Exploring In Vitro and In Vivo Pharmacology of Echinacea Purpurea (L.) Moench

Background Echinacea purpurea has long been used for the treatment and prevention of respiratory tract infections. The medicinal plant has originally been discovered by the Native American population, who squeezed the sap from fresh plant or chewed dried roots. Today, commercially available preparations vary greatly in terms of Echinacea concentration, manufacturing methods, plant parts used, et cetera. This heterogeneity results in tremendously fluctuating bio-activities between products. Some of these products finally failed to show efficacy in large clinical studies raising principal questions about the value of the medicinal plant. Objectives The aim of this doctoral work was to explore in vitro and in vivo pharmacological effects, as well as clinical efficacy in prevention and acute treatment of respiratory tract infections for a single, phytochemically characterized and standardized Echinacea purpurea extract (Echinaforce®, EF). Methodology In vitro antiviral and anti-inflammatory (immune-modulatory) activities of EF were researched studying the most relevant respiratory pathogens including influenza, respiratory syncytial virus (RSV) or coronavirus (CoV) and using cytokine assays for interleukins IL-6 or IL-8 in airway epithelial cells. Test tube experiments were sought to be confirmed in organotypic tissues and upon peroral administration of EF ex vivo, whereas bio-availability of alkylamides in the extract was investigated to estimate systemic relevance. Two clinical studies aimed to investigate efficacy of EF for the treatment and the prevention of respiratory tract infections and subanalyses served to confirm above proposed pharmacological actions in vivo. Finally, EF’s therapeutic potential beyond its traditional use for colds and flu was researched by looking at the prevention of bacterial superinfections including bronchitis or pneumonia. Results EF was demonstrated to inhibit a wide range of respiratory agents, showing a primary specificity to enveloped viruses (e.g. influenza, RSV and CoV) in vitro and in a clinical prevention study. The extract modulated overexpression of inflammatory cytokines in epithelial cells and in the presence of respiratory pathogens. It is thereby expected not only to impact occurrence but also the symptomatic development of viral infections. Alkylamides were found to play a role in the systemic immune-modulation as bio-availability was demonstrated after peroral ingestion of EF. Next, EF was administered for the treatment of clinically diagnosed influenza (flu) to find non-inferiority to the gold-standard therapy Oseltamivir in this indication. Comparable recovery rates were observed for virologically confirmed influenza infections, demonstrating clinical efficacy in the treatment of viral respiratory infections. Another large clinical study investigated EF for the prevention of respiratory tract infections. In the placebo group a total of 188 cold episodes were identified, which lasted for 850 days in comparison to 149 episodes and 672 sick days with EF extract (p < 0.05). Enveloped viruses (influenza, RSV and CoV) were found in 24 patients with EF and in 47 with placebo (p < 0.05). In vitro EF reduced the expression of bacteria-binding receptors (e.g. of intracellular adhesion molecule, ICAM-1) on airway epithelial cells after infection with respiratory viruses. Thereby, EF prevented the attraction of pathogenic bacteria potentially inducing bacterial superinfections of initial viral infections. Conclusion The evidence generated by this PhD work substantiates the medicinal value of Echinacea purpurea for the treatment and prevention of respiratory tract infections. By focussing on a single, chemically standardized extract (Echinaforce®) problems with heterogeneity between Echinacea products could be overcome to reach more consistent conclusions. EF exhibits antiviral and anti-inflammatory effects to not only prevent occurrence but also the symptomatic development of infections. Alkylamides are bio-available and capable to systemically modulate the immune response. Bacteria-binding receptors on the epithelium are controlled with EF to finally prevent respiratory complications including bronchitis or pneumonia

Lone Pair Effect, Structural Distortions and Potential for Superconductivity in Tl Perovskites

Drawing the analogy to BaBiO3, we investigate via ab-initio electronic structure calculations potential new superconductors of the type ATlX3 with A = Rb, Cs and X = F, Cl, and Br, with a particular emphasis on RbTlCl3. Based on chemical reasoning, supported by the calculations, we show that Tl-based perovskites have structural and charge instabilities driven by the lone pair effect, similar to the case of BaBiO3, effectively becoming A2Tl1+Tl3+X6. We find that upon hole doping of RbTlCl3, structures without Tl1+, Tl3+ charge disproportionation become more stable, although the ideal cubic perovskite, often viewed as the best host for superconductivity, should not be the most stable phase in the system. The known superconductor (Sr,K)BiO3 and hole doped RbTlCl3, predicted to be most stable in the same tetragonal structure, display highly analogous calculated electronic band structures.Comment: 5 pages, 5 figure

