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排序方式: 共有322条查询结果,搜索用时 15 毫秒
1.
Stijnen Annemiek M. Hovinga Suzanne Langemeijer Mariska W. E. Hoogerkamp Arendien van Bezooijen Cornells F. A. Danhof Meindert 《Pharmaceutical research》1993,10(7):1046-1051
The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.5 mg/min/kg. The infusion was terminated when the anticonvulsant effect intensity had reached the maximum attainable level or at a total infusion time of three hours. A nonlinear relationship between valproate concentration and anticonvulsant effect intensity was observed with no maximal effect in the concentration range up to 1200 mg · L–1. With increasing age a parallel shift in the concentration versus anticonvulsant effect relationships toward lower concentrations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.Suzanne Hovinga: Deceased January 30, 1991. 相似文献
2.
Joost B. M. M. van Bree Anne V. Baljet Anton van Geyt Albertus G. de Boer Meindert Danhof Douwe D. Breimer 《Journal of pharmacokinetics and pharmacodynamics》1989,17(4):441-462
The unit impulse response theory has been adapted to characterize the transport profile of drugs into the central nervous system (CNS). From the obtained input function, the cumulative plasma volume (V) cleared by transport into the CNS in time can be calculated. Simulation studies demonstrated that transport governed by passive diffusion resulted in a linear relationship between V and time, while the slope of the line, the blood- brain barrier (BBB) clearance, proved to be an adequate and model independent parameter to characterize drug transport into the CNS. The error in the result of the numerical procedure could be limited to less than 10% of the theoretically predicted value. Superposition of 5 or 10% random noise on simulated data did not result in significant differences between the calculated and theoretically predicted clearance values. Simulations of carrier-mediated transport resulted in nonlinear transport curves; the degree of nonlinearity, and thus the detectability, was dependent on the initial degree of saturation of the system, the rate of desaturation, as caused by drug elimination processes and the noise level on the data. In vivoexperiments in the rat were performed, using atenolol, acetaminophen, and antipyrine as model drugs. Linear transport relationships were obtained for all drugs, indicating that transport was dependent on passive diffusion or a low affinity carrier system. BBB- clearance values were 7±1 l/min for atenolol, 63±7 ul/min for acetaminiphen and 316±25 l/min for antipyrine. These experiments validate the applicability of the presented technique in in vivostudies. 相似文献
3.
Non-lymphoid and lymphoid cells in acute, chronic and relapsing experimental colitis. 总被引:1,自引:2,他引:1 下载免费PDF全文
M J Palmen L A Dieleman M B van der Ende A Uyterlinde A S Pea S G Meuwissen E P van Rees 《Clinical and experimental immunology》1995,99(2):226-232
In rodents, intracolonic administration of ethanol 30% induces an acute colitis, while administration of 2,4,6-trinitrobenzene sulphonic acid (TNBS) in ethanol induces a longer lasting colitis. In the acute and chronic stages of experimental colitis, lymphoid and non-lymphoid cells were studied in the colon by immunohistochemistry. During the acute inflammation a high damage score of the colon was observed, which was related to an increase in the number of macrophages and granulocytes. Also a change in distributional patterns of macrophage subpopulations was found. The chronic stage of TNBS-ethanol-induced colitis was characterized by an increase in the number of lymphocytes, especially T cells. These data suggest that macrophages and granulocytes are important in the acute phase of experimental colitis, while lymphocytes play a pivotal role in the chronic stage. As most inflammatory bowel disease (IBD) patients have relapses during the chronic disease, we attempted to induce a relapse during experimental colitis by giving a second i.p. or s.c. dose of TNBS. This resulted in increased damage scores of the colon, new areas of ulceration and a further increase in macrophage numbers. No effect on the number of granulocytes was seen. These results indicate that it is possible to mimic relapses in experimental colitis by a second administration of TNBS, and suggest that the rats had been sensitized by the first dose of TNBS, given into the colon. 相似文献
4.
5.
The Use of Intracerebral Microdialysis to Determine Changes in Blood-Brain Barrier Transport Characteristics 总被引:2,自引:0,他引:2
de Lange Elizabeth C. M. Hesselink Mayke B. Danhof Meindert de Boer Albertus G. Breimer Douwe D. 《Pharmaceutical research》1995,12(1):129-133
The aim of this study was to determine whether changes in the transport of drugs into the brain could be determined by in vivo intracerebral microdialysis. Atenolol was used as a model drug to determine blood-brain barrier (BBB) transport characteristics. In rats, unilateral opening of the blood-brain barrier was achieved by infusion of hyperosmolar mannitol (25%, w/v) into the left internal carotid artery. BBB transport, expressed as the ratio of the area under the curve (AUC) of atenolol in brain extracellular fluid over plasma, was three times higher for the mannitol treated hemisphere as compared with the contralateral brain or after infusion of saline, being (mean ± SEM) 0.094 ± 0.024 (n = 16), 0.029 ± 0.007 (n = 12) and 0.030 ± 0.009 (n = 12) respectively. Further evaluation of the data indicated that for experiments performed in the morning the mannitol infusion had little effect on the extent of transport of atenolol into the brain, while in the afternoon BBB transport was about 10-fold higher than in the contralateral and saline group. The mean afternoon ratios ± SEM were 0.155 ± 0.038 (n = 8), 0.012 ± 0.003 (n = 6) and 0.018 ± 0.006 (n = 6) respectively. It is concluded that intracerebral microdialysis is capable of revealing changes in BBB transport and regional and time-dependent differences in drug levels can be demonstrated with the use of this technique. 相似文献
6.
