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排序方式: 共有3472条查询结果,搜索用时 15 毫秒
991.
Smits RA Lim HD Stegink B Bakker RA de Esch IJ Leurs R 《Journal of medicinal chemistry》2006,49(15):4512-4516
A series of dibenzodiazepine derivatives was synthesized to probe the binding site of the recently discovered histamine H4 receptor (H4R). Optimization of the lead structure clozapine (2) resulted in (E)-7-chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine (7j), a potent H4R agonist (H4R, pKi = 7.6). Pharmacological data suggests that the series of nonimidazole compounds can be used to describe the orthosteric binding site of the H4R because both 2 and 7j displace [3H]histamine in a competitive manner. Furthermore, it is demonstrated that the effects of 7j are competitively antagonized by the selective H4R antagonist JNJ 7777120 (1), indicating considerable overlap of their binding sites. On the basis of the derived structure-activity relationships and additional pharmacological results, a pharmacophore model was constructed, which will be the premise for the design of novel H4R ligands. 相似文献
992.
Elkhuizen SG Limburg M Bakker PJ Klazinga NS 《International journal of health care quality assurance incorporating Leadership in health services》2006,19(6-7):477-499
PURPOSE: Business process redesign (BPR) is used to implement organizational transformations towards more customer-focused and cost-effective care. Ideally, these innovations should be carefully described and evaluated so that "best practices" can be re-applied. To investigate this, available evidence was collected on patient care redesign projects. DESIGN/METHODOLOGY/APPROACH: The Ebsco Business Source Premier, Embase and Medline databases were searched. Studies on innovations related to re-engineering patient care that used before-after design as minimum prerequisites were selected. General characteristics, logistic parameters and other outcome measures to determine the objectives and results and interventions used were looked at. FINDINGS: A total of 86 studies that conformed to the criteria were found: a minority mentioned measurable parameters in their objectives. In the majority of studies, multiple interventions were combined within single studies, making it impossible to compare the effects of individual interventions. Only three randomized controlled trials were found. Furthermore, inconsistencies were noted between the study objectives and the reported results. Many more issues were reported in the results than were mentioned in the study aims. It would appear that publications were hard to find owing to a lack of specific MeSH headings. Nearly 7,500 abstracts were scanned and from these it was concluded that clear and univocal research methods, terms and reporting guidelines are advisable and must be developed in order to learn and benefit from BPR innovations in health care organizations. ORIGINALITY/VALUE: This appears to be the first time available evidence about redesign projects in hospitals has been systematically collected and assessed. 相似文献
993.
van den Heuvel EG Wils D Pasman WJ Bakker M Saniez MH Kardinaal AF 《European journal of clinical nutrition》2004,58(7):1046-1055
OBJECTIVE: To determine the tolerance of increasing dosages of an incompletely hydrolysed and/or incompletely absorbed food dextrin coming from wheat starch, NUTRIOSE FB, at daily levels of 10 and 15 g up to 60 and 80 g, respectively. DESIGN: A randomized, double-blind, multiple dose, placebo-controlled, combined crossover and parallel trial. SETTING: The metabolic ward of TNO Nutrition and Food Research. SUBJECTS: A total of 20 healthy men (age 31.7 +/- 9.1 y; BMI 24.5 +/- 2.9 kg/m2). INTERVENTION: One group of 10 subjects consumed on top of their diet 10, 30 and 60 g of NUTRIOSE FB or maltodextrin (placebo) daily. The other group of 10 subjects consumed 15, 45 and 80 g daily. Each dose was consumed for 7 days. RESULTS: Compared with placebo, flatulence occurred more frequently over the last 6 days on 30, 60 or 80 g/day of NUTRIOSE FB (P < 0.05). During the last 24 h, that is, days 6-7, of 60 and 80 g/day of NUTRIOSE FB, the frequency of flatulence was even higher (P < 0.05). During the last 24 h on a daily dose of 60 g NUTRIOSE FB, the frequency of defecation decreased (P < 0.05). Bloating occurred more often during the last 24 h on 80 g/day of NUTRIOSE FB (P < 0.05). None of the doses of NUTRIOSE FB resulted in diarrhoea. Compared to baseline levels, breath H2 excretion, which was only measured after a week with 10 and 15 g of NUTRIOSE FB daily, increased (P < 0.05). However, no difference in area under the curve was found. CONCLUSIONS: NUTRIOSE FB is a fermentable carbohydrate and is well tolerated up to a dose of 45 g daily. Higher daily dosages (60 and 80 g) may result in flatulence, but does not result in diarrhoea. SPONSORSHIP: TNO Nutrition and Food Research was assigned by Roquette Frères to perform the study. 相似文献
994.
Bruysters M Pertz HH Teunissen A Bakker RA Gillard M Chatelain P Schunack W Timmerman H Leurs R 《European journal of pharmacology》2004,487(1-3):55-63
Histaprodifens constitute a new class of histamine H(1)-receptor agonists. These ligands can be regarded as hybrid molecules, consisting of a histamine moiety linked at the two-position of the imidazole ring by a propyl chain to two phenyl rings, one of the characteristic features of several H(1)-receptor antagonists. To delineate the binding site of various histaprodifen-like ligands, we generated mutant histamine H(1) receptors, in which various amino acids, involved in the binding of either histamine or H(1)-receptor antagonists, were replaced by alanine. Wild-type and mutant H(1) receptors were transiently expressed in African green monkey kidney cells (COS-7) and evaluated for their interaction with histamine and various histaprodifens by [(3)H]mepyramine radioligand-binding studies and by nuclear factor kappaB (NF-kappaB) reporter-gene assays. Our data show that, within the histamine H(1)-receptor binding pocket, histaprodifens interact with both agonist and antagonist binding sites, resulting in high affinity histamine H(1)-receptor agonists. 相似文献
995.
