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The affinities of the (+) and (-) enantiomers of the antimuscarinic benzothiazepinone derivative, cis-2,3-dihydro-3-(4-methyl-1-piperazinylmethyl)-2-phenyl-1,5-benzoth iazepin-4 (5H)-one (BTM-1041 and BTM-1086), for muscarinic receptor subtypes, histamine H1-receptors and alpha 1-adrenoceptors were determined in vitro using isolated organs: field-stimulated rabbit vas deferens (M1-receptors), guinea-pig left atrium (M2-receptors), guinea-pig ileum (M3- and histamine H1-receptors) and rat vas deferens (alpha 1-adrenoceptors). We also assessed the binding profile of BTM-1041 and BTM-1086 at muscarinic receptor subtypes in guinea-pig cortex (M1), heart (M2) and salivary glands (M3) as well as at alpha 1-adrenoceptors in rat cerebral cortex. Functional and binding experiments showed that the (-) enantiomer (BTM-1086) had a high affinity (pA2 = 7.98-8.81; pKi = 8.31-9.15) for the three muscarinic receptor subtypes, whereas the (+) enantiomer (BTM-1041) showed a low antimuscarinic potency (pA2 = 4.87-5.31; pKi = 4.85-5.55). This results in an extremely high stereoselectivity for these optical isomers [-)/(+) ratios = 1023 to 6918). The affinity of the (-) enantiomer BTM-1086 was lower for both histamine H1- and alpha 1-receptors than for muscarinic receptors, whereas the reverse was true for the (+) enantiomer, BTM-1041. Thus, the stereochemical demands for the two optical isomers were most stringent at muscarinic receptors but were inverse and less pronounced at histamine H1- and alpha 1-receptors (stereoselectivity ratios = 0.16-0.22). 相似文献
3.
The purpose of this paper is to review our experience in the management of penetrating chest injuries and their outcome in spite of the shortage of equipment for thoracic surgery at the Gonder Hospital. The study was based on prospective analysis of 32 cases treated at this hospital between February 1987 and February 1988. About 30% of our cases has associated injuries to other organs. Simple pleural space drainage was done in 19 cases. Only 4 of the patients required immediate or delayed thoracotomy while 3 other cases required laparotomy. Complications occurred in 8 patients, of whom 6 died. In 6 cases only conservative treatment was indicated. About 80% of our patients with penetrating chest chest injuries were treated successfully with no, or only minimal, residual defects. Availability of of simple and effective materials in rural hospitals is recommended. 相似文献
4.
The internal sphincter in anorectal malformations: morphologic investigations in neonatal pigs 总被引:5,自引:0,他引:5
The knowledge of sphincter anatomy in anorectal malformations is still inadequate and contradictory. Therefore, morphologic investigations were carried out in 33 neonatal piglets with congenital anal atresias. Of the 24 male animals 12 had high anomalies with a rectourethral fistula. The remaining 12 piglets had low anomalies; in nine cases we were able to demonstrate an anocutaneous fistula. Of the nine female animals, six had high anomalies with a rectovaginal fistula. The three female piglets with low anomalies had an anovestibular or an anocutaneous fistula. In all animals we could demonstrate a normal internal sphincter, which surrounded the proximal part of the fistulae. The position of the internal sphincter therefore depended on the localization of the fistula orifice into the rectal pouch. This differed greatly. The form of the internal sphincter also differed greatly. Sometimes the muscle had the form of a tube or an acute-angled funnel as in healthy piglets. However, mostly the internal sphincter was spread out wide and had the form