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991.
Joachim BrouwersBart Anneveld Gert-Jan GoudappelGuus Duchateau Pieter AnnaertPatrick Augustijns Evelijn Zeijdner 《European journal of pharmaceutics and biopharmaceutics》2011,77(2):313-319
In the present study, we demonstrated the value of two advanced tools, the TNO gastric and small Intestinal Model (TIM-1) and magnetic resonance imaging (MRI), for the in vitro evaluation of food-dependent disintegration of immediate release fosamprenavir tablets. Upon introduction of a tablet with the nutritional drink Scandishake Mix® in the stomach compartment of TIM-1, simulating the fed state, disintegration and fosamprenavir dissolution were significantly postponed compared to the fasted state (lag time 80 ± 23 min). This resulted in a lag in the appearance of bioaccessible fosamprenavir (<5% during the first 2 h), even though the nutritional state did not significantly alter the cumulative bioaccessibility after 5 h. These results were in agreement with the previously observed postprandial delay in gastric fosamprenavir tablet disintegration and subsequent amprenavir absorption in healthy volunteers. Therefore, TIM-1 can be used in tablet development to identify food-induced disintegration issues causing unexpected clinical behavior. From a mechanistic perspective, we applied MRI to illustrate impaired water ingress in fosamprenavir tablets immersed in the nutritional drink compared to simulated gastric fluid. This effect may be attributed to both competition between nutritional components and the tablet for the available water (indicated by reduced rotational and translational diffusion) as well as the possible formation of a food-dependent precipitation layer on the HPMC-coated tablet. 相似文献
992.
Hanna Mannell Joachim Pircher Franziska Fochler Yvonn Stampnik Thomas Räthel Bernhard Gleich Christian Plank Olga Mykhaylyk Chiheb Dahmani Markus Wörnle Andrea Ribeiro Ulrich Pohl Florian Krötz 《Nanomedicine : nanotechnology, biology, and medicine》2012,8(8):1309-1318
Site specific vascular gene delivery for therapeutic implications is favorable because of reduction of possible side effects. Yet this technology faces numerous hurdles that result in low transfection rates because of suboptimal delivery. Combining ultrasonic microbubble technology with magnetic nanoparticle enhanced gene transfer could make it possible to use the systemic vasculature as the route of application and to magnetically trap these compounds at the target of interest. In this study we show that magnetic nanoparticle-coated microbubbles bind plasmid DNA and successfully deliver it to endothelial cells in vitro and more importantly transport their cargo through the vascular system and specifically deliver it to the vascular wall in vivo at sites where microbubbles are retained by magnetic force and burst by local ultrasound application. This resulted in a significant enhancement in site specific gene delivery compared with the conventional microbubble technique. Thus, this technology may have promising therapeutic potential.From the Clinical EditorThis work focuses on combining ultrasonic microbubble technology with magnetic nanoparticle enhanced gene transfer to enable targeted gene delivery via the systemic vasculature and magnetic trapping of these compounds at the target of interest. 相似文献
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Tagalakis AD Grosse SM Meng QH Mustapa MF Kwok A Salehi SE Tabor AB Hailes HC Hart SL 《Biomaterials》2011,32(5):1370-1376
Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics. 相似文献
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The U.S. Environmental Protection Agency (EPA) has instituted the Chemical Safety for Sustainability (CSS) research program for assessing the health and environmental impact of manufactured chemicals. This is a broad program wherein one of the tasks is to develop high throughput screening (HTS) methods and follow-up confirmation for toxicity at realistic environmental exposure levels. The main tools under this task are in vitro toxicity testing, in silico molecular modeling, and in vivo (systemic) measurements documentation. The in vivo research component is intended to support and corroborate in vitro chemical toxicity prioritization with observations of systemic perturbations and statistical parameters derived from intact (living) organisms. Based on EPA's Biomonitoring Framework for human health research, such observations are intended to link environmental exposures to a cascade of biomarker chemicals to help identify and clarify adverse outcome pathways within the context of systems biology. This commentary discusses the issues regarding interpretation of in vitro changes from HTS as an adverse result, an adaptive (non-adverse) response, or a random/irrelevant occurrence. A second goal is to inform in vitro strategies as to relevant dosing (potency) levels at the cellular level that reflect realistic systemic exposures. Although we recognize the high value of in vivo animal toxicity testing, herein we focus on observational (minimally invasive) human biomonitoring methods and propose complementary in vivo testing that could help guide the design of high-throughput analyses and the ultimate interpretation of their outcomes. 相似文献
999.
