Gedeon Richter Ltd.

Budapest, Hungary

Gedeon Richter Ltd.

Budapest, Hungary

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Sarvari M.,Hungarian Academy of Sciences | Kocsis P.,Gedeon Richter Ltd. | Deli L.,Gedeon Richter Ltd. | Gajari D.,Gedeon Richter Ltd. | And 6 more authors.
PLoS ONE | Year: 2014

The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1A) are pivotal regulators of hypothalamic feeding centers and reward processing neuronal circuits of the brain. These systems operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter messages and metabolic signals. Functional magnetic resonance imaging was employed in the current study to map BOLD responses to ghrelin in different brain regions with special reference on homeostatic and hedonic regulatory centers of energy balance. Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied. Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response in all studied regions of interest (ROI) within the limbic system. This effect was antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin effects in the presence or absence of JMV2959 in individual ROIs revealed significant changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost identical to those observed in males. Ovariectomy and chronic estradiol replacement had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by rimonabant significantly attenuated the response of the nucleus accumbens and septum. In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling energy balance in both sexes. The endocannabinoid signaling system contributes to the manifestation of ghrelin's BOLD effect in a region specific manner. In females, the estradiol milieu does not influence the BOLD response to ghrelin. © 2014 Sárvári et al.


Kallai-Szabo N.,Semmelweis University | Luhn O.,ReSearch Pharmaceutical Services | Bernard J.,ReSearch Pharmaceutical Services | Kallai-Szabo B.,Gedeon Richter Ltd. | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2014

Layered and coated pellets were formulated to control the release of the diclofenac sodium selected as model drug. A highly water soluble isomalt inert pellet core material was used to osmotically modulate the drug release through the swellable polyvinyl acetate coating layer. Image analysis was applied to determine the shape parameters and the swelling behavior of the pellets. UV-spectroscopy and liquid chromatography with refractive index detection were applied to measure the concentration of the model drug and the core materials. Simultaneous dissolution of both the diclofenac sodium and isomalt was observed. Relationship was found between the dissolution profile of the drug and the core material which linear correlation was independent on the coating level. The latter enables the modulation of drug release beside the permeability control of the swelled coating polymer. © 2014 Elsevier B.V.


Pal Z.,Semmelweis University | Varga Z.,Gedeon Richter Ltd | Semsei T.,Semmelweis University | Remenyi V.,Semmelweis University | And 6 more authors.
Human Immunology | Year: 2012

Autoimmune myasthenia gravis is a T-cell-dependent, antibody-mediated, rare neuromuscular disorder. Interleukin-4, acting via interleukin-4 receptor alpha, plays a pivotal role in B-cell differentiation and antibody production and has been implicated to influence disease progression in experimental autoimmune myasthenia gravis. Polymorphisms of the interleukin-4 receptor alpha gene have been shown to be associated with various autoimmune diseases. We compared the distribution of three polymorphisms of the interleukin-4 receptor alpha gene (S503P, rs1805015, Q576R, rs1801275, I75V, rs1805010), all affecting interleukin-4 signaling, in two cohorts of myasthenia gravis patients with ethnically matched controls. Although the distribution of the S503P and Q576R polymorphisms did not differ significantly between the groups, the frequency of the GG rare homozygote genotype of the I75V polymorphism was significantly higher in patients with myasthenia gravis. Our data suggest that the reduced responsiveness to interleukin-4 because the I75V polymorphism may contribute to the pathogenesis of myasthenia gravis. © 2012 American Society for Histocompatibility and Immunogenetics.


Lancastre J.J.H.,University of Lisbon | Falcao A.N.,University of Lisbon | Margaca F.M.A.,University of Lisbon | Ferreira L.M.,University of Lisbon | And 4 more authors.
Applied Surface Science | Year: 2015

Organic-inorganic materials have been the object of intense research due to their wide range of properties and therefore innumerous applications. We prepared organic-inorganic hybrid materials by direct energy deposition on a mixture of polydimethylsiloxane silanol terminated (33 wt% fixed content), tetraethylorthosilicate and a minor content of zirconium propoxide that varied from 1 to 5 wt% using gamma radiation from a Co-60 source. The samples, dried in air at room temperature, are bulk, flexible and transparent. Their nanostructure was investigated by small angle neutron scattering. It was found that the inorganic oxide network has fractal structure, which becomes denser as the zirconium propoxide content decreases. The results suggest that oxide nanosized regions grow from the OH terminal group of PDMS which are the condensation seeds. Their number and position remains unaltered with the variation of zirconium propoxide content that only affects their microstructure. A model is proposed for the nanostructure of the oxide network that develops in the irradiation processed hybrid materials. © 2015 Elsevier B.V. All rights reserved.


