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51.
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Irena Loryan Vikash Sinha Claire Mackie Achiel Van Peer Wilhelmus Drinkenburg An Vermeulen Denise Morrison Mario Monshouwer Donald Heald Margareta Hammarlund-Udenaes 《Pharmaceutical research》2014,31(8):2203-2219
Purpose
The current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties of new chemical entities (NCEs), thereby optimizing the routine of evaluation and selection of novel neurotherapeutics.Methods
Forty compounds covering a wide range of physicochemical properties and various CNS targets were investigated. The combinatory mapping approach was used for the assessment of the extent of blood-brain and cellular barriers transport via estimation of unbound-compound brain (Kp,uu,brain) and cell (Kp,uu,cell) partitioning coefficients. Intra-brain distribution was evaluated using the brain slice method. Intra- and sub-cellular distribution was estimated via calculation of unbound-drug cytosolic and lysosomal partitioning coefficients.Results
Assessment of Kp,uu,brain revealed extensive variability in the brain penetration properties across compounds, with a prevalence of compounds actively effluxed at the blood-brain barrier. Kp,uu,cell was valuable for identification of compounds with a tendency to accumulate intracellularly. Prediction of cytosolic and lysosomal partitioning provided insight into the subcellular accumulation. Integration of the neuroPK parameters with pharmacodynamic readouts demonstrated the value of the proposed approach in the evaluation of target engagement and NCE selection.Conclusions
With the rather easily-performed combinatory mapping approach, it was possible to provide quantitative information supporting the decision making in the drug discovery setting. 相似文献53.
Factorial Design-of-Experiment analyses were applied for conventional and beam oscillation fiber laser cutting of 10 mm thick AISI 304 stainless steel. Considered factors in case of the conventional process with a static beam involve both laser and cutting gas parameters, in particular the laser power, the focal plane position, the cutting gas pressure, the nozzle stand-off distance as well as the nozzle diameter. The conducted trials were evaluated with respect to the achievable cutting speed, the cut kerf geometry and the cut edge roughness. Noticeable correlations between cut edge roughness and cut kerf geometry stimulated the development of a corresponding Computational Fluid Dynamics (CFD) model of the cutting gas flow through the kerf. A specific approach of data synchronization revealed that the experimentally determined roughness values do well correlate with numerically computed values of the backward directed component of the gas-induced shear stress and that the cut kerf geometry as internal process-inherent boundary condition influences relevant cutting characteristics more than controllable external cutting gas parameters. Finally, effects of circular beam oscillation were investigated by an additional factorial analysis considering the laser power, the focal plane position, the oscillation frequency and the oscillation amplitude as factors. The results demonstrate the potential of beam oscillation techniques for quality improvements in laser cutting. 相似文献
54.
The microstructural free volume evolution during a photopolymerization process was studied on a commercial photopolymer (SPOT LV) in situ by positron annihilation lifetime spectroscopy (PALS) and concomitant NIR-photorheology. Analysis of the positron lifetime spectra revealed a high sensitivity of the PALS technique to the different phases of photopolymerization associated with different reaction rates as well as to the evolution of microstructural free-volume shrinkage, which was described at the molecular level by the Kohlrausch–Williams–Watts equation. The in situ PALS study of microstructural changes in photopolymerization was related to the vitrification (gel point) accompanied by shrinkage stress registered via NIR-photorheology. The simultaneous NIR measurements yield information on the monomer conversion of SPOT LV, which can be correlated to the occurrence of the gel point and the evolution of the microstructural free volume. This combined study allows us to see deeper into the crosslinking process and its influence on the resulting material characteristics.Positron annihilation lifetime spectroscopy is a sensitive tool for the in situ study of the microstructural evolution during photopolymerization. 相似文献
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Endothelial cell protein C receptor plays an important role in protein C activation in vivo 总被引:21,自引:7,他引:21 下载免费PDF全文
