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991.
992.
Jan Ploen Jens Andersch Michael Heschel 《Drug development and industrial pharmacy》2013,39(10):1210-1218
Background: An extended release pellet formulation (ACES®) of the weakly basic drug propiverine was developed with spheronized citric acid crystals as starter cores. Method: Coated pellets, consisting of several layers of functional coatings, were manufactured by fluid bed coating. Different coating levels were examined with regard to their effect on drug release. Release profiles from the formulations with or without pH modifier and the free base as well as the hydrochloride salt of the active ingredient were compared. Results: The coated citric acid starter cores led to a controlled release of the drug and the pH modifier, resulting from modulation of the microenvironmental pH throughout the dissolution period of 17 hours. If microcrystalline cellulose pellets are used as starter cores drug release is strongly pH-dependent. Significant differences in the drug release profiles were observed between the formulations containing the free drug base and those with the hydrochloride salt as a result of an altered microenvironmental pH. Conclusion: The presented extended release pellet formulation is able to maintain a low pH within the pellet core and thus a sufficiently high drug solubility. By maintaining a low pH inside the pellets, a controlled drug release can be achieved. 相似文献
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Dr. Reik Löser Dr. Ralf Bergmann Dr. Maxim Frizler Dr. Birgit Mosch Lilli Dombrowski Manuela Kuchar Prof. Dr. Jörg Steinbach Prof. Dr. Michael Gütschow Prof. Dr. Jens Pietzsch 《ChemMedChem》2013,8(8):1330-1344
A fluorinated cathepsin inhibitor based on the azadipeptide nitrile chemotype was prepared and selected for positron emission tomography (PET) tracer development owing to its high affinity for the oncologically relevant cathepsins L, S, K and B. Labelling with fluorine‐18 was accomplished in an efficient and reliable two‐step, one‐pot radiosynthesis by using 2‐[18F]fluoroethylnosylate as a prosthetic agent. The pharmacokinetic properties of the resulting radiotracer compound were studied in vitro, ex vivo and in vivo in normal rats by radiometabolite analysis and small‐animal positron emission tomography. These investigations revealed rapid conjugate formation of the tracer with glutathione in the blood, which is associated with slow blood clearance. The potential of the developed 18F‐labelled probe to image tumour‐associated cathepsin activity was investigated by dynamic small‐animal PET imaging in nude mice bearing tumours derived from the human NCI‐H292 lung carcinoma cell line. Computational analysis of the obtained image data indicated the time‐dependent accumulation of the radiotracer in the tumours. The expression of the target enzymes in the tumours was confirmed by immunohistochemistry with specific antibodies. This indicates that azadipeptide nitriles have the potential to target thiol‐dependent cathepsins in vivo despite their disadvantageous pharmacokinetics. 相似文献
994.
Markus Laube Wilma Neumann Dr. Matthias Scholz Dr. Peter Lönnecke Brenda Crews Prof. Dr. Lawrence J. Marnett Prof. Dr. Jens Pietzsch Dr. Torsten Kniess Prof. Dr. Evamarie Hey‐Hawkins 《ChemMedChem》2013,8(2):329-335
Cyclooxygenase‐2 (COX‐2) inhibitors have been the focus of medicinal chemistry efforts for years, and many compounds that exhibit high selectivity and affinity have been developed. As carbaboranes represent interesting pharmacophores as phenyl mimetics in drug development, this paper presents the synthesis of carbaboranyl derivatives of COX‐2‐selective 2,3‐disubstituted indoles. Despite the lability of carbaboranes under reducing conditions, 2‐carbaborane‐3‐phenyl‐1H‐indoles could be synthesized by McMurry cyclization of the corresponding amides. Whereas the meta‐carbaboranyl‐substituted derivatives lacked COX inhibitory activity, an ortho‐carbaboranyl analogue was active, but showed a selectivity shift toward COX‐1. 相似文献
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This study examines the use of an aeration scheme to remediate low oxygen conditions in a saline stratified system. The Tawe estuary was impounded in 1992 and quickly developed saline stratification during the summer months which led to an anoxic hypolimnon. In 1998 trials began in which a suite of aerators was applied to remediate the water quality; the trial was later extended to a full aeration scheme. This study examines pre-aeration conditions in order to delineate conditions under which poor water quality would develop, and would therefore be the conditions when aeration would be necessary. Furthermore, the study compared identical periods within the impoundment during which the following conditions existed: no aeration; and aeration with first 44, then 88, aerators. The study shows that (i) destratification occurred naturally under flows of >10 m3/s, and no low dissolved oxygen conditions were observed at higher flows; (ii) the presence of all levels of aeration had a statistically significant effect upon dissolved oxygen (DO) levels; the effect of increasing the number of aerators was approximately linear; (iii) the average effect of aeration was an increase of up to 3 mg/L DO in the deepest water; (iv) the frequency of low DO conditions decreased from 19% to 3% with the operation of aerators; and (v) aeration is most effective during periods of no tidal incursion and further from the saline water source. This study is the first to demonstrate the effectiveness of aeration in a saline stratified system. 相似文献
999.
几位捷克僧侣被纽约的Calvin Klein旗舰店吸引,他们决定让同一设计师设计他们的修道院,而这是捷克境内半个多世纪来的第一座新建修道院。于是诞生了简约派建筑典范——Novy Dvur修道院。这位建筑师提出了比Mies"Less is more"更激进最简主张,即"Almost nothing is more"。 相似文献
1000.
Globalization and the use of technology call for an adaptation of value creation strategies. As the potential for rationalization
and achieving flexibility within companies is to the greatest possible extent exhausted, approaches to the corporate reorganization
of value creation are becoming increasingly important. In this process, the spread and further development of information
and communication technology often provide the basis for a reorganization of cross-company value nets and lead to a redistribution
of roles and tasks between the actors involved in value creation. While cooperative, decentralized and self-organizing value
creation processes are in fact being promoted, the associated potential for development and production engineering is being
underestimated and hence not implemented sufficiently. This contribution will introduce a value creation taxonomy and then,
using its notion and structure, describe the emerging transformations in value creation on the basis of case studies. Finally
an adequate framework for analysing and configuring value creation will be presented. 相似文献