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151.
BACKGROUND: A catheter-based approach for local endovascular drug delivery has been developed. The catheter is deployed percutaneously, while the end of the catheter is in the form of a helix that is placed just proximal to the vascular site to be treated. The helices are in contact with the vessel wall. A number of small holes is drilled in the coils of the catheter through which drug is infused, so that the infused drug remains within the blood fluid 'boundary layer' adjacent to the vessel wall. This approach is expected to be highly efficient for administration of antithrombotic and antiproliferative agents that target processes leading to vascular occlusion, heart attacks, and strokes. METHODS: The helical catheter was qualitatively evaluated using optical dye density measurements of Evans blue dye infused using an in vitro steady flow system under a physiologic range of conditions. To further demonstrate the efficiency of the technique, its capacity to inhibit thrombosis was evaluated in a baboon thrombosis model. The catheter was inserted into a femoral arteriovenous shunt (blood flow rate = 100 ml/min) and placed proximal to a segment of highly thrombogenic Dacron vascular graft (4.0 mm i.d.). Integrelin (an inhibitor of platelet glycoprotein IIb/IIIa; doses: 0.25-1.0 microg/min) and hirudin (an antithrombin; doses: 10-100 microg/min) were used to inhibit thrombus formation. RESULTS: Experimental flow visualization studies demonstrated that high concentrations of the infused Evans blue dye were retained near the vessel wall. In the animal experiments, platelet deposition on the Dacron graft surface was reduced by 82-97% (Integrelin) and 68-92% (hirudin) over 1-2 h of blood exposure. The local antithrombotic effects produced were found to be 200-fold and 30-fold more efficient than systemic administration of the same agents. CONCLUSIONS: Local drug infusion using the helical catheter approach can achieve high drug concentration levels at target sites, may avoid systemic effects, and can reduce cost of therapy by reducing total drug requirements. 相似文献
152.
Bioassay-directed fractionation of an EtOH extract of Curcuma zedoaria led to isolation of an active curcuminoid, which was identified as demethoxycurcumin (2) by comparison of its 1H and 13C NMR spectra with literature data and by direct comparison with synthetic material. Curcumin (1) and bisdemethoxycurcumin (3) were also obtained. Curcuminoids (1-3) were synthesized and demonstrated to be cytotoxic against human ovarian cancer OVCAR-3 cells. The observed CD50 values of 1, 2, and 3 were 4.4, 3.8, and 3.1 microg/mL, respectively. Three additional novel compounds, 3, 7-dimethylindan-5-carboxylic acid (4), curcolonol (5), and guaidiol (6), were also isolated from the EtOH extract. The structures and relative stereochemistry of 4-6 were determined by spectroscopic methods and X-ray crystallographic analysis. 相似文献
153.
MV Nogués M Moussaoui E Boix M Vilanova M Ribó CM Cuchillo 《Canadian Metallurgical Quarterly》1998,54(8):766-774
The enzymatic catalysis of polymeric substrates such as proteins, polysaccharides or nucleic acids requires precise alignment between the enzyme and the substrate regions flanking the region occupying the active site. In the case of ribonucleases, enzyme-substrate binding may be directed by electrostatic interactions between the phosphate groups of the RNA molecule and basic amino acid residues on the enzyme. Specific interactions between the nitrogenated bases and particular amino acids in the active site or adjacent positions may also take place. The substrate-binding subsites of ribonuclease A have been characterized by structural and kinetic studies. In addition to the active site (p1), the role of other noncatalytic phosphate-binding subsites in the correct alignment of the polymeric substrate has been proposed. p2 and p0 have been described as phosphate-binding subsites that bind the phosphate group adjacent to the 3' side and 5' side, respectively, of the phosphate in the active site. In both cases, basic amino acids (Lys-7 and Arg-10 in p2, and Lys-66 in p0) are involved in binding. However, these binding sites play different roles in the catalytic process of ribonuclease A. The electrostatic interactions in p2 are important both in catalysis and in the endonuclease activity of the enzyme, whilst the p0 electrostatic interaction contributes only to binding of the RNA. 相似文献
154.