Oexle K Ried JS Hicks AA Tanaka T Hayward C Bruegel M Gögele M Lichtner P Müller-Myhsok B Döring A Illig T Schwienbacher C Minelli C Pichler I Fiedler GM Thiery J Rudan I Wright AF Campbell H Ferrucci L Bandinelli S Pramstaller PP Wichmann HE Gieger C Winkelmann J Meitinger T 《Human molecular genetics》2011,20(5):1042-1047
The level of body iron storage and the erythropoietic need for iron are indicated by the serum levels of ferritin and soluble transferrin receptor (sTfR), respectively. A meta-analysis of five genome-wide association studies on sTfR and ferritin revealed novel association to the PCSK7 and TMPRSS6 loci for sTfR and the HFE locus for both parameters. The PCSK7 association was the most significant (rs236918, P = 1.1 × 10E-27) suggesting that proprotein convertase 7, the gene product of PCSK7, may be involved in sTfR generation and/or iron homeostasis. Conditioning the sTfR analyses on transferrin saturation abolished the HFE signal and substantially diminished the TMPRSS6 signal while the PCSK7 association was unaffected, suggesting that the former may be mediated by transferrin saturation whereas the PCSK7-associated effect on sTfR generation appears to be more direct. 相似文献
1000.
Sulfonamide treatment of piglets against neonatal coccidiosis has frequently been suggested in the literature. In order to
evaluate the efficacy of sulfonamides against experimental Isospora suis infections in suckling piglets (oral infection with 1,500 sporulated oocysts of I. suis per piglet on the fourth day of life), two trials were conducted. In trial I, oral sulfadimidine (group Sulfa-Oral) was applied
in doses of 100 mg/kg of body weight (BW) 1 day before infection and 75 mg/kg BW daily for the following 5 days, and sulfamethoxypyrimidine
(SMP) was applied parenterally in daily doses of 75 mg/kg BW for the same time period. In trial II, SMP was applied parenterally
in doses of 75 mg/kg BW (a) from the day of infection daily for 7 days (SMP-Standard), (b) for 2 days starting on the day
of infection (SMP-Early), (c) for 3 days starting 2 days post-infection (d.p.i.; SMP-Middle), (d) for 2 days starting 5 d.p.i.
(SMP-Late), and (e) every other day from the day of infection until 6 d.p.i. (SMP-Alternating), as well as (f) orally in doses
of 75 mg/kg BW from the day of infection for 7 days (SMP-Oral). The sulfonamide-treated groups were compared to a toltrazuril-treated
group (single oral treatment with Baycox? 5% suspension, 20 mg/kg BW 2 d.p.i.) and to a water-treated Control group. Each
group consisted of seven to nine piglets. The parameters evaluated were oocyst excretion and fecal consistency/diarrhea from
4 to 15 d.p.i. Sulfa-Oral, SMP-Early, and SMP-Late had no significant effect in reduction of oocyst excretion and diarrhea,
whereas treatment for 3–7 days with SMP reduced both parasite shedding and diarrhea significantly. Oral treatment with SMP
was comparable to parenteral application. Baycox? in a single application had the most pronounced effect and completely suppressed
oocyst excretion and diarrhea during the examination period. It could be shown that repeated application of sulfonamides,
provided that the appropriate time period after infection is covered, can in principle be used to control piglet coccidiosis;
however, the amount of work required is considerable, and the practicability is poor. Due to the short half-life of sulfonamides
in pigs and the lack of predictability of the time point of infection, an efficient application of sulfonamides to control
piglet coccidiosis under field conditions appears unlikely. Baycox?, on the other hand, applied once during the prepatent
period of infection, had a lasting effect and can be used to most effectively control I. suis. 相似文献