Pharmacology and Drug Safety Research

Budapest, Hungary

Pharmacology and Drug Safety Research

Budapest, Hungary
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Zimnisky R.,Columbia University | Zimnisky R.,New York State Psychiatric Institute | Chang G.,Columbia University | Chang G.,New York State Psychiatric Institute | And 5 more authors.
Psychopharmacology | Year: 2013

Rationale: A major challenge in the pharmacological treatment of psychotic disorders is the effective management of the associated cognitive dysfunctions. Novel concepts emphasize a potential benefit of partial agonists acting upon dopamine D2-like receptors in ameliorating these cognitive deficits, and pre-clinical studies suggest that D3-receptor-preferring compounds can exert pro-cognitive effects. Objective: The objective of the study was to use acute phencyclidine (PCP) treatment to model the cognitive deficits of schizophrenia in mice, and to test the efficacy of the novel, dopamine D 3-receptor-preferring drug cariprazine in ameliorating the severity of PCP-triggered cognitive deficits. Methods: One group of wild-type or D 3-receptor knockout mice was acutely treated with either saline or phencyclidine (PCP, 1 mg/kg). A separate group of mice was treated with cariprazine prior to PCP administration. Both groups were then tested in three cognitive tasks: social interaction/recognition and recognition memory, spatial working memory, and attention-set-shifting. Results: PCP effectively disrupted social recognition and social recognition memory, spatial working memory, and extradimensional attention set-shifting. Cariprazine pretreatment significantly attenuated the emergence of these cognitive deficits in PCP-treated wild-type mice, but not in PCP-treated D3-receptor knockout mice. Conclusions: In an animal model of PCP-induced cognitive impairment, cariprazine pretreatment significantly diminished PCP-triggered cognitive deficits, and studies on knockout mice show that dopamine D3 receptors contribute to this effect. © 2012 Springer-Verlag Berlin Heidelberg.


Roman V.,Pharmacology and Drug Safety Research | Gyertyan I.,Pharmacology and Drug Safety Research | Saghy K.,Pharmacology and Drug Safety Research | Kiss B.,Pharmacology and Drug Safety Research | Szombathelyi Z.,Pharmacology and Drug Safety Research
Psychopharmacology | Year: 2013

Rationale: Cariprazine (RGH-188) is a D3-preferring dopamine D3/D2 receptor partial agonist antipsychotic candidate for the treatment of schizophrenia and bipolar mania. Substance abuse is a frequent comorbidity of both disorders and is associated with serious health issues. Based on preclinical efficacy, dopamine D2 and D3 receptor partial agonists and antagonists are assumed to have relapse-preventing potential in human cocaine addiction. Objectives: We investigated the anti-abuse potential of cariprazine in cocaine self-administration paradigms. Aripiprazole and bifeprunox were used as comparators because of their pharmacological similarity to cariprazine. Methods: The effects of compounds on cocaine's rewarding effect were investigated in a continuous self-administration regimen. The relapse-preventing potential of drugs was studied in rats with a history of cocaine self-administration after a period of complete abstinence in a relapse to cocaine-seeking paradigm. Results: Cariprazine, as well as aripiprazole and bifeprunox, were able to reduce the rewarding effect of cocaine (minimum effective doses were 0.17, 1, and 0.1 mg/kg, respectively) and attenuated relapse to cocaine seeking with half maximal effective dose [ED50] values of 0.2, 4.2, and 0.17 mg/kg, respectively. Conclusions: These results may predict a relapse-preventing action for cariprazine in humans in addition to its already established antipsychotic and antimanic efficacy. © 2012 Springer-Verlag Berlin Heidelberg.


PubMed | Opto Neuropharmacology Group, University of Medicine and Pharmacy of Targu Mures, Hungarian Academy of Sciences, Pharmacology and Drug Safety Research and Semmelweis University
Type: | Journal: Frontiers in pharmacology | Year: 2015

The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One-way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3, and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone, and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa) of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule), which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel). Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively.


PubMed | Szent Istvan University, BioTalentum Ltd. and Pharmacology and Drug Safety Research
Type: Journal Article | Journal: Stem cell research | Year: 2016

Peripheral blood was collected from a clinically characterized female Kleefstra syndrome patient with a heterozygous, de novo, premature termination codon (PTC) mutation (NM_024757.4(EHMT1):c.3413G>A; p.Trp1138Ter). Peripheral blood mononuclear cells (PBMCs) were reprogrammed with the human OSKM transcription factors using the Sendai-virus (SeV) delivery system. The pluripotency of transgene-free iPSC line was verified by the expression of pluripotency-associated markers and by in vitro spontaneous differentiation towards the 3 germ layers. Furthermore, the iPSC line showed normal karyotype. Our model might offer a good platform to study the pathomechanism of Kleefstra syndrome, also for drug testing, early biomarker discovery and gene therapy studies.


