with whole blood and the decline of vital bacteria was determined at a defined timepoint. Analyzed timepoint: 180 min. The decline of vital bacterial cells was illustrated on the y-axis as the change in log CFU / ml of the respective inoculum (for more detail information see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132703#sec002" target="_blank">Material and Methods</a>). n = 6. Error bars indicate ± SD *<i>P</i> < 0.05 **<i>P</i> < 0.01 compared to fMLF.</p