BACKGROUND & AIMS: Intestinal smooth muscle cells (ISMCs) express major histocompatibility complex II (MCH II) and intercellular adhesion molecule 1 (ICAM-1) after exposure to interferon gamma (IFN-gamma). T lymphocytes invade the intestinal musculature during Crohn's disease or pseudoobstruction. The aim of this study was to determine whether ISMCs activate syngeneic T cells via MHC II and ICAM-1. METHODS: Cultured murine ISMCs were exposed to IFN-gamma for 72 hours and analyzed for Mac-1 (CD11B CD18) antigen, MHC II, and ICAM-1 expression using enzyme-linked immunosorbent assay and fluorescence-activated cell sorter scan. T lymphocytes from mesenteric lymph nodes of ovalbumin-sensitized mice were examined for their ability to proliferate after coculture with IFN-gamma-pretreated and ovalbumin-pretreated ISMCs using [3H]thymidine incorporation. RESULTS: ISMCs expressed smooth muscle alpha-actin before and after IFN-gamma exposure. No macrophages were identified in these cultures. Exposure to IFN-gamma and ovalbumin for 72 hours induced MHC II and ICAM-1 expression; these treated ISMCs induced T-cell proliferation, whereas untreated ISMCs did not. T-cell proliferation was markedly enhanced by adding interleukin 2 and was blocked by antibodies against MHC II and ICAM-1. CONCLUSIONS: ISMCs activate T lymphocytes in an MHC II-linked manner and thus possess the ability to modulate immune function in the gut. 相似文献
155.
We examined whether timeline icons improved older and younger adults' comprehension of medication information. In Experiment 1, comprehension of instructions with the icon (icon/text format) and without the icon (text-only format) was assessed by questions about information that was (a) implicit in the text but depicted explicitly by the icon (total dose in a 24 hour period), (b) stated and depicted in the icon/text condition (medication dose and times), and (c) stated but not depicted by the icon (e.g., side effects). In a separate task, participants also recalled medication instructions (with or without the icon) after a study period. We found that questions about dose and time information were answered more quickly and accurately when the icon was present in the instructions. Notably, icon benefits were greater for information that was implicit rather than stated in the text. This finding suggests that icons can improve older and younger adults' comprehension by reducing the need to draw some inferences. The icon also reduced effective study time (study time per item recalled). In Experiment 2, icon benefits did not occur for a less integrated version of the timeline icon that, like the text, required participants to integrate dose and time information in order to identify the total daily dose. The integrated version of the icon again improved comprehension, as in Experiment 1, as well as drawing inferences from memory. These findings show that integrated timeline icons improved comprehension primarily by aiding the integration of dose and time information. These findings are discussed in terms of a situation model approach to comprehension. 相似文献
156.
TH Lee RR Stromberg JW Heitman L Sawyer CV Hanson MP Busch 《Canadian Metallurgical Quarterly》1998,38(6):580-588
BACKGROUND: Although inactivation of enveloped viruses transmitted by plasma derivatives has been successful, no methods for virus inactivation or removal have been established for platelet concentrates or red cell (RBC) components. Relatively little is known regarding the extent or significance of virus interactions with the cellular constituents in these components. STUDY DESIGN AND METHODS: Units of whole blood were collected from six HIV type 1 (HIV-1)-positive, asymptomatic individuals and separated into peripheral blood mononuclear cells (PBMNCs), cell-free plasma, white cell-reduced platelet concentrate, and white cell-reduced RBCs. DNA and RNA polymerase chain reaction and virus culture methods were used to study the compartmentalization of HIV-1 immediately after component preparation and after storage. RESULTS: As expected, HIV DNA and infectious virus were detected in fresh blood and in PBMNCs, and virion-associated RNA was detected in fresh plasma from all six donors. The levels of viral nucleic acids in these preparations remained relatively stable with 4 degrees C storage, whereas infectivity of PBMNCs was rapidly lost. Washed RBCs tested negative for HIV in all assays at all time points. Platelets retained high levels of HIV RNA (but not infectivity) after extensive washing, as well as after storage at 4 and 22 degrees C. High-level platelet-associated HIV-1 was also demonstrated in samples collected during early seroconversion. Periseroconversion and postseroconversion levels of platelet-associated HIV-1 correlated with the level of plasma viremia and with the rate of progression to AIDS. Cell-free virus from donor plasma and tissue culture fluid rapidly and firmly attached to platelets from noninfected donors. Infectivity of tissue culture virus bound to platelets was demonstrated in vitro. CONCLUSION: Significant levels of HIV-1 are associated with platelets during all stages of infection. Platelet-associated HIV could either mediate virus clearance or facilitate virus dissemination and expanded tropism. Finally, virus inactivation research must address virus associations with platelets. 相似文献
157.