Endothelial cell protein C receptor (EPCR) augments protein C activation by the thrombin-thrombomodulin complex about 5-fold in vitro. Augmentation is EPCR concentration dependent even when the EPCR concentration is in excess of the thrombomodulin. EPCR is expressed preferentially on large blood vessel endothelium, raising questions about the importance of protein C-EPCR interaction for augmenting systemic protein C activation. In these studies, this question was addressed directly by infusing thrombin into baboons in the presence or absence of a monoclonal antibody to EPCR that blocks protein C binding. Activated protein C levels were then measured directly by capturing the enzyme on a monoclonal antibody and assaying with chromogenic substrate. Blocking protein C-EPCR interaction resulted in about an 88% decrease in circulating activated protein C levels generated in response to thrombin infusion. Leukocyte changes, fibrinogen consumption, fibrin degradation products, and vital signs were similar between the animals infused with thrombin alone and those infused with thrombin and the anti-EPCR antibody. The results indicate that EPCR plays a major role in protein C activation and suggest that defects in the EPCR gene might contribute to increased risk of thrombosis. 相似文献
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Tanja Djurdjevic MD Alexander Loizides MD Wolfgang Löscher MD Hannes Gruber MD Michaela Plaikner MD Siegfried Peer MD 《Muscle & nerve》2014,49(1):35-39
Introduction: Posterior interosseous nerve (PIN) syndrome is a rare compression neuropathy of the PIN in the region of the supinator muscle, most common by the arcade of Frohse. We aimed to specify ultrasonographic findings in patients with PIN syndrome in comparison to healthy volunteers. Methods: Ultrasound images and clinical data of 13 patients with PIN syndrome confirmed by neurological examination and electrophysiological testing were evaluated retrospectively. Anteroposterior nerve diameters measured at the arcade of Frohse were compared with those of 20 healthy volunteers. The echotexture and the presence of a caliber change of the PIN were additionally assessed. Results: Enlargement of the PIN was seen in all patients with PIN syndrome, but not in volunteers (statistically significant difference in mean diameter P < 0.05). Furthermore, edema and caliber change of the PIN were present in all patients. Conclusions: High‐resolution ultrasound allows for differentiation between patients with PIN syndrome and healthy volunteers. Muscle Nerve 49 : 35–39, 2014 相似文献
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Denis J. Schrier Craig M. Flory Martin Finkel Susan L. Kuchera Mark E. Lesch Peer B. Jacobson 《Arthritis \u0026amp; Rheumatology》1996,39(8):1292-1299
Objective. To evaluate the effects of the phospho-lipase A2 (PLA2) inhibitor manoalide on cartilage degradation, stromelysin expression, and inflammatory cell accumulation in rabbits treated intraarticularly with recombinant human interleukin-1α (rHuIL-1α). Methods. Rabbits were given an intraarticular injection of rHuIL-1α. At various time points over a 24-hour period, the rabbits were euthanized and the articular space was lavaged with sterile PBS. The proteoglycan content of the lavage fluid was measured using a dimethylmethylene blue assay. PLA2 activity and differential cell counts were also measured. The femur was removed and cartilage proteoglycan content determined. In some experiments, levels of synovial stromelysin messenger RNA (mRNA) were assessed. Manoalide or vehicle was administered 30 minutes before the rHuIL-1α injection. Results. The rHuIL-1α-induced arthritic response is characterized by significant accumulation of inflammatory cells, loss of proteoglycan from the condylar cartilage, and induction of mRNA for stromelysin. PLA2 activity was also elevated in synovial fluids from rHuIL-1α-injected joints. Pretreatment with manoalide (0.3 mg/joint) significantly inhibited PLA2 activity in the synovial fluid, prevented the loss of proteoglycan from the condylar cartilage, and reduced proteoglycan levels in lavage fluids. However, manoalide either had no effect on, or stimulated, cell accumulation. To assess the relationship between the induction of PLA2 and stromelysin, levels of stromelysin mRNA were measured in synovial tissue from manoalide- and vehicle-treated joints. Stromelysin message levels were significantly suppressed in a dose-dependent manner. Conclusion. These studies demonstrate that manoalide is a potent inhibitor of inflammation and cartilage catabolism, and suggest that PLA2 is involved in the pathophysiology of rHuIL-1α-induced arthritis in rabbits. 相似文献