of a disc or a flat dish. The proximal region of the fistulae in anal atresias has most features of a normal anal opening: (1) it is surrounded by an internal sphincter, (2) the rectal pouch in the region of the internal sphincter as well as the fistulae are hypoganglionotic, (3) the proximal fistula region is lined by transitional epithelium, and (4) it contains anal glands. We, therefore, consider that the fistula should be designated as an ectopic anal canal. The most important result was the demonstration of a normal internal sphincter even in high and intermediate anomalies of anal atresias.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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Selective antagonists provide evidence that M1 muscarinic receptors may mediate carbachol-induced drinking in the rat 总被引:1,自引:0,他引:1
C Polidori M Massi G Lambrecht E Mutschler R Tacke C Melchiorre 《European journal of pharmacology》1990,179(1-2):159-165
The present study served to investigate the ability of seven selective muscarinic antagonists to inhibit carbachol-induced drinking in the rat. The muscarinic antagonists were given by intracerebroventricular (i.c.v.) injection 1 min before the i.c.v. injection of carbachol (1 microgram/rat). The M2 antagonist, methoctramine, was inactive up to 80.3 nmol/rat. The M3 antagonist, p-fluoro-hexahydro-sila-difenidol, elicited a modest (42%) but statistically significant inhibition of drinking only at 80 nmol/rat. On the other hand, the selective M1 antagonists, (R)-trihexphenidyl, o-methoxy-sila-hexocyclium and pirenzepine, produced a marked and dose-dependent inhibition of carbachol-induced drinking, their ID50 values being 0.51, 7.36 and 9.31 nmol/rat. Also the M1/M3 antagonists, 4-diphenylacetoxy-N-methylpiperidine methiodide and hexahydro-sila-difenidol, were potent inhibitors of carbachol-induced drinking, their ID50 values (0.28 and 11.09 nmol/rat) being related to their pA2 values for M1 receptors in rabbit vas deferens. These data suggest that carbachol-induced drinking may be mediated by activation of muscarinic M1 receptors. 相似文献
7.
Fabienne Rauw Bénédicte Lambrecht Achille Fran?ois Patrick Langlois Thierry van den Berg 《Journal of interferon & cytokine research》2007,27(2):111-118
In this study, a replicative fowl adenovirus serotype 1 (CELO) recombinant expressing chicken interferon-gamma (ChIFN-gamma) was constructed. In the engineered recombinant, the ChIFN-gamma gene was placed under the control of cytomegalovirus (CMV) promoter. The ChIFN-gamma expression cassette was inserted in the right end of the CELO genome (D fragment), which was able to carry the largest insertion of foreign DNA without affecting the replication functions of the vector. The recombinant ChIFN-gamma (rChIFN-gamma) produced in the CELO-virus expression system was characterized by comparing its biologic activities with that of rChIFN-gamma produced via the baculovirus expression system (Bac-ChIFN-gamma). CELO-ChIFN-gamma inhibited the replication of cytolytic virus in chicken embryo fibroblasts (CEFs) and activated macrophages in a better manner than did Bac-ChIFN-gamma . Moreover, the in vitro and in vivo stability of the CELO-derived rChIFN-gamma was considerably higher than that of the Bac-ChIFN-gamma. The CELO-ChIFN-gamma recombinant vector was able to replicate in vitro in the loghorn male hepatoma (LMH) hepatocyte cell line and to produce detectable levels of recombinant cytokine in supernatant as early as 90 min post-infection. Therefore, the CELO-virus expression system is an appropriate system for high-level expression of biologically active and stable ChIFN-gamma. 相似文献
8.