Evolution of magnetic fluctuations through the Fe-induced paramagnetic to ferromagnetic transition in Cr2_2B

In itinerant ferromagnets, the quenched disorder is predicted to dramatically affect the ferromagnetic to paramagnetic quantum phase transition driven by external control parameters at zero temperature. Here we report a study on Fe-doped Cr$_2$B, which, starting from the paramagnetic parent, orders ferromagnetically for Fe-doping concentrations $x$ larger than $x_{\rm c}=2.5$\%. In parent Cr$_2$B, $^{11}$B nuclear magnetic resonance data reveal the presence of both ferromagnetic and antiferromagnetic fluctuations. The latter are suppressed with Fe-doping, before the ferromagnetic ones finally prevail for $x>x_{\rm c}$. Indications for non-Fermi liquid behavior, usually associated with the proximity of a quantum critical point, were found for all samples, including undoped Cr$_2$B. The sharpness of the ferromagnetic-like transition changes on moving away from $x_{\rm c}$, indicating significant changes in the nature of the magnetic transitions in the vicinity of the quantum critical point. Our data provide constraints for understanding quantum phase transitions in itinerant ferromagnets in the limit of weak quenched disorder.Comment: 8 pages, 7 figure

Superconducting NdCeCuO Bicrystal Grain Boundary Josephson Junctions

We have studied the electric transport properties of symmetrical [001] tilt NdCeCuO bicrystal grain boundary Josephson junctions (GBJs) fabricated on SrTiO bicrystal substrates with misorientation angles of 24 and 36.8 degree. The superconducting properties of the NdCeCuO-GBJs are similar to those of GBJs fabricated from the hole doped high temperature superconductors (HTS). The critical current density Jc decreases strongly with increasing misorientation angle. The products of the critical current Ic and the normal resistance Rn (about 0.1 mV at 4.2 K) are small compared to the gap voltage and fit well to the universal scaling law (IcRn is proportional to the square root of Jc) found for GBJs fabricated from the hole doped HTS. This suggests that the symmetry of the order parameter, which most likely is different for the electron and the hole doped HTS has little influence on the characteristic properties of symmetrical [001] tilt GBJs.Comment: 3 pages, 4 figures, to be published in Applied Physics Letter

Andreev Bound States in High Temperature Superconductors

Andreev bound states (ABS) at the surface of superconductors are expected for any pair potential showing a sign change in different k-directions with their spectral weight depending on the relative orientation of the surface and the pair potential. We report on the observation of ABS in HTS employing tunneling spectroscopy on bicrystal grain boundary Josephson junctions (GBJs). The tunneling spectra were studied as a function of temperature and applied magnetic field. The tunneling spectra of GBJ formed by YBCO, BSCCO, and LSCO show a pronounced zero bias conductance peak that can be interpreted in terms of Andreev bound states at zero energy that are expected at the surface of HTS having a d-wave symmetry of the order parameter. In contrast, for the most likely s-wave HTS NCCO no zero bias conductance peak was observed. Applying a magnetic field results in a shift of spectral weight from zero to finite energy. This shift is found to depend nonlinearly on the applied magnetic field. Further consequences of the Andreev bound states are discussed and experimental evidence for anomalous Meissner currents is presented.Comment: 17 pages, 10 figures, to appear in Eur. Phys. J.

Correlation of Crystal Quality and Extreme Magnetoresistance of WTe2_2

High quality single crystals of WTe$_2$ were grown using a Te flux followed by a cleaning step involving self-vapor transport. The method is reproducible and yields consistently higher quality single crystals than are typically obtained via halide assisted vapor transport methods. Magnetoresistance (MR)values at 9 Tesla and 2 Kelvin as high as 1.75 million \%, nearly an order of magnitude higher than previously reported for this material, were obtained on crystals with residual resistivity ratio (RRR) of approximately 1250. The MR follows a near B$^2$ law (B = 1.95(1)) and, assuming a semiclassical model, the average carrier mobility for the highest quality crystal was found to be ~167,000 cm$^2$/Vs at 2 K. A correlation of RRR, MR ratio and average carrier mobility ($\mu_{avg}$) is found with the cooling rate during the flux growth.Comment: 7 pages, 3 figures, 1 tabl