med Translational Research Centers

Budapest, Hungary

med Translational Research Centers

Budapest, Hungary
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Varga Z.,Hungarian Academy of Sciences | Varga Z.,Semmelweis University | Szigyarto I.C.,Hungarian Academy of Sciences | Gyurko I.,Hungarian Academy of Sciences | And 6 more authors.
Contrast Media and Molecular Imaging | Year: 2017

The in vivo biodistribution of liposomal formulations greatly influences the pharmacokinetics of these novel drugs; therefore the radioisotope labeling of liposomes and the use of nuclear imaging methods for in vivo studies are of great interest. In the present work, a new procedure for the surface labeling of liposomes is presented using the novel 99mTc-tricarbonyl complex. Liposomes mimicking the composition of two FDA approved liposomal drugs were used. In the first step of the labeling, thiol-groups were formed on the surface of the liposomes using Traut’s reagent, which were subsequently used to bind 99mTc-tricarbonyl complex to the liposomal surface. The labeling efficiency determined by size exclusion chromatography was 95%, and the stability of the labeled liposomes in bovine serum was found to be 94% over 2 hours. The obtained specific activity was 50MBq per 1 μmol lipid which falls among the highest values reported for 99mTc labeling of liposomes. Quantitative in vivo SPECT/CT biodistribution studies revealed distinct differences between the labeled liposomes and the free 99mTc-tricarbonyl, which indicates the in vivo stability of the labeling. As the studied liposomes were non-PEGylated, fast clearance from the blood vessels and high uptake in the liver and spleen were observed. © 2017 Zoltán Varga et al.


Dios P.,University of Pécs | Szigeti K.,Semmelweis University | Budan F.,med Translational Research Centers | Budan F.,University of Pécs | And 7 more authors.
European Journal of Pharmaceutical Sciences | Year: 2016

The objective of the study was to reveal the influence of necessarily added barium sulfate (BaSO4) X-ray contrast material on floating drug delivery tablets. Based on literature survey, a chosen floating tablet composition was determined containing HPMC and carbopol 943P as matrix polymers. One-factor factorial design with five levels was created for evaluation of BaSO4 (X1) effects on experimental parameters of tablets including: floating lag time, total floating time, swelling-, erosion-, dissolution-, release kinetics parameters and X-ray detected volume changes of tablets. Applied concentrations of BaSO4 were between 0 and 20.0% resulting in remarkable alteration of experimental parameters related especially to flotation. Drastic deterioration of floating lag time and total floating time could be observed above 15.0% BaSO4. Furthermore, BaSO4 showed to increase the integrity of tablet matrix by reducing eroding properties. A novel evaluation of dissolutions from floating drug delivery systems was introduced, which could assess the quantity of drug dissolved from dosage form in floating state. In the cases of tablets containing 20.0% BaSO4, only the 40% of total API amount could be dissolved in floating state. In vitro fine resolution X-ray CT imagings were performed to study the volume change and the voxel distributions as a function of HU attenuations by histogram analysis of the images. X-ray detected relative volume change results did not show significant difference between samples. After 24 h, all tablets containing BaSO4 could be segmented, which highlighted the fact that enough BaSO4 remained in the tablets for their identification. © 2016 Elsevier B.V.


Cannabinoid type-1 receptors (CB 1Rs) modulate synaptic neurotransmission by participating in retrograde signaling in the adult brain. Increasing evidence suggests that cannabinoids through CB 1Rs play an important role in the regulation of motor activities in the striatum. In the present study, we used human brain samples to examine the relationship between CB 1R and dopamine receptor density in case of Parkinson's disease (PD).Post mortem putamen, nucleus caudatus and medial frontal gyrus samples obtained from PD patients were used for CB 1R and dopamine D 2/D 3 receptor autoradiography. [ 125I]SD7015, a novel selective CB 1R inverse agonist, developed by a number of the present co-authors, and [ 3H]raclopride, a dopamine D 2/D 3 antagonist, were used as radioligands. Our results demonstrate unchanged CB 1R density in the putamen and nucleus caudatus of deceased PD patients, treated with levodopa (l-DOPA). At the same time dopamine D 2/D 3 receptors displayed significantly decreased density levels in case of PD putamen (control: 47.97±10.00fmol/g, PD: 3.73±0.07fmol/g (mean±SEM), p<0.05) and nucleus caudatus (control: 30.26±2.48fmol/g, PD: 12.84±5.49fmol/g, p<0.0005) samples. In contrast to the putamen and the nucleus caudatus, in the medial frontal gyrus neither receptor densities were affected.Our data suggest the presence of an unaltered CB 1R population even in late stages of levodopa treated PD. This further supports the presence of an intact CB 1R population which, in line with the conclusion of earlier publications, may be utilized as a pharmacological target in the treatment of PD. Furthermore we found discrepancy between a maintained CB 1R population and a decreased dopamine D 2/D 3 receptor population in PD striatum. The precise explanation of this conundrum requires further studies with simultaneous examination of the central cannabinoid and dopaminergic systems in PD using higher sample size. © 2012 Elsevier Inc.


