Tissue Distribution and Elimination of Isavuconazole following Single and Repeat Oral-Dose Administration of Isavuconazonium Sulfate to Rats

ABSTRACT Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration of isavuconazole in rats following single and repeated oral-dose administration of radiolabeled isavuconazonium sulfate, the prodrug of isavuconazole. Following a single-dose administration of radiolabeled isavuconazonium sulfate (labeled on the active moiety), radioactivity was detectable within 1 h postdose in 56 of 65 tissue/fluid specimens. The highest maximum concentrations ( C max ) were observed in bile and liver (66.6 and 24.7 μg eq/g, respectively). The lowest C max values were in bone and eye lens (0.070 and 0.077 μg eq/g, respectively). By 144 h postdose, radioactivity was undetectable in all tissues/fluids except liver (undetectable at 336 h) and adrenal gland tissues (undetectable at 672 h). Following daily administration for up to 21 days, 1-h-postdose C max values were the highest on or before day 14 in all except seven tissues/fluids, of which only rectum mucosa and small intestine mucosa had C max values &gt;25% higher than all other 1-h-postdose values. For 24-h-postdose C max values, only large intestine, large intestine mucosa, and urine had the highest C max values at day 21. The penetration of single oral doses of unlabeled isavuconazole (25 mg/kg of body weight isavuconazonium sulfate) and voriconazole (50 mg/kg) into rat brain (assessed using liquid chromatography-tandem mass spectrometry) was also compared. Brain concentration/plasma concentration ratios reached approximately 1.8:1 and 2:1, respectively. These data suggest that isavuconazole penetrates most tissues rapidly, reaches a steady state in most or all tissues/fluids within 14 days, does not accumulate in tissues/fluids over time, and achieves potentially efficacious concentrations in the brain. </jats:p

The Added Value of Large-Eddy and Storm-Resolving Models for Simulating Clouds and Precipitation

More than one hundred days were simulated over very large domains with fine (0.156 km to 2.5 km) grid spacing for realistic conditions to test the hypothesis that storm (kilometer) and large-eddy (hectometer) resolving simulations would provide an improved representation of clouds and precipitation in atmospheric simulations. At scales that resolve convective storms (storm-resolving for short), the vertical velocity variance becomes resolved and a better physical basis is achieved for representing clouds and precipitation. Similarly to past studies we found an improved representation of precipitation at kilometer scales, as compared to models with parameterized convection. The main precipitation features (location, diurnal cycle and spatial propagation) are well captured already at kilometer scales, and refining resolution to hectometer scales does not substantially change the simulations in these respects. It does, however, lead to a reduction in the precipitation on the time-scales considered – most notably over the ocean in the tropics. Changes in the distribution of precipitation, with less frequent extremes are also found in simulations incorporating hectometer scales. Hectometer scales appear to be more important for the representation of clouds, and make it possible to capture many important aspects of the cloud field, from the vertical distribution of cloud cover, to the distribution of cloud sizes, and to the diel (daily) cycle. Qualitative improvements, particularly in the ability to differentiate cumulus from stratiform clouds, are seen when one reduces the grid spacing from kilometer to hectometer scales. At the hectometer scale new challenges arise, but the similarity of observed and simulated scales, and the more direct connection between the circulation and the unconstrained degrees of freedom make these challenges less daunting. This quality, combined with already improved simulation as compared to more parameterized models, underpins our conviction that the use and further development of storm-resolving models offers exciting opportunities for advancing understanding of climate and climate change

Search for neutral charmless B decays at LEP

A search for rare charmless decays of \Bd and \Bs mesons has been performed in the exclusive channels \Bd_{(\mathrm s)}\ra\eta\eta, \Bd_{(\mathrm s)}\ra\eta\pio and \Bd_{(\mathrm s)}\ra\pio\pio. The data sample consisted of three million hadronic \Zo decays collected by the L3 experiment at LEP from 1991 through 1994. No candidate event has been observed and the following upper limits at 90\% confidence level on the branching ratios have been set \begin{displaymath} \mathrm{Br}(\Bd\ra\eta\eta)<4.1\times 10^{-4},\,\, \mathrm{Br}(\Bs\ra\eta\eta)<1.5\times 10^{-3},\,\, \end{displaymath} \begin{displaymath} \mathrm{Br}(\Bd\ra\eta\pio)<2.5\times 10^{-4},\,\, \mathrm{Br}(\Bs\ra\eta\pio)<1.0\times 10^{-3},\,\, \end{displaymath} \begin{displaymath} \mathrm{Br}(\Bd\ra\pio\pio)<6.0\times 10^{-5},\,\, \mathrm{Br}(\Bs\ra\pio\pio)<2.1\times 10^{-4}. \end{displaymath} These are the first experimental limits on \Bd\ra\eta\eta and on the \Bs neutral charmless modes

Ionic liquids at electrified interfaces

Until recently, “room-temperature” (<100–150 °C) liquid-state electrochemistry was mostly electrochemistry of diluted electrolytes(1)–(4) where dissolved salt ions were surrounded by a considerable amount of solvent molecules. Highly concentrated liquid electrolytes were mostly considered in the narrow (albeit important) niche of high-temperature electrochemistry of molten inorganic salts(5-9) and in the even narrower niche of “first-generation” room temperature ionic liquids, RTILs (such as chloro-aluminates and alkylammonium nitrates).(10-14) The situation has changed dramatically in the 2000s after the discovery of new moisture- and temperature-stable RTILs.(15, 16) These days, the “later generation” RTILs attracted wide attention within the electrochemical community.(17-31) Indeed, RTILs, as a class of compounds, possess a unique combination of properties (high charge density, electrochemical stability, low/negligible volatility, tunable polarity, etc.) that make them very attractive substances from fundamental and application points of view.(32-38) Most importantly, they can mix with each other in “cocktails” of one’s choice to acquire the desired properties (e.g., wider temperature range of the liquid phase(39, 40)) and can serve as almost “universal” solvents.(37, 41, 42) It is worth noting here one of the advantages of RTILs as compared to their high-temperature molten salt (HTMS)(43) “sister-systems”.(44) In RTILs the dissolved molecules are not imbedded in a harsh high temperature environment which could be destructive for many classes of fragile (organic) molecules