Koedoot CG Oort FJ de Haan RJ Bakker PJ de Graeff A de Haes JC 《European journal of cancer (Oxford, England : 1990)》2004,40(2):225-235
This study aimed to determine the content and the amount of information given by medical oncologists when proposing palliative chemotherapy and whether this information given is influenced by patient or physician background characteristics. In a prospective study, 95 patients with incurable cancer were interviewed before they consulted their medical oncologist. Their first consultation was audiotaped, and their eventual decision scored. A coding scheme comprised six categories of information given during the consultation. Medical oncologists mentioned or explained the disease course (53%), symptoms (35%) and prognosis (39%). Most patients were told about the absence of cure (84%). Watchful-waiting was mentioned to only half of the patients, either in one sentence (23%) or explained more extensively (27%). Multilevel analysis revealed that the patients' age, patient's marital status, and consulting in an academic hospital explained 38% of the amount of information given. Most of the physicians' attention is spent on the 'active' treatment option. Older patients, married patients and patients in academic hospitals receive more information. 相似文献
996.
997.
Pun SH Tack F Bellocq NC Cheng J Grubbs BH Jensen GS Davis ME Brewster M Janicot M Janssens B Floren W Bakker A 《Cancer biology & therapy》2004,3(7):641-650
Short nucleic acid sequences specific to oncogene targets such as bcl-2, bcr-abl, and c-myc have been shown to exhibit specific anti-cancer activity in vitro through antigene or antisense activity. Efficient in vivo delivery of oligonucleotides remains a major limitation for the therapeutic application of these molecules. We report herein on the preparation of transferrin-modified nanoparticles containing DNAzymes (short catalytic single-stranded DNA molecules) for tumor targeting as well as their biodistribution using various methods of administration in the mouse. Linear, beta-cyclodextrin-based polymers are complexed with DNAyzme molecules to form sub-50 nm particles termed "polyplexes". The surface properties of the cyclodextrin-containing polyplexes are modified by exploiting the ability of the beta-cyclodextrin substructure and adamantane to form inclusion complexes. Accordingly, conjugates of adamantane with poly(ethylene glycol) (PEG) are prepared and combined with the polyplexes. The adamantane form inclusion complexes with the surface cyclodextrins of the polyplexes to provide a sterically stabilizing layer of PEG. The stabilized polyplexes are also modified with transferrin for increasing targeting to tumor cells expressing transferrin receptors. The preparation, characterization, and in vitro application of these nanoparticles are discussed. The transferrin-polyplexes containing fluorescently-labeled DNAzyme molecules are administered to tumor-bearing nude mice and their biodistribution and clearance kinetics are monitored using a fluorescence imaging system. Four methods of administration are studied: intraperitoneal bolus and infusion, intravenous bolus, and subcutaneous injection. DNAzymes packaged in polyplex formulations are concentrated and retained in tumor tissue and other organs, whereas unformulated DNAzyme is eliminated from the body within 24 hours post-injection. Intravenous and intraperitoneal bolus injections result in the highest fluorescent signal (DNAzyme) at the tumor site. Tumor cell uptake is observed with intravenous bolus injection only, and intracellular delivery requires transferrin targeting. 相似文献
998.
Nijsen JF Seppenwoolde JH Havenith T Bos C Bakker CJ van het Schip AD 《Radiology》2004,231(2):491-499
PURPOSE: To investigate the use of magnetic resonance (MR) imaging in the administration and biodistribution of holmium-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) in liver tumors. MATERIALS AND METHODS: MR imaging measurements were obtained in phantoms, three ex vivo rabbit livers, and four livers in living rabbits. When applicable, measurements were compared with those on scintigraphic images. The transverse relaxivity R2* of the Ho-PLLA-MS was determined in a phantom study. The in vivo animal experiments were performed by using rabbits with an implanted VX2 tumor. Detection of passing Ho-PLLA-MS to estimate lung shunting was performed in a scaled model of the vena cava. RESULTS: In the ex vivo liver experiments, the feasibility of real-time MR imaging during administration of microspheres was demonstrated. The in vivo rabbit experiments demonstrated that MR imaging can depict radioactive, nonradioactive, and decayed Ho-PLLA-MS after treatment for as long as they remain in the body. Furthermore, this study showed the ability of dynamic MR imaging to detect single doses of passing Ho-PLLA-MS. CONCLUSION: Ho-PLLA-MS used for internal radionuclide therapy can be imaged clearly in vivo with MR imaging. 相似文献
999.
1000.
Since the cloning of the histamine H(3) receptor cDNA in 1999 by Lovenberg and co-workers, this histamine receptor has gained the interest of many pharmaceutical companies as a potential drug target for the treatment of various important disorders, including obesity, attention-deficit hyperactivity disorder, Alzheimer's disease, schizophrenia, as well as for myocardial ischaemia, migraine and inflammatory diseases. Here, we discuss relevant information on this target protein and describe the development of various H(3) receptor agonists and antagonists, and their effects in preclinical animal models. 相似文献