Farkas S.,Debrecen University | Nagy K.,Debrecen University | Palkovits M.,Semmelweis University | Kovacs G.G.,Medical University of Vienna | And 9 more authors.
Neurochemistry International | Year: 2012

The cannabinoid type-1 receptor (CB 1R) is one of the most abundant members of the G protein-coupled receptor family in the central nervous system. Once activated by their cognate ligands, endocannabinoids, CB 1Rs generally limit the timing of neurotransmitter release at many cortical synapses. Prior studies have indicated the involvement of CB 1R in neurodegeneration and in various neuronal insults, with an emphasis on their neuroprotective role. In the present study we used a novel selective CB 1R radioligand to investigate regional variations in CB 1R ligand binding as a factor of progressive Braak tau pathology in the frontal cortex of Alzheimer's disease (AD) patients. The frontal cortex was chosen for this study due to the high density of CB 1Rs and their well-characterized involvement in the progression of AD. Post-mortem prefrontal cortex samples from AD patients from Braak stages I to VI and controls were subjected to CB 1R autoradiography with [ 125I]SD-7015 as radioligand. Regional concentration of [ 125I]SD-7015, corresponding to, and thereby representing, regional CB 1R densities, were expressed in fM/g-tissue. The results show that CB 1R density inversely correlates with Braak tau pathology with the following tendency: controls


Szigeti K.,Semmelweis University | Horvath I.,Semmelweis University | Veres D.S.,Semmelweis University | Martinecz B.,Institute of Experimental Medicine | And 7 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2015

Inflammation that develops in the brain and peripheral organs after stroke contributes profoundly to poor outcome of patients. However, mechanisms through which inflammation impacts on brain injury and overall outcome are improperly understood, in part because the earliest inflammatory events after brain injury are not revealed by current imaging tools. Here, we show that single-photon emission computed tomography (NanoSPECT/CT Plus) allows visualization of blood brain barrier (BBB) injury after experimental stroke well before changes can be detected with magnetic resonance imaging (MRI). Early 99mTc-DTPA (diethylene triamine pentaacetic acid) signal changes predict infarct development and systemic inflammation preceding experimental stroke leads to very early perfusion deficits and increased BBB injury within 2 hours after the onset of ischemia. Acute brain injury also leads to peripheral inflammation and immunosuppression, which contribute to poor outcome of stroke patients. The SPECT imaging revealed early (within 2 hours) changes in perfusion, barrier function and inflammation in the lungs and the gut after experimental stroke, with good predictive value for the development of histopathologic changes at later time points. Collectively, visualization of early inflammatory changes after stroke could open new translational research avenues to elucidate the interactions between central and peripheral inflammation and to evaluate in vivo 'multi-system' effects of putative anti-inflammatory treatments. © 2015 ISCBFM.


Fulop A.,Semmelweis University | Szijarto A.,Semmelweis University | Harsanyi L.,Semmelweis University | Budai A.,Semmelweis University | And 7 more authors.
PLoS ONE | Year: 2014

Objectives: In the early recognition of portal vein ligation (PVL) induced tumor progression, positron emission tomography and magnetic resonance imaging (PET/MRI) could improve diagnostic accuracy of conventionally used methods. It is unknown how PVL affects metabolic patterns of tumor free hepatic tissues. The aim of this preliminary study is to evaluate the effect of PVL on glucose metabolism, using PET/MRI imaging in healthy rat liver. Materials and Methods: Male Wistar rats (n = 30) underwent PVL. 2-deoxy-2-(18F)fluoro-D- glucose (FDG) PET/MRI imaging (nanoScan PET/MRI) and morphological/histological examination were performed before (Day 0) and 1, 2, 3, and 7 days after PVL. Dynamic PET data were collected and the standardized uptake values (SUV) for ligated and non-ligated liver lobes were calculated in relation to cardiac left ventricle (SUVVOI/SUVCLV) and mean liver SUV (SUV VOI/SUVLiver). Results: PVL induced atrophy of ligated lobes, while non-ligated liver tissue showed compensatory hypertrophy. Dynamic PET scan revealed altered FDG kinetics in both ligated and non-ligated liver lobes. SUVVOI/SUVCLV significantly increased in both groups of lobes, with a maximal value at the 2nd postoperative day and returned near to the baseline 7 days after the ligation. After PVL, ligated liver lobes showed significantly higher tracer uptake compared to the non-ligated lobes (significantly higher SUVVOI/SUVLiver values were observed at postoperative day 1, 2 and 3). The homogenous tracer biodistribution observed before PVL reappeared by 7th postoperative day. Conclusion: The observed alterations in FDG uptake dynamics should be taken into account during the assessment of PET data until the PVL induced atrophic and regenerative processes are completed. © 2014 Fülöp et al.