Breast cancer is one of the most common forms of cancer observed in women, and endogenous estrogen is thought to play a major role in its development. Because of this, any conditions or exposures which enhance estrogenic responses would result in an increased risk for breast cancer. The role of xenoestrogenic compounds, such as DDT, in the etiology of breast cancer is still very controversial. In the following paper we discuss recently-published observations by ourselves and others which indicate that xenoestrogens may play a significant role in the development of breast cancer. Specifically, we hypothesize that during periods of high growth rates and during breast development the sensitivity of breast cells to estrogenic compounds is sufficiently great for xenoestrogens to significantly enhance risk for breast cancer. 相似文献
158.
BACKGROUND AND PURPOSE: A diagnosis of cancer is a contraindication for the use of therapeutic ultrasound (US). Continuous US applied to murine tumors has resulted in larger and heavier tumors compared with controls. We compared tumor growth using low-power continuous US and energy-matched pulsed US. SUBJECTS: Female C57BL/6 mice (N = 174) were used. METHODS: Animals received subcutaneous injections of methylcholanthrene tumor cells. The mice were randomly divided into three groups: 60 mice that received low-power continuous US for 5 minutes at 0.75 W/cm2 (LC US group), 63 mice that received pulsed US for 12.5 minutes at 1.5 W/cm2 (pulsed US group), and 51 mice that served as a control group. The LC and pulsed US groups received equal US energy. Both experimental groups received 10 treatments of 3-MHz US, which was applied directly over the tumor. The control group received identical handling but no US. After treatment, the tumors were excised, weighed, and measured. A one-way analysis of variance, followed by Newman-Keuls post hoc testing, was used to analyze the data. RESULTS: Mean tumor weights (in grams) and volumes (in cubic millimeters) were 0.563 g and 564 mm3 for the LC US group, 0.560 g and 525 mm3 for the pulsed US group, and 0.516 g and 406 mm3 for the control group. CONCLUSION AND DISCUSSION: Reducing total US energy will result in less growth of murine tumors. When infusing equal energy, continuous and pulsed US will produce similar effects on tumor growth. 相似文献
159.
CM Lessells 《Canadian Metallurgical Quarterly》1998,56(2):395-407
Strong anion-exchange (SAX) chromatography and reversed-phase liquid chromatography (RPLC) followed by different mass spectrometric techniques for the separation and identification of conjugated and unconjugated 14C-labelled eltanolone (5beta-Pregnan-3alpha-ol-20-one) metabolites in biological fluids are presented. Conjugates of estradiol were used as model compounds for the development of a SAX based group separation of neutral steroids, glucuronides, sulfates and di-conjugated steroids. The usefulness of the technique is demonstrated by the analysis of 14C-labelled eltanolone metabolites in dog urine. The analytical SAX column used prior to RPLC improved the capacity to separate the metabolites from each other and from endogenous components, compared to a single reversed-phase system. Liquid chromatography negative ion electrospray-mass spectrometry (LC-ESI-MS) was used for the molecular mass determination of conjugated eltanolone metabolites. Unconjugated metabolites and hydrolysed conjugates were identified using gas chromatography-mass spectrometry with an electron impact ion source (GC-MS) after trimethylsilyl (TMS) derivatization. An unexpected finding in dog urine was the diglucuronide formation of eltanolone (presumably after enolisation of its carbonyl group). 相似文献
160.
JB Thomas SW Mascarella RB Rothman JS Partilla H Xu KB McCullough CM Dersch BE Cantrell DM Zimmerman FI Carroll 《Canadian Metallurgical Quarterly》1998,41(11):1980-1990
A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [35S]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor. 相似文献