Nano- and microcrystals of griseofulvin subcutaneously administered to rats resulted in improved bioavailability and sustained release

Griseofulvin is a commonly used antifungal agent which is administered per oral (p.o.). The oral administration route, however, shows rather low bioavailability. The aim of this study was to improve the bioavailability and to evaluate and interpret the pharmacokinetic profiles after subcutaneous (s.c.) administration of crystalline griseofulvin nano- and microsuspensions. Both formulations were injected at 5 and 500 µmol/kg to rats. For the lower concentration, the profiles were similar after s.c. injection but extended as compared to p.o. administration. For the higher concentration, injection of microsuspension resulted in a maintained plateau whereas the nanosuspension resulted in an obvious peak exposure followed by extended elimination. Both suspensions showed improved exposure with dose. The differences in peak exposures between nano- and microparticles, at the high dose, were mainly ascribed to differences in dissolution rate, experimentally determined in vitro, using spectroscopic methods. The extended appearance in the circulation may depend on the physicochemical properties of the compound and the physiological conditions at the injection site. The bioavailability was improved for both formulations compared with an orally administered nanosuspension, suggesting the s.c. route to be a preferred administration option for compounds with low oral bioavailability regarding both overall exposure and extended efficacy.     

Influence of the Bio‐Based Epoxy Prepolymer Structure on Network Properties

Three different bio‐based epoxy prepolymers are studied: one that is synthesized from isosorbide and two that are commercial prepolymers derived from sorbitol and cardanol. The chemical structures are analyzed by SEC, ESI–TOF MS, and FTIR analyses. The bio‐based prepolymers exhibit different structures, either aromatic with long aliphatic chains for the epoxy prepolymer derived from cardanol (DGECAR), with high functionality for the sorbitol polyglycidyl ether (SPGE) or a short and cyclic structure for the epoxy prepolymer derived from isosorbide (DGEDAS₀). A traditional petroleum‐based epoxy prepolymer, diglycidyl ether of bisphenol A (DGEBA) is also used for comparison. Gelation and reactivity of the different precursors with an isophorone diamine hardener are studied using rheological measurements and differential scanning calorimetry. Glass transition temperatures of the epoxy networks are evaluated and the thermal stability is also studied by thermo‐gravimetric analysis.

     

民族志方法在公共空间设计中的应用

以丹麦的设计实践为基础,探讨了建筑师和城市规划师以及社会学家共同合作,从社会学研究领域,特别是民族志方法中汲取灵感,提供更好的公共空间的过程。     

The majority of minerals present in natural rubber are associated with the macrogel: An ICP‐MS and SEM/EDX investigation

The mineral composition of the insoluble (macrogel) and soluble fractions of two natural rubber (NR) samples made from the latex of two different clones (RRIM600 from Thailand and GT1 from Côte d'Ivoire) was determined using inductively coupled plasma mass spectrometry (ICP‐MS). The ICP‐MS results showed that mineral elements were concentrated in the macrogel. The major mineral elements found in macrogel were phosphorus, magnesium, potassium, and sulfur. Some mineral elements were mostly concentrated in micron‐sized mineral aggregates, visible at the surface of the samples using scanning electron microscopy coupled with an energy dispersive X‐ray microanalyzer (SEM/EDX). The nature of these mineral aggregates was found to be highly variable. Their inhomogeneous distribution in the macrogel indicates that these aggregates do not have a major influence on macrogel structure. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43062.     

Design of highly tough poly(l‐lactide)‐based ternary blends for automotive applications

Technical renewable poly(l ‐lactide) (PLA)‐based blends represent an elegant way to achieve attractive properties for engineering applications. Recently, the miscibility between PLA and poly(methyl methacrylate) (PMMA) gave rise to new formulations with enhanced thermo‐mechanical properties but their high brittleness still remains a challenge to be overcome. This work here focuses on rubber‐toughened PLA/PMMA formulations for injection‐molding processes upon the addition of a commercially available ethylene‐acrylate impact modifier (BS). The miscibility between PLA and PMMA is not altered by the presence of BS but the incorporation of BS (17% by weight) into a PLA/PMMA matrix could enhance both ductility and toughness of PLA/PMMA blends for PMMA content up to 50 wt %. An optimum range of particle sizes (d_n ～0.5 µm) of the dispersed domains for high impact toughness is identified. These bio‐based ternary blends appear as promising alternatives to petro‐sourced blends such as ABS‐based blends in engineering injection‐molding parts. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43402.     

