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91.
Michael Krause Agns Rouleau Holger Stark Peter Luger Monique Garbarg Jean-Charles Schwartz Walter Schunack 《Archiv der Pharmazie》1996,329(4):209-215
The therapeutic value of histamine H3-receptor ligands is under current investigation. On the basis of recently described diaryl imine prodrugs of the histamine H3-receptor agonist (R)-α-methyl-histamine ( 1 ) a series of new azomethine prodrugs containing five- and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vitro activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five-membered heterocycles appeared to be highly effective for the CNS delivery of 1 , and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino](1H-pyrrol-2-yl)methyl]phenol ( 8c ), the 2-furanyl analogue 8d , and its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a ‘retard’ prodrug. Assuming that a therapeutic indication of histamine H3-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use. 相似文献
92.
93.
Introns and gene evolution 总被引:5,自引:0,他引:5
Sandro J. de Souza Manyuan Long & Walter Gilbert 《Genes to cells : devoted to molecular & cellular mechanisms》1996,1(6):493-505
In one scenario of gene evolution, exon shuffling has a fundamental role in increasing gene diversity. As DNA sequences accumulate in the databases, the picture of the intron/exon structures of genes becomes more and more clear. We discuss in this review some features of this picture that suggest that introns have been present since the early stages of evolution, and that exon shuffling was a fundamental process in the construction of ancient as well as modern genes. 相似文献
94.
Summary The effect of the complement-derived polypeptide C3adesArg as a mediator of inflammation in the central nervous system was examined. Twenty-five anesthetized cats received 4 mg of this polypeptide by intraventricular injection, 20 cats who served as controls received saline. Cerebrospinal fluid (CSF) was sampled 3 h after intraventricular injection and the brains were removed. For assessment of the permeability of the blood-brain barrier the CSF penetration of four antibiotics, which were given intravenously, was measured. Five control animals were employed for each antibiotic (tobramycin, ampicillin, imipenem, fosfomycin), whereas six C3adesArg-treated animals were used for each antibiotic and seven for tobramycin. Besides CSF levels of glucose, the prostanoids 6-keto-prostaglandin F1, thromboxane B2 and prostaglandin E2 were measured. The morphological examinations in the CSF sediments and histological brain sections in the C3adesArg-treated animals disclosed a distinct inflammation with leptomeningeal and perivascular infiltration of polymorphonuclear granulocytes compared to normal findings in the controls. The CSF/serum ratios of all of the antibiotics were markedly elevated compared to controls, indicating a blood-brain barrier disruption. The levels of all prostanoids were significantly higher in the treatment group than in the control group, whereas the glucose levels were lower. These findings are in accordance with a granulocytic meningitis as seen in some infections at the acute stage. It is concluded that C3adesArg acts as a mediator of inflammation in the central nervous system. 相似文献
95.
Heinz Schurawitzki M.D. Paul C. Hajek Josef Kramer Florian Grabenwöger Walter Klepetko Anton Moritz 《Cardiovascular and interventional radiology》1989,12(1):10-13
In a radiologic search for embolized leaflets of Edwards-Duromedics bileaflet valves in 2 patients, the embolized fragments were localized in the iliac vessels using computed tomography. Sonography was successful in one case and standard X-ray films of the abdomen were negative in both cases.In vitro investigations with Björk-Shiley and Edwards-Duromedics leaflets suggested that standard X-ray films of the abdomen and pelvis should be considered as the first investigational technique. If negative, computed tomography of the lower abdomen should be done. 相似文献
96.
Cardiovascular risk factor prevention in black schoolchildren: two-year results of the "Know Your Body" program 总被引:2,自引:0,他引:2
P J Bush A E Zuckerman P K Theiss V S Taggart C Horowitz M J Sheridan H J Walter 《American journal of epidemiology》1989,129(3):466-482
A five-year intervention study of the effectiveness of the "Know Your Body" program in reducing coronary heart disease risk factors among black students in the District of Columbia, who were in grades 4-6 at baseline, was begun in 1983. Nine schools were stratified on socioeconomic status and randomly assigned to control and intervention groups. The "Know Your Body" curriculum focuses on nutrition, fitness, and the prevention of cigarette smoking. At baseline, 1,234 students were eligible for the screening in which the following target risk factors were measured: systolic and diastolic blood pressures, ponderosity index, triceps skinfold thickness, postexercise pulse recovery rate, serum total and high density lipoprotein (HDL) cholesterol, and serum thiocyanate. After two years of intervention, results indicated that the program may have had a favorable impact on the following risk factors: systolic and diastolic pressures, HDL cholesterol, ratio of total to HDL cholesterol, fitness (postexercise pulse recovery rate), and smoking. Significant net changes in the favorable direction also were found for health knowledge and attitude toward smoking. Blood pressure reduction was associated with decreased ponderosity and improved fitness, and increased HDL cholesterol was associated with decreased ponderosity. These results are consistent with other evaluations of the "Know Your Body" program, suggesting that the program may be effective in reducing chronic disease risk in diverse school populations. 相似文献
97.