Tombol Z.,Semmelweis University | Eder K.,Hungarian Academy of Sciences | Kovacs A.,Semmelweis University | Szabo P.M.,Semmelweis University | And 10 more authors.
Modern Pathology | Year: 2010

MicroRNAs are involved in the pathogenesis of several tumors, however, there have been no data on microRNA expression in pheochromocytomas to date. The objective of our study was to perform microRNA expression profiling in sporadic and hereditary benign, and recurring adrenomedullary tumors. Furthermore, the applicability of formalin-fixed paraffin-embedded tissue samples for the analysis of microRNA expression in pheochromocytomas was examined. MicroRNA expression data of three matched frozen and formalin-fixed paraffin-embedded samples were correlated. A total of 21 formalin-fixed paraffin-embedded samples (sporadic benign, multiple endocrine neoplasia 2, von Hippel-Lindau disease, sporadic recurring) were subjected to microRNA expression profiling using microarrays. MicroRNAs with significant differences in expression were validated and sample sizes were extended including tumors from neurofibromatosis type 1 patients by real-time quantitative reverse-transcription PCR (n33). MicroRNA target prediction was carried out by TargetScan and MicroCosm Targets. Pathway analysis of targets was performed by Ingenuity Pathway Analysis and DIANA mirPath. Furthermore, microRNA expression profiles of a malignant pheochromocytoma and a pair of primary and recurrent tumors were studied by TaqMan Human MicroRNA Cards. MicroRNA expression correlated well between frozen and formalin-fixed paraffin-embedded samples (70-92%). Microarray analysis revealed 16 significantly differentially expressed microRNAs. Five of these were validated by real-time RT-PCR. miR-139-3p, miR-541 and miR-765 were significantly differentially expressed between sporadic benign and von Hippel-Lindau-related pheochromocytomas. Significantly higher expression of miR-885-5p and miR-1225-3p was found in multiple endocrine neoplasia type 2 and sporadic recurring pheochromocytomas, respectively. Pathway analysis revealed the possible involvement of Notch- and G-protein-coupled receptor signaling in tumor recurrence. MicroRNA expression profiles in the primary recurrent and recurring malignant comparisons have been similar. In conclusion, we have proved that formalin-fixed paraffin-embedded samples can be used for the analysis of microRNA expression in pheochromocytomas. MicroRNA expression patterns differ between various sporadic, hereditary and recurring tumors and miR-1225-3p may be useful for identifying recurring pheochromocytomas. © 2010 USCAP, Inc. All rights reserved.


Lancastre J.J.H.,University of Lisbon | Falcao A.N.,University of Lisbon | Margaca F.M.A.,University of Lisbon | Ferreira L.M.,University of Lisbon | And 4 more authors.
Radiation Physics and Chemistry | Year: 2015

Hybrid materials have been the object of intense research due to their potential for biomedical applications as well as in other fields. They are usually prepared by sol-gel but the method of gamma irradiation of the precursors is an alternative avoiding the addition of any other chemicals. The study of the hybrids prepared by this method has been progressing to understand the impact of different variables on the microstructure. In this work, the influence of the polymer's molecular weight on the microstructure of the materials is investigated. Hybrids were obtained from a mixture of polydimethylsiloxane (PDMS) silanol terminated, tetraethylorthosilicate (TEOS) and zirconium propoxide (PrZr) in the wt% composition 20PDMS-73TEOS-7PrZr varying only the PDMS molecular weight. The obtained materials are homogeneous, transparent and flexible and their microstructure was analysed by Scanning Electron Microscopy (SEM) and Small-Angle Neutron Scattering (SANS). It was found that different microstructures were obtained, depending on the polymer molecular weight. © 2014 Elsevier Ltd.


