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1.
Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.  相似文献   
2.
Summary Dynamic light scattering was used to investigate the dynamics of sodium poly(styrene sulfonate) and fully neutralized poly(acrylic acid) gels as a function of the degree of swelling and weight ratio of cross-linking agent. It was shown that the collective diffusion coefficient increases with increasing degree of swelling and that the diffusion coefficient shows stronger concentration dependence than predicted by scaling arguments. For gel samples measured at the swelling equilibrium, the diffusion coefficient increases with increasing gel concentration for both gel systems.  相似文献   
3.
A manufacturing technique for monolithic dye-sensitised solar cells is presented. Encapsulated modules designed for indoor low-power applications have been prepared using industrial methods and equipment. Under certain conditions (light intensity <5000 lx, temperature between –10°C and 50°C, and relative humidity of appr. 50%), the modules have performed well and shown excellent long-term stability. Moreover, modules withstand illumination in combination with storage at 100% relative humidity. However, a certain degradation of the module performance takes place at illuminations exceeding 5000 lx and temperatures exceeding 50°C.  相似文献   
4.
The 1977 Broadcasting‐Satellite Service (BSS) Plan for Region 1 & 3 had been widely acknowledged to be out‐of‐date by the late 1980s. Development of digital modulation in the early 1990s provided an opportunity to update the technical provisions of the Plan to make it more economically viable. After a decade of work and three World Radiocommunication Conferences (WRCs), the revision of Region 1 & 3 BSS Plan was finally completed in 2003. The new Plan increased channel assignments from 5 to 10 analog‐equivalent channels for each country in Region 1, and from 4 to 12 channels for each country in Region 3. Yet, despite the increase in capacity, the new Plan is surprisingly similar to the original one in terms of the technical parameters. It is still based on national coverage, and the channel plan, orbital location, orbital spacing, and polarization are also the same. As a result, the new Plan is no more economically viable to implement than the old. To create economically viable BSS systems would most likely require modifications to the assignment in the Plan. Yet, modification procedures were made more difficult to apply after replanning. Less future implementation of BSS networks than would otherwise have occurred can be expected, and an inefficient usage of these frequency bands will likely result. On the other hand, less implemented systems will mean more capacity set aside for future use. This is important for countries that currently do not have satellite operations. In the end, BSS replanning reflects the eternal conflict between efficient usage and guaranteed future access. Copyright © 2005 John Wiley & Sons, Ltd.  相似文献   
5.
The transmission of millimeter waves through a semiconductor changes according to the amount of light falling on it. In the experiments reported here, a pattern of light and shadow is projected onto a sheet of semiconductor and the regions of greater and lesser transmission serve as a diffracting object for a millimeter-wave beam. The light source is a quartz tungsten halogen lamp. A lock-in amplifier is employed to overcome difficulties due to the differences in transmitted power being small.  相似文献   
6.
Histamine is an important mediator in allergic reactions, gastric acid secretions, and neurotransmission in the central nervous system. Basophils and mast cells are the main sources of histamine, which is formed from L-histidine by histidine decarboxylase (HDC). However, the regulatory mechanism of HDC in these cells remains unclear. We examined the regulation of HDC activity and gene expression using a unique human mast cell line, HMC-1, after stimulation with phorbol 12-myristate 13-acetate (PMA) or ionomycin. HDC activity was increased from 52.1+/-0.4 (mean+/-standard deviation) to 154+/-6.9, or 105.6+/-6.2 pmol/min/mg protein (n = 3), 4 hours after stimulation with PMA (10 ng/mL) or ionomycin (10[-6] M). Although actinomycin D had no effect on this increase, cycloheximide completely inhibited the increase caused by these stimuli. The population of HMC-1 cells containing HDC protein was increased after stimulation with either PMA or ionomycin as evaluated by immunocytochemical analysis with anti-HDC antibody as a marker. HMC-1 constitutively expressed HDC mRNA, and its level was not increased with these stimuli. These results suggest that the increase of HDC activity in HMC-1 induced by PMA or ionomycin is regulated at the translational level.  相似文献   
7.
