Poor aqueous solubility is a major challenge in today's biopharmaceutics. While solubility-enabling formulations can significantly increase the apparent solubility of the drug, the concomitant effect ...on the drug's apparent permeability has been largely overlooked. The mathematical equation to describe the membrane permeability of a drug comprises the membrane/aqueous partition coefficient, which in turn is dependent on the drug's apparent solubility in the GI milieu, suggesting that the solubility and the permeability are closely related, exhibit a certain interplay between them, and treating the one irrespectively of the other may be insufficient. In this article, an overview of this solubility–permeability interplay is provided, and the available data is analyzed in the context of the effort to maximize the overall drug exposure.
Overall, depending on the type of solubility–permeability interplay, the permeability may decrease, remain unchanged, and even increase, in a way that may critically affect the formulation capability to improve the overall absorption. Therefore, an intelligent design of solubility-enabling formulation needs to consider both the solubility afforded by the formulation and the permeability in the new luminal environment resulting from the formulation.
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Music has been an essential constituent of Shakespeare's plays from the sixteenth century to the present day, yet its significance has often been overlooked or underplayed in the history of ...Shakespearean performance. Providing a long chronological sweep, this collection of essays traces the different uses of music in the theatre and in film from the days of the first Globe and Blackfriars to contemporary, global productions. With a unique concentration on the performance aspects of the subject, the volume offers a wide range of voices, from scholars to contemporary practitioners (including an interview with the critically acclaimed composer Stephen Warbeck), and thus provides a rich exploration of this fascinating history from diverse perspectives.
THE ENERGY STORAGE PROBLEM Lindley, David
Nature (London),
01/2010, Letnik:
463, Številka:
7277
Journal Article
Recenzirano
Odprti dostop
Denmark already gets about 20% of its electricity from land- and sea-based wind farms, and it is aiming to increase that figure to 50% by 2025. Because the North Sea winds can drop to low levels for ...days at a time, however, countries such as Denmark and the Netherlands are increasing their grid connectivity to Norway, which gets the vast majority of its power from hydroelectric plants.
Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) ...model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed C
and area under the curve of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect, and exposure of an amorphous solid dispersion formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of biopharmaceutics classification system IV compounds.
Hydrotropy refers to increasing the water solubility of otherwise poorly soluble compound by the presence of small organic molecules. While it can certainly increase the apparent solubility of a ...lipophilic drug, the effect of hydrotropy on the drugs' permeation through the intestinal membrane has not been studied. The purpose of this work was to investigate the solubility-permeability interplay when using hydrotropic drug solubilization. The concentration-dependent effects of the commonly used hydrotropes urea and nicotinamide, on the solubility and the permeability of the lipophilic antiepileptic drug carbamazepine were studied. Then, the solubility-permeability interplay was mathematically modeled, and was compared to the experimental data. Both hydrotropes allowed significant concentration-dependent carbamazepine solubility increase (up to ∼30-fold). A concomitant permeability decrease was evident both
and
(∼17-fold for nicotinamide and ∼9-fold for urea), revealing a solubility-permeability tradeoff when using hydrotropic drug solubilization. A relatively simplified simulation approach based on proportional opposite correlation between the solubility increase and the permeability decrease at a given hydrotrope concentration allowed excellent prediction of the overall solubility-permeability tradeoff. In conclusion, when using hydrotropic drug solubilization it is prudent to not focus solely on solubility, but to account for the permeability as well; achieving optimal solubility-permeability balance may promote the overall goal of the formulation to maximize oral drug exposure.
Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene ...silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.
Traditional methods to measure body lengths of aquatic vertebrates rely on anesthetics, and extended handling times. These procedures can increase stress, potentially affecting the animal's welfare ...after its release. We developed a simple procedure using digital images to estimate body lengths of coastal cutthroat trout (Oncorhynchus clarkii clarkii) and larval coastal giant salamander (Dicamptodon tenebrosus). Images were postprocessed using ImageJ2. We measured more than 900 individuals of these two species from 200 pool habitats along 9.6 river kilometers. The percent error (mean ± SE) of our approach compared to the use of a traditional graded measuring board was relatively small for all length metrics of the two species. Total length of trout was −2.2% ± 1.0. Snout–vent length and total length of larval salamanders was 3.5% ± 3.3 and −0.6% ± 1.7, respectively. We cross‐validated our results by two independent observers that followed our protocol to measure the same animals and found no significant differences (p > .7) in body size distributions for all length metrics of the two species. Our procedure provides reliable information of body size reducing stress and handling time in the field. The method is transferable across taxa and the inclusion of multiple animals per image increases sampling efficiency with stored images that can be reviewed multiple times. This practical tool can improve data collection of animal size over large sampling efforts and broad spatiotemporal contexts.
We developed a procedure to estimate body length of aquatic vertebrates using digital images of live animals in the field and post processing using ImageJ2. This method is reliable and reduces stress and handling time in the field. This tool can improve our understanding about species responses to disturbances over large sampling efforts and broader spatiotemporal contexts.
Initial studies indicate that the newly developed hCMEC/D3 cell line may prove to be a useful model for studying the physiology of the human blood−brain barrier (BBB) endothelium. The purpose of this ...study was to assess the mRNA expression of several ABC and SLC transporters, with an emphasis on the proton-coupled oligopeptide transporter superfamily (POT) transporters in this immortalized BBB cell model. The transport kinetics of POT-substrates was also evaluated. The hCMEC/D3 cell line was maintained in a modified EGM-2 medium in collagenated culture flasks and passaged every 3−4 days at approximately 85%−95% confluence. Messenger RNA (mRNA) expression of a variety of ABC and SLC transporters was evaluated using qRT-PCR arrays, while additional qRT-PCR primers were designed to assess the expression of POT members. The transport kinetics of mannitol and urea were utilized to quantitatively estimate the intercellular pore radius, while POT substrate transport was also determined to assess the suitability of the cell model from a drug screening perspective. Optimization of the cell line was attempted by culturing with on laminin and fibronectin enhanced collagen and in the presence of excess Ca2+. hCMEC/D3 cells express both hPHT1 and hPHT2, while little to no expression of either hPepT1 or hPepT2 was observed. The relative expression of other ABC and SLC transporters is discussed. While POT substrate transport does suggest suitability for BBB drug permeation screening, the relative intercellular pore radius was estimated at 19 Å, significantly larger than that approximated in vivo. Culturing with extracellular matrix proteins did not alter mannitol permeability. These studies characterized this relevant human hCMEC/D3 BBB cell line with respect to both the relative mRNA expression of various ABC and SLC transporters and its potential utility as an in vitro screening tool for brain permeation. Additional studies are required to adequately determine the potential to establish an in vivo correlation.
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