Boyle B.,Semmelweis University | Butz H.,Semmelweis University | Liko I.,Gedeon Richter Ltd. | Zalatnai A.,Semmelweis University | And 6 more authors.
Steroids | Year: 2010

Introduction: Glucocorticoid receptor (GR) is expressed in the normal human adrenal gland, however, no study has been performed to evaluate the separate expression of α- and β-isoforms (GRα and GRβ) in normal human adrenals and in adrenocortical adenomas. Experimental: GRα and GRβ mRNA expression was examined by quantitative real-time PCR in 31 adrenal tissues including 19 non-functioning adenomas (NFA), 6 cortisol-producing adenomas (CPA) and 6 normal adrenocortical tissues. In addition, the presence and cellular localization of GRα and GRβ proteins in adrenal tissues were studied by immunohistochemistry. Results: Compared to normal adrenocortical tissues, both GRα and GRβ mRNAs were significantly increased in CPA but not in NFA. Using anti-GRα antibody a strong nuclear staining was observed in NFA and CPA, and a less remarkable immunoreactivity was detected in some nuclei of normal adrenocortical cells.GRβ immunostaining was absent in normal adrenal tissues and NFA, while a strong cytoplasmic and nuclear immunoreaction was found in CPA. Conclusions: Altered expression of GRα and GRβ in CPA raises their possible role in the pathophysiology of these adrenal tumors, although further studies are needed to elucidate the potential significance of these findings. © 2010 Elsevier Inc. All rights reserved.


Kadar Z.,University of Szeged | Frank E.,University of Szeged | Schneider G.,University of Szeged | Molnar J.,University of Szeged | And 4 more authors.
Arkivoc | Year: 2012

A simple and convenient synthetic route is reported for the formation of novel 2α-triazolylcholestane derivatives. The scheme involves transformation of the starting cholestanone to the corresponding azido compound and efficient conversions of 2α-azido-5α-cholestan-3-one (3) with various terminal alkynes through use of the 'click' chemistry approach. Finally, the oxo group of these heterocyclic steroidal derivatives was reduced, and the resultant mixtures of epimeric triazolyl alcohols were separated. The antiproliferative activities of the synthesized 2-triazolyl-3-ketones against three human cancer cell lines were screened. Nevertheless, only a few of the tested compounds exerted moderate cell-growth inhibition. © ARKAT-USA, Inc.


PubMed | Gedeon Richter Ltd., ReSearch Pharmaceutical Services and Semmelweis University
Type: | Journal: Journal of pharmaceutical and biomedical analysis | Year: 2014

Layered and coated pellets were formulated to control the release of the diclofenac sodium selected as model drug. A highly water soluble isomalt inert pellet core material was used to osmotically modulate the drug release through the swellable polyvinyl acetate coating layer. Image analysis was applied to determine the shape parameters and the swelling behavior of the pellets. UV-spectroscopy and liquid chromatography with refractive index detection were applied to measure the concentration of the model drug and the core materials. Simultaneous dissolution of both the diclofenac sodium and isomalt was observed. Relationship was found between the dissolution profile of the drug and the core material which linear correlation was independent on the coating level. The latter enables the modulation of drug release beside the permeability control of the swelled coating polymer.


PubMed | Gedeon Richter Ltd.
Type: | Journal: Brain research bulletin | Year: 2013

Tolperisone is a voltage gated sodium channel blocker, centrally acting muscle relaxant drug, with a very advantageous side effect profile. Like other sodium channel blockers, it has weak affinity to the resting state and high affinity to the open/inactivated state of the channel. In this paper, its effect on BOLD responses in rat brain were elucidated both on the resting brain and paw stimulation evoked BOLD responses. Tolperisone did not exert any visible effect on resting brain, but strongly inhibited the paw stimulation evoked BOLD responses, showing somewhat higher efficacy in brain areas involved in pain sensation. This finding is in a good agreement with its sodium channel blocking profile. In the resting brain, most of the channels are in resting state. Electric train stimuli of the paw results in over activated neurons, where most sodium channels are in open or inactivated state. These data suggest that the very advantageous profile of tolperisone can be explained by its selective action on open or inactivated sodium channels of over-activated neurons in various brain regions rather than by a selective effect in the spinal cord as suggested previously.

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