Veres D.S.,Semmelweis University | Mathe D.,med Translational Research Centers | Futo I.,Semmelweis University | Horvath I.,Semmelweis University | And 3 more authors.
Molecular Imaging and Biology | Year: 2014

Purpose: The aim of this paper is to present a simple and quantitative data analysis method with a new potential in the application of liver single-photon emission computed tomography (SPECT) imaging. We have established quantitative SPECT/computed tomography (CT) in vivo imaging protocols for determination of liver tumor burden based on the known role of Kupffer cells in cancer of the liver. Procedures: As it is also known that functional Kupffer cells accumulate particulate material contained in the arterial blood of liver supply, we used radiolabeled macro-aggregated albumin particles ([99mTc]-MAA) injected intravenously to image liver disease. Quantification of cold spot liver lesion imaging was also a general objective. Methods: We examined a healthy control group (BALB/C mice, n = 6) and group of induced hepatocellular carcinoma (HCC, matrilin-2 transgenic KO mice, n = 9), where hepatocellular carcinoma was induced by diethylnitrosamine. We used [99mTc]-MAA as radiopharmaceutical for liver SPECT imaging in a small animal SPECT/CT system. A liver radioactivity overview map was generated. Segmentation of the liver was calculated by Otsu thresholding method. Based on the segmentation the radioactivity volume and the summarized liver activity were determined. Results: Tumor burden of the livers was quantitatively determined by creating parametric data from the resulting volumetric maps. Ex vivo liver mass data were applied for the validation of in vivo measurements. An uptake with cold spots as tumors was observed in all diseased animals in SPECT/CT scans. Isotope-labeled particle uptake (standardized uptake concentration) of control (median 0.33) and HCC (median 0.18) groups was significantly different (p = 0.0015, Mann Whitney U test). Conclusion: A new potential application of [99mTc]-MAA was developed and presents a simple and very effective means to quantitatively characterize liver cold spot lesions resulting from Kupffer cell dysfunctions as a consequence of tumor burden. © 2013 World Molecular Imaging Society.


PubMed | Institute of Experimental Medicine, med Translational Research Centers and Semmelweis University
Type: Journal Article | Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism | Year: 2015

Inflammation that develops in the brain and peripheral organs after stroke contributes profoundly to poor outcome of patients. However, mechanisms through which inflammation impacts on brain injury and overall outcome are improperly understood, in part because the earliest inflammatory events after brain injury are not revealed by current imaging tools. Here, we show that single-photon emission computed tomography (NanoSPECT/CT Plus) allows visualization of blood brain barrier (BBB) injury after experimental stroke well before changes can be detected with magnetic resonance imaging (MRI). Early 99mTc-DTPA (diethylene triamine pentaacetic acid) signal changes predict infarct development and systemic inflammation preceding experimental stroke leads to very early perfusion deficits and increased BBB injury within 2hours after the onset of ischemia. Acute brain injury also leads to peripheral inflammation and immunosuppression, which contribute to poor outcome of stroke patients. The SPECT imaging revealed early (within 2hours) changes in perfusion, barrier function and inflammation in the lungs and the gut after experimental stroke, with good predictive value for the development of histopathologic changes at later time points. Collectively, visualization of early inflammatory changes after stroke could open new translational research avenues to elucidate the interactions between central and peripheral inflammation and to evaluate in vivo multi-system effects of putative anti-inflammatory treatments.


PubMed | University of Pécs and med Translational Research Centers
Type: | Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V | Year: 2015

The aim of this study was to design a local, floating, mucoadhesive drug delivery system containing metronidazole for Helicobacter pylori eradication. Face-centered central composite design (with three factors, in three levels) was used for evaluation and optimization of in vitro floating and dissolution studies. Sodium alginate (X1), low substituted hydroxypropyl cellulose (L-HPC B1, X2) and sodium bicarbonate (X3) concentrations were the independent variables in the development of effervescent floating tablets. All tablets showed acceptable physicochemical properties. Statistical analysis revealed that tablets with 5.00% sodium alginate, 38.63% L-HPC B1 and 8.45% sodium bicarbonate content showed promising in vitro floating and dissolution properties for further examinations. Optimized floating tablets expressed remarkable floating force. Their in vitro dissolution studies were compared with two commercially available non-floating metronidazole products and then microbiologically detected dissolution, ex vivo detachment force, rheological mucoadhesion studies and compatibility studies were carried out. Remarkable similarity (f1, f2) between in vitro spectrophotometrically and microbiologically detected dissolutions was found. Studies revealed significant ex vivo mucoadhesion of optimized tablets, which was considerably increased by L-HPC. In vivo X-ray CT studies of optimized tablets showed 8h gastroretention in rats represented by an animation prepared by special CT technique.


PubMed | University of Pécs, med Translational Research Centers and Semmelweis University
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2016

The objective of the study was to reveal the influence of necessarily added barium sulfate (BaSO

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