Famotidine and selected H2-antagonists were evaluated with respect to toxicity and selected pharmacological activities. When administered intraperitoneally to mice at a dose equivalent to 10 times their respective H2-antagonist ED50 values, no deaths were observed. Similarly, no alteration in brain ACh concentrations or overt pharmacological effects were noted. However, at 400 mg/kg, ranitidine produced 89% lethality, followed by cimetidine (11%) and famotidine. Only cimetidine and famotidine at this dose significantly elevated brain acetylcholine levels. These results do not correlate with the in vitro data, where ORF-17578 and ranitidine were the most potent entities with respect to acetylcholinesterase inhibition (1–2 × 10–6
M), followed by nizatidine > cimetidine > famotidine. The sulfoxide metabolites of ranitidine and cimetidine were approximately one-tenth as potent as their parent compounds with respect to inhibition of acetylcholinesterase. Direct muscarinic stimulation or potentiation of acetylcholine-induced contraction in ileal tissue was not observed for any of the H2-antagonists. 相似文献
98.
Localization of SNARE proteins and secretory organelle proteins in astrocytes in vitro and in situ 总被引:1,自引:0,他引:1
Wilhelm A Volknandt W Langer D Nolte C Kettenmann H Zimmermann H 《Neuroscience research》2004,48(3):249-257
Astrocytes are capable of regulated release of messenger molecules. Astrocytes cultured from new born rodent brain express a variety of classical presynaptic proteins. We investigated the question whether the capability to express synaptic proteins in culture was a feature only of immature astrocytes, and whether these proteins were also expressed by astrocytes in situ. Experiments were performed with transgenic mice expressing the enhanced green fluorescent protein under the control of the human glial fibrillary acidic protein promoter. Using double fluorescence and astrocytes cultured from 1 to 16 day-old animals we show that the astrocytic expression of synaptic proteins in culture is invariant of the age of donor animals. Culturing can induce the astrocytic expression of specific synaptic proteins such as SV2, synaptophysin and SNAP-25. Astrocytes in brain sections of 1-16 day-old animals revealed a punctuate immunofluorescence for secretory carrier membrane protein (SCAMP), SNAP-23, synaptobrevin II, and cellubrevin, to a minor extent for SNAP-25 and synaptophysin, and none for SV2. Our results demonstrate that cultured astrocytes express synaptic proteins not present in situ. Nevertheless, astrocytic organelles in situ are equipped with molecules that could be involved in regulated exocytosis of messenger substances. 相似文献
99.
The Modality Specificity of the Slow Negative Wave 总被引:1,自引:0,他引:1
Event-related potentials were recorded in a simple reaction time task using a 3-sec interval between S1 and S2. The sensory modalities of S1 and S2 were varied across 4 conditions to yield all possible combinations of tones and flashes. A negative component which peaked between 600 and 800 msec after S1 was specific in scalp distribution to the modality of S1 but not S2. It was concluded that this negative component is a response to S1 and not related to processes associated with anticipation of S2. A slow negative shift which peaked at S2 was largest at the vertex in all conditions, suggesting its motor origin. A trend for the latter activity to be more negative in posterior recordings when S2 was visual than auditory leaves open the possibility that the terminal CNV is a combination of motor activities and anticipation of the sensory modality of S2. 相似文献
100.
Summary A simple organ culture method for culturing embryonic skin was developed. A piece of skin with a part of the neural tube from mouse embryo (11 to 12 d) was placed on a 25 mm d membrane filter. The filter was folded to wrap the explant and inserted into glass tubing. The explant and filter in the glass tubing were placed in a rotating tissue culture tube containing 5 ml culture medium (Ham's F12 supplemented with 15 to 20% fetal bovine serum) and filled with a mixture of 95% air:5% CO2. In explants cultured for 6 d fully differentiated melanocytes were observed in the epidermis. 相似文献