Corine C Visser Sanja Stevanovi? L Heleen Voorwinden Louis van Bloois Pieter J Gaillard Meindert Danhof Daan J A Crommelin Albertus G de Boer 《European journal of pharmaceutical sciences》2005,25(2-3):299-305
In this study, we aim to target pegylated liposomes loaded with horseradish peroxidase (HRP) and tagged with transferrin (Tf) to the BBB in vitro. Liposomes were prepared with the post-insertion technique: micelles of polyethylene glycol (PEG) and PEG-Tf were inserted into pre-formed liposomes containing HRP. Tf was measured indirectly by measuring iron via atomic absorption spectroscopy. All liposomes were around 100 nm in diameter, contained 5-13 microg HRP per mumol phospholipid and 63-74 Tf molecules per liposome (lipo Tf) or no Tf (lipo C). Brain capillary endothelial cells (BCEC) were incubated with liposomes at 4 degrees C (to determine binding) or at 37 degrees C (to determine association, i.e. binding+endocytosis) and the HRP activity, rather than the HRP amount was determined in cell lysates. Association of lipo Tf was two- to three-fold higher than association of lipo C. Surprisingly, the binding of lipo Tf at 4 degrees C was four-fold higher than the association of at 37 degrees C. Most likely this high binding and low endocytosis is explained by intracellular degradation of endocytosed HRP. In conclusion, we have shown targeting of liposomes loaded with protein or peptide drugs to the BCEC and more specifically to the lysosomes. This is an advantage for the treatment of lysosomal storage disease. However, drug targeting to other intracellular targets also results in intracellular degradation of the drug. Our experiments suggest that liposomes release some of their content within the BBB, making targeting of liposomes to the TfR on BCEC an attractive approach for brain drug delivery. 相似文献
7.
Elma J. Gussenhoven Meindert A. Taams Jos Roelandt Klaas Bom Jan Honkoop Nico de Jong Kees M. Ligtvoet 《The International Journal of Cardiac Imaging》1987,2(4):231-239
Summary The diagnostic value of oesophageal echocardiography is most striking in patients in whom precordial studies are of inadequate quality or fail to establish a definitive diagnosis. Oesophageal studies have excellent image quality, can be completed within 10 minutes without complications and, in most instances, enables the clinical question to be answered. In 50 patients referred for suspected thoracic aorta pathology, oesophageal echocardiography correctly excluded or diagnosed the type of aortic dissection, aortic aneurysm or the site of coarctation. Of 35 patients referred with suspected infective endocarditis, oesophageal echocardiography revealed complications in 18 patients, including vegetation, mycotic aneurysm, abscess or chordal rupture. Oesophageal echocardiography is extremely helpful to visualize intracardiac mass lesions. In 27 patients with a history of systemic or pulmonary embolism, the technique confirmed the presence, size and position of a mass lesion in 11 patients. Oesophageal color Doppler flow imaging further expands the diagnostic capabilities, particularly in patients with mitral valve prosthesis. Our experience indicates that oesophageal echocardiography significantly extends the diagnostic potential of echocardiography. Detailed knowledge of cardiothoracic anatomy and its pathologic sequelae is, however, a prerequisite for the efficient and safe application of this method. 相似文献
8.
9.
Tarjinder Sahota Ian Sanderson Meindert Danhof Oscar Della Pasqua 《British journal of pharmacology》2015,172(15):3861-3874
Background and Purpose
Despite the increasing importance of biomarkers as predictors of drug effects, toxicology protocols continue to rely on the experimental evidence of adverse events (AEs) as a basis for establishing the link between indicators of safety and drug exposure. Furthermore, biomarkers may facilitate the translation of findings from animals to humans. Combined with a model-based approach, biomarker data have the potential to predict long-term effects arising from prolonged drug exposure. Here, we used naproxen as a paradigm to explore the feasibility of a biomarker-guided approach for the prediction of long-term AEs in humans.Experimental Approach
An experimental toxicology protocol was set up for evaluating the effects of naproxen in rats, in which four active doses were tested (7.5, 15, 40 and 80 mg·kg−1). In addition to AE monitoring and histology, a few blood samples were also collected for the assessment of drug exposure, TXB2 and PGE2 levels. Non-linear mixed effects modelling was used to analyse the data and identify covariate factors on the incidence and severity of AEs.Key Results
Modelling results showed that besides drug exposure, maximum PGE2 inhibition and treatment duration were also predictors of gastrointestinal ulceration. Although PGE2 levels were clearly linked to the incidence rates, it appeared that ulceration severity is better predicted by measures of drug exposure.Conclusions and Implications
These results show that the use of a model-based approach provides the opportunity to integrate pharmacokinetics, pharmacodynamics and toxicity data, enabling optimization of the design, analysis and interpretation of toxicology experiments. 相似文献10.
Chiara Piana Wei Zhao Kimberly Adkison David Burger Evelyne Jacqz-Aigrain Meindert Danhof Oscar Della Pasqua 《British journal of clinical pharmacology》2014,77(5):861-872