Effect of ozone exposure on allergic sensitization and airway inflammation induced by dendritic cells 总被引:2,自引:0,他引:2
P. O. Depuydt B. N. Lambrecht G. F. Joos R. A. Pauwels 《Clinical and experimental allergy》2002,32(3):391-396
BACKGROUND: Epidemiological studies suggest that ozone exposure is related to increased asthma symptoms. Dendritic cells (DCs) are the principal antigen-presenting cells in the airways. OBJECTIVE: We have examined whether ambient doses of ozone (100 ppb for 2 h) enhance allergic sensitization and/or airway inflammation in a mouse model. METHODS: C57BL/6 mice were sensitized to inhaled ovalbumin (OVA) by intratracheal instillation of OVA-pulsed DCs on day 0. Daily exposure to OVA aerosol on days 14-20 resulted in an eosinophilic airway inflammation, as reflected in bronchoalveolar lavage fluid and lung histology. In a first experiment, mice were exposed to ozone or room air immediately prior to and following sensitization. Subsequently, we tested the effect of ozone exposure during antigen challenge in DC-sensitized mice. RESULTS: Exposure to ozone during sensitization did not influence airway inflammation after subsequent allergen challenge. In contrast, in sensitized mice, challenge with OVA together with ozone (days 14-20) resulted in enhanced airway eosinophilia and lymphocytosis, as compared with mice exposed to OVA and room air (1.91 x 106 +/- 0.46 x 106 vs. 0.16 x 106 +/- 0.06 x 106 eosinophils/mL lavage fluid; P = 0.015; 0.49 x 106 +/- 0.11 x 106 vs. 0.08 x 106 +/- 0.03 x 106 lymphocytes/mL lavage fluid; P = 0.004). Ozone exposure without subsequent OVA exposure did not cause airway inflammation. CONCLUSION: Ozone exposure does not increase allergic sensitization but enhances antigen-induced airway inflammation in mice that are sensitized via the airways. 相似文献
9.
Adenoviral vectors expressing siRNAs for discovery and validation of gene function 总被引:5,自引:0,他引:5 下载免费PDF全文
Arts GJ Langemeijer E Tissingh R Ma L Pavliska H Dokic K Dooijes R Mesić E Clasen R Michiels F van der Schueren J Lambrecht M Herman S Brys R Thys K Hoffmann M Tomme P van Es H 《Genome research》2003,13(10):2325-2332
RNA interference is a powerful tool for studying gene function and for drug target discovery in diverse organisms and cell types. In mammalian systems, small interfering RNAs (siRNAs), or DNA plasmids expressing these siRNAs, have been used to down-modulate gene expression. However, inefficient transfection protocols, in particular, for primary cell types, have hampered the use of these tools in disease-relevant cellular assays. To be able to use this technology for genome-wide function screening, a more robust transduction protocol, resulting in a longer duration of the knock-down effect, is required. Here, we describe the validation of adenoviral vectors that express hairpin RNAs that are further processed to siRNAs. Infection of cell lines, or primary human cells, with these viruses leads to an efficient, sequence-specific, and prolonged reduction of the corresponding target mRNA, resulting in a reduction of the encoded protein level in the cell. For knock-down of one of the targets, GalphaS, we have measured inhibition of ligand-dependent, G-protein-coupled signaling. It is expected that this technology will prove to be of great value in target validation and target discovery efforts. 相似文献
10.
Charles R. Kiefer James B. McKenney Jane F. Trainor Richard W. Lambrecht Herbert L. Bonkovsky Lawrence M. Lifshitz C. Robert Valeri L. Michael Snyder 《The American journal of pathology》1998,153(3):703-708
To further the understanding of oxidative effects on inflammation injury to muscle fiber structure, fluorescent imaging analysis of human striated muscle tissues from a variety of inflammatory or postinflammatory etiologies was undertaken in a search for accumulated coproporphyrin, a red autofluorescent byproduct of heme biosynthesis that would theoretically be formed under oxidative insult. Using a differential excitation method of in situ analysis, porphyrin autofluorescence was detected in intact fibers within the context of the yellow autofluorescent subsarcolemmal lipofuscin granules. Relative measurements of porphyrin concentration in the granules from different patients indicated that the acute/subacute inflammatory specimens grouped significantly higher than the more chronic inflammatory and nonpathological specimens. Myoglobin was also found to be associated with the granules. Myoglobin heme iron could potentially serve as a Fenton reagent for the intracellular generation of hydroxyl radicals, which are responsible for the oxidation of the porphyrinogens. High-performance liquid chromatography analysis of extracted dense particles revealed coproporphyrin as the sole porphyrin present. The observation of coproporphyrin within lipofuscin granules, previously unreported, suggests that lipofuscin accumulation in striated muscle may begin under conditions of acute oxidative stress, as marked by the oxidation of extramitochondrial porphyrinogens that are immediately incorporated into the granules. 相似文献