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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.
van Hoogdalem Ewoud J. Heijligers-Feijen Cornelia D. de Boer Albertus G. Verhoef J. Coos Breimer Douwe D. 《Pharmaceutical research》1989,6(1):91-95
The stability of the neuroleptic peptide des-enkephalin--endorphin (DEE; Org 5878) in the rectal lumen and the rectal bioavailability of DEE were investigated in conscious rats. Furthermore, the influence of peptidase inhibition, peptidase saturation, and absorption enhancement on DEE bio-availability were evaluated. Na2EDTA (0.25%, w/v) prolonged the degradation half-life of DEE in the ligated colon from 33 ± 7 to 93 ± 45 min. Without adjuvant, tritium-labeled DEE was absorbed from the rat rectum to a very low extent (0–4%). After administration of an excess of unlabeled DEE or with Na2EDTA, comparable results were obtained. The medium-chain glyceride preparation MGK markedly enhanced the rectal DEE bioavailability, up to 8–20%, which was further increased to 10–44% by coadministration of Na2EDTA. No substantial influence of varying the rectal delivery rate was observed. The results suggest that absorption enhancement and enzyme inhibition both are essential for effective increase of rectal peptide bioavailability. 相似文献
4.
Attention to Color: An Analysis of Selection, Controlled Search, and Motor Activation, Using Event-Related Potentials 总被引:3,自引:0,他引:3
Albertus A. Wijers Gijsbertus Mulder Tsunetaka Okita Lambertus J.M. Mulder Marten K. Scheffers 《Psychophysiology》1989,26(1):89-109
In this study the organization of information processing in a selective search task was examined by analyzing event-related potentials. This task consisted of searching for target letters in a relevant (attended) color. The ERPs revealed two different effects of attention: an early occipital negativity (+/- 150 ms) reflecting feature-specific attention, and a later, central N2b component (+/- 240 ms) reflecting covert orienting of attention. A later, prolonged negativity (search-related negativity) (+/- 300 ms), maximal at Cz, was related to controlled search to letters in the attended color. Detection of relevant targets resulted in a parietal P3b component. Depending on stimulus presentation conditions an earlier response to both attended and unattended targets was found: an N2 component (+/- 250 ms). In these same conditions, C'3-C'4 asymmetries (Corrected Motor Asymmetries--CMA) suggested motor activation at +/- 300 ms, in the same time range as search-related negativity. It was argued that N2 and CMA suggest the existence of a preattentive target detection system, operating in parallel with a slower serial attentive system, as reflected by N2b and search negativity. 相似文献
5.
de Leede Leo G. J. de Boer Albertus G. Havermans Jacques P. J. M. Breimer Douwe D. 《Pharmaceutical research》1984,1(4):164-168
The extent of first-pass elimination of racemic propranolol and dextropropranolol in doses of 0.25 or 0.50 mg was investigated in relation to the site of drug administration in the rectum of rats. The compounds were given orally, i.v., and rectally at distances of 2 and 1 cm from and directly at the anus by low volume zero-order 30 min infusion. Unchanged propranolol was determined in blood, and propranolol and three metabolites were measured in urine. The systemic availability of propranolol after oral administration was approximately 6 %. Rectal administration at 2 cm, at 1 cm and directly at the anus (0.2 cm) gave two, three and six times higher values, respectively. The more distal application site produced urinary metabolite profiles that were comparable to those observed after oral administration, while application directly at the anus was similar to i.v. dosing. In all experiments log-linear elimination phases with comparable elimination half-lives (range 12–18 min) were found, except with the 0.50 mg dose after i.v. and rectal administration close to the anus which showed a non-linear profile. The mean systemic availability after rectal administration of 0.25 mg dextro-propranolol close to the anus was 50 and 64 % as compared to a 0.25 and 0.125 mg i.v. dose, respectively. The rectal route may be used for propranolol to partially prevent hepatic first-pass metabolism. However, avoidance of presys-temic elimination is maximal only in the immediate vicinity of the anus as the venous blood supply of the upper part of the rectum of rats appears to be connected to the portal system and the lower part to the general circulation. 相似文献
6.
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
7.
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
8.
9.
van Geel AN Jansen PP van Klaveren RJ van der Sijp JR;Rotterdam Oncological Thorax Study Group 《Chest》2003,124(5):1841-1846
STUDY OBJECTIVES: Relapse-free survival in patients with sulcus superior tumors. DESIGN: Prospective registration study. SETTING: Department of surgical oncology of a university hospital. PATIENTS: Twenty-one patients treated with preoperative radiotherapy (46 Gy), lobectomy and chest-wall resection, and intraoperative radiotherapy (10 Gy). RESULTS: After a median follow-up of 18 months, 18 patients (85%) were free from locoregional relapse, while 8 patients were still alive. CONCLUSIONS: The results show that this protocol can achieve excellent local tumor control and can even be used for palliative treatment. 相似文献
10.
Balancing research interests and patient interests: A qualitative study into the intertwinement of care and research in paediatric oncology 下载免费PDF全文