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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.
The architecture of normal colonic mucosa suggest that terminally differentiated epithelial cells near the top of the crypt are extruded into the colonic lumen. Morphological studies have identified apoptotic cells among the differentiated phenotypes near the crypt-lumen interface, suggesting a link between pathways of differentiation, apoptosis, and cellular shedding. We studied these processes in HT29 and SW620 cells and found that compared to adherent cells, those cells which were shed during standard, uninduced culture conditions exhibited nonrandom DNA fragmentation characteristic of apoptosis. Moreover, these apoptotic cells, which accumulate in the media, exhibited a more differentiated phenotype. Because short-chain fatty acids (SCFAs) are natural effectors of colonic cell differentiation in vivo, we investigated the specificity of three 4-carbon atom SCFAs on potentiating differentiation and apoptosis, and thus accumulation of shed cells in the conditioned media, in these colonic carcinoma cell lines. Whereas the unbranched SCFA butyrate induced a more differentiated phenotype and enhanced apoptosis, two derivatives of butyrate, branched isobutyric acid and a nonmetabolizable fluorine-substituted analogue, heptafluorobutyric acid, were ineffective in inducing either differentiation or apoptosis. Thus, potentiated differentiation and apoptosis in colonic carcinoma cells were linked to SCFA structure and, most likely, utilization.  相似文献   
3.
Increased detection thresholds for pure tones were observed in a large cohort of children exposed to lead environmentally while smaller studies in lead-exposed workers have reported conflicting results on assessments of auditory function. Pure tone detection thresholds were determined in a group of monkeys (Macaca fascicularis) dosed with 2 mg/kg/day of lead from birth through testing at 13 years of age. Blood lead concentrations were stable at about 30 micrograms/dl until monkeys were 10-11 years of age at which time they increased to between 50 and 70 micrograms/dl. Five age- and rearing-matched monkeys served as controls. Detection thresholds were determined at six frequencies between 0.125 and 31.5 kHz. Ear phones were fit over both ears, and thresholds were determined for each ear separately. The monkey signaled detection of the tone by breaking contact with a stainless steel bar. Three lead-exposed monkeys exhibited normal pure tone detection functions. Three monkeys had thresholds outside of the control range at some frequencies; there was a tendency for higher frequencies to be differentially more affected. These findings are consistent with reports of elevated pure tone thresholds in humans exposed to lead developmentally, although the effect is smaller than might have been predicted given the concurrent blood lead concentrations of these monkeys.  相似文献   
4.
A novel guarded surface leakage test structure is used to isolate the surface and bulk leakage contributions to gate current in AlGaN/GaN HFETs. Passivation with various recipes of SiN/sub x/ always resulted in the commonly observed increase in gate leakage, which was found to be dominated by bulk leakage through the AlGaN. However, high temperature deposited SiN/sub x/ recipes gave a 1-2 orders reduction in surface leakage, whereas low temperature deposition gave an increase. Gate lag measurements were found to correlate closely with the surface leakage component, giving direct evidence that the key device problem of current slump is associated with current flow at the AlGaN surface.  相似文献   
5.
A high energy focused ion beam microprobe using a doublet arrangement of short magnetic quadrupole lenses was used to focus 1-3 MeV protons to spot sizes of 1x1 microm2 and 1-4.5 MeV carbon and silicon ion beams to spot sizes of 1.5x1.5 microm2. The results presented clearly demonstrate that this simple doublet configuration can provide high energy microbeams for microanalysis and microfabrication applications.  相似文献   
6.
A high-accuracy cryogenic radiometer has been developed at the National Institute of Standards and Technology to serve as a primary standard for optical power measurements. This instrument is an electrical-substitution radiometer that can be operated at cryogenic temperatures to achieve a relative standard uncertainty of 0.021% at an optical power level of 0.8 mW. The construction and operation of the high-accuracy cryogenic radiometer and the uncertainties in optical power measurements are detailed.  相似文献   
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A new method for evaluating antiarrhythmic drug efficacy   总被引:1,自引:0,他引:1  
To develop standards for distinguishing antiarrhythmic drug effect from spontaneous variability of premature ventricular complexes (PVCs), 21 males (mean age 56 +/- 8 years) with chronic ischemic heart disease and PVCs underwent symptom-limited treadmill exercise testing and 24-hour ambulatory monitoring before and after 2 weeks of placebo medication. Linear regression analysis was used to describe the relationship between baseline and placebo PVC frequency for various indexes of ventricular ectopic activity and to establish 95% and 99% one-tailed confidence intervals for this relationship within the group of 21 patients. The lower limit of baseline PVC frequency for which the procedure could distinguish a placebo from a true drug response, termed the "sensitivity threshold," was an average frequency of 2.2 PVCs/hour for ambulatory electrocardiographic monitoring and 1.2 PVCs/min for treadmill exercise testing. All patients exceeded the sensitivity threshold on baseline ambulatory ECGs, but only 38% of patients did so on baseline treadmill exercise tests. To establish antiarrhythmic efficacy with 95% confidence, the minimal percent reduction of PVCs between baseline and placebo visits was 68% for treadmill exercise testing and 65% for ambulatory electrocardiography. Although these standards were developed in patients with chronic ischemic heart disease, the model can be used to establish antiarrhythmic drug efficacy in any patient group.  相似文献   
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The performance analysis of packet switched networks usually does not account for the loss of transmission bandwidth caused by the switch processing time. In wide area networks, where transmission channels are of the order of 64 kbps or less, this is a valid approach since switch processing time is negligible compared to average transmission times for packets. However, in Local Area Networks (LANs), the transmission channels are usually of the order of 1 mbps or greater and thus when evaluating the performance of a LAN that is based on a packet switch, it is necessary to consider the effect of the switch processing time which is now comparable to that of the average packet's transmission time. This paper investigates the effect of this processing time on network performance, and an exhaustive cyclic queueing algorithm to minimise this effect on overall network performance is discussed. An approximate analytical technique for evaluating the performance of such a LAN is derived. This technique makes it possible to do interactive calculations which can be used in the provisioning and configuring of such networks.  相似文献   
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