Patients with unstable angina, refractory to intensive medical therapy, are at high risk for developing thrombotic complications, such as recurrent ischemia, myocardial infarction and coronary occlusion during coronary angioplasty. As both platelet aggregation and/or thrombus formation play an important role in this ongoing ischemic process, a monoclonal platelet GPIIb/IIIa receptor antibody (c7E3) or thrombolytic therapy (alteplase) might be able to modify the clinical course and underlying coronary lesion morphology. To evaluate whether alteplase or c7E3 could influence the incidence of complications, we randomized 36 and 60 patients, respectively to alteplase or placebo, or c7E3 or placebo. All patients exhibited dynamic ECG changes and recurrent pain attacks, despite maximal tolerated medical therapy. Patients were randomized in both studies after initial angiography had demonstrated a culprit lesion amenable for angioplasty. After study drug infusion quantitative angiography was repeated and angioplasty performed. Recurrent ischemia during study drug infusion occurred in 5, 6, 9 and 16 patients from the alteplase, placebo, c7E3 and placebo group, respectively. Major events defined as death, myocardial infarction or urgent intervention occurred in 7, 3, 1 and 7 patients, respectively. Two patients died: one in the alteplase group and one in the placebo group from the c7E3 study. The first patient due to retroperitoneal hemorrhage, the second as a result of recurrent infarction. Qualitative angiography showed resolution of clots in the c7E3 group only, while the same group of patients showed in 20% an improvement in TIMI flow grade, without deterioration in any patient from this group.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   
8.
Glutamine synthesis, the major pathway of ammonia detoxification, and the intracellular concentration of organic osmolytes in primary astrocytes and F98 glioma cells were investigated with multinuclear magnetic resonance spectroscopy. Acute exposure to ammonia (3 h incubation with NH4Cl) raised the concentration of glutamine and other amino acids, such as glutamate and aspartate, and decreased myo-inositol, hypotaurine, and taurine concentrations. The loss of these osmolytes was partially reversed by co-treatment with the glutamine synthetase inhibitor, methionine sulphoximine. Glutamate, the precursor of glutamine, is provided by stimulated anaplerotic flux via pyruvate carboxylase and glutamate dehydrogenase activity. Thus, the glutamine increase and myo-inositol decrease observed by in vivo magnetic resonance spectroscopy on patients with hepatic encephalopathy may be due to the disturbed osmoregulation in astrocytes caused by accumulation of glutamine and the subsequent loss of organic osmolytes.  相似文献   
9.
The design, fabrication, and characterization of thermally excited silicon oxide beam and bridge resonators by a modern industrial CMOS process combined with one additional maskless etching step is reported. The resonant frequencies, vibration amplitudes, and mode shapes of the devices are measured using a laser heterodyne interferometer. The acoustic transmitting and receiving sensitivities of the resonant structures in air are investigated in order to test their possible application as ultrasound transducers for proximity sensing. The experimental results are compared with finite element simulations using ANSYS  相似文献   
10.
A new CAMAC based data acquisition system has been installed at the Lund Nuclear Microprobe facility. This paper reports on the development and present status of the data acquisition system. The system is a true multiparameter CAMAC based system with fast Fera bus readout and in crate memory buffer. The user interface is based on Sparrow Kmax software for a Power Macintosh platform. The system read out and tag the event data with position on-line, which make fast on-line monitoring of spectra or element maps possible.Simultaneously, all data can be saved event by event for off-line analysis. The beam scanning part is software controlled through a timed D/A converter, this allows fast scanning of the beam. With a CCD-camera and video card the area to be analysed could be defined directly from the image, and the sample position can be moved. Any kind of irregular scan patterns could be defined.  相似文献   
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