Active Site Mutations as a Suitable Tool Contributing to Explain a Mechanism of Aristolochic Acid I Nitroreduction by Cytochromes P450 1A1, 1A2 and 1B1

Aristolochic acid I (AAI) is a plant drug found in Aristolochia species that causes aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. AAI is activated via nitroreduction producing genotoxic N-hydroxyaristolactam, which forms DNA adducts. The major enzymes responsible for the reductive bioactivation of AAI are NAD(P)H:quinone oxidoreductase and cytochromes P450 (CYP) 1A1 and 1A2. Using site-directed mutagenesis we investigated the possible mechanisms of CYP1A1/1A2/1B1-catalyzed AAI nitroreduction. Molecular modelling predicted that the hydroxyl groups of serine122/threonine124 (Ser122/Thr124) amino acids in the CYP1A1/1A2-AAI binary complexes located near to the nitro group of AAI, are mechanistically important as they provide the proton required for the stepwise reduction reaction. In contrast, the closely related CYP1B1 with no hydroxyl group containing residues in its active site is ineffective in catalyzing AAI nitroreduction. In order to construct an experimental model, mutant forms of CYP1A1 and 1A2 were prepared, where Ser122 and Thr124 were replaced by Ala (CYP1A1-S122A) and Val (CYP1A2-T124V), respectively. Similarly, a CYP1B1 mutant was prepared in which Ala133 was replaced by Ser (CYP1B1-A133S). Site-directed mutagenesis was performed using a quickchange approach. Wild and mutated forms of these enzymes were heterologously expressed in Escherichia coli and isolated enzymes characterized using UV-vis spectroscopy to verify correct protein folding. Their catalytic activity was confirmed with CYP1A1, 1A2 and 1B1 marker substrates. Using ³²P-postlabelling we determined the efficiency of wild-type and mutant forms of CYP1A1, 1A2, and 1B1 reconstituted with NADPH:CYP oxidoreductase to bioactivate AAI to reactive intermediates forming covalent DNA adducts. The S122A and T124V mutations in CYP1A1 and 1A2, respectively, abolished the efficiency of CYP1A1 and 1A2 enzymes to generate AAI-DNA adducts. In contrast, the formation of AAI-DNA adducts was catalyzed by CYP1B1 with the A133S mutation. Our experimental model confirms the importance of the hydroxyl group possessing amino acids in the active center of CYP1A1 and 1A2 for AAI nitroreduction.     

Robust imaging of hippocampal inner structure at 7T: in vivo acquisition protocol and methodological choices

Objective

Motion-robust multi-slab imaging of hippocampal inner structure in vivo at 7T.

Materials and methods

Motion is a crucial issue for ultra-high resolution imaging, such as can be achieved with 7T MRI. An acquisition protocol was designed for imaging hippocampal inner structure at 7T. It relies on a compromise between anatomical details visibility and robustness to motion. In order to reduce acquisition time and motion artifacts, the full slab covering the hippocampus was split into separate slabs with lower acquisition time. A robust registration approach was implemented to combine the acquired slabs within a final 3D-consistent high-resolution slab covering the whole hippocampus. Evaluation was performed on 50 subjects overall, made of three groups of subjects acquired using three acquisition settings; it focused on three issues: visibility of hippocampal inner structure, robustness to motion artifacts and registration procedure performance.

Results

Overall, T2-weighted acquisitions with interleaved slabs proved robust. Multi-slab registration yielded high quality datasets in 96 % of the subjects, thus compatible with further analyses of hippocampal inner structure.

Conclusion

Multi-slab acquisition and registration setting is efficient for reducing acquisition time and consequently motion artifacts for ultra-high resolution imaging of the inner structure of the hippocampus.

     

Alternative energy sources: Solar project due diligence

While any energy project has risks, more conventional risks include anything in the wide area including site control, permitting, securing finance, equipment supply, operations and maintenance agreements, and confidence in energy production estimates. With renewable projects, the intermittent fuel or resource adds additional risk. Due to the nature and diversity of these challenges, independent assessments are encouraged throughout the project development life cycle.