Balogh P.,Semmelweis University | Magyar M.,Semmelweis University | Szabo A.,Semmelweis University | Mullner N.,Semmelweis University | And 3 more authors.
European Journal of Cell Biology | Year: 2015

We previously showed that intraperitoneal administration of Freund's adjuvant treatment resulted in acute peritonitis and TGF-β was found to be one of the main organizers of the subsequent EMT in mesothelial cells. In the present study, we investigated whether TGF-β signaling molecules are present in mesothelial cells and how their compartmentalization pattern changes with the dynamics of inflammatory events in vivo. In addition, we tried to evaluate the turnover of endosomal compartments concomitant with the internalization of signaling molecules and examine whether caveola-mediated internalization might play a role in the termination of TGF-β signaling. Using immunocytochemical approach, we could detect TβRII in EEA1 positive compartments and as the inflammation progressed, at D3, the receptor appeared in caveolin-1 positive intracellular structures as well. The latter event was accompanied by the appearance of negative regulatory protein, Smad7 in caveolae. We also found EEA1 and caveolin-1 double positive vesicular structures that were corresponded to forming MVBs affirmed by our immuno-electron microscopical results. Fine structural, morphometric and immunoblot analysis proved that Cd63 positive multivesicular body (MVB) formation was significantly increased by D3 and the IP results confirmed that TβRII as well as caveolin-1 were strongly associated with these endosomal compartments at this time. In contrast, by the termination of inflammation, by D5, caveolin-1 was found to be associated with late endosomal marker, Rab7 and entirely degraded from the system. Despite the limitations of an in vivo system, our results provide both morphological and biochemical data about the endosomal compartments involved in the internalization of TβRII upon inflammatory stimuli. Furthermore, our study implies the possible role of caveola-mediated endocytosis in the attenuation of TGF-β signaling and highlight the significance of endosomal compartments via which caveolae might meet the classical endocytic pathway under in vivo inflammatory conditions. © 2015 Elsevier GmbH.


Balogh P.,Semmelweis University | Magyar M.,Semmelweis University | Szabo A.,Semmelweis University | Mullner N.,Semmelweis University | And 3 more authors.
European journal of cell biology | Year: 2015

We previously showed that intraperitoneal administration of Freund's adjuvant treatment resulted in acute peritonitis and TGF-β was found to be one of the main organizers of the subsequent EMT in mesothelial cells. In the present study, we investigated whether TGF-β signaling molecules are present in mesothelial cells and how their compartmentalization pattern changes with the dynamics of inflammatory events in vivo. In addition, we tried to evaluate the turnover of endosomal compartments concomitant with the internalization of signaling molecules and examine whether caveola-mediated internalization might play a role in the termination of TGF-β signaling. Using immunocytochemical approach, we could detect TβRII in EEA1 positive compartments and as the inflammation progressed, at D3, the receptor appeared in caveolin-1 positive intracellular structures as well. The latter event was accompanied by the appearance of negative regulatory protein, Smad7 in caveolae. We also found EEA1 and caveolin-1 double positive vesicular structures that were corresponded to forming MVBs affirmed by our immuno-electron microscopical results. Fine structural, morphometric and immunoblot analysis proved that Cd63 positive multivesicular body (MVB) formation was significantly increased by D3 and the IP results confirmed that TβRII as well as caveolin-1 were strongly associated with these endosomal compartments at this time. In contrast, by the termination of inflammation, by D5, caveolin-1 was found to be associated with late endosomal marker, Rab7 and entirely degraded from the system. Despite the limitations of an in vivo system, our results provide both morphological and biochemical data about the endosomal compartments involved in the internalization of TβRII upon inflammatory stimuli. Furthermore, our study implies the possible role of caveola-mediated endocytosis in the attenuation of TGF-β signaling and highlight the significance of endosomal compartments via which caveolae might meet the classical endocytic pathway under in vivo inflammatory conditions. Copyright © 2015 Elsevier GmbH. All rights reserved.


PubMed | HAS SE Lendulet Hereditary Endocrine Tumors Research Group, Pharmacology and Drug Safety Research and Semmelweis University
Type: Journal Article | Journal: European journal of cell biology | Year: 2015

We previously showed that intraperitoneal administration of Freunds adjuvant treatment resulted in acute peritonitis and TGF- was found to be one of the main organizers of the subsequent EMT in mesothelial cells. In the present study, we investigated whether TGF- signaling molecules are present in mesothelial cells and how their compartmentalization pattern changes with the dynamics of inflammatory events in vivo. In addition, we tried to evaluate the turnover of endosomal compartments concomitant with the internalization of signaling molecules and examine whether caveola-mediated internalization might play a role in the termination of TGF- signaling. Using immunocytochemical approach, we could detect TRII in EEA1 positive compartments and as the inflammation progressed, at D3, the receptor appeared in caveolin-1 positive intracellular structures as well. The latter event was accompanied by the appearance of negative regulatory protein, Smad7 in caveolae. We also found EEA1 and caveolin-1 double positive vesicular structures that were corresponded to forming MVBs affirmed by our immuno-electron microscopical results. Fine structural, morphometric and immunoblot analysis proved that Cd63 positive multivesicular body (MVB) formation was significantly increased by D3 and the IP results confirmed that TRII as well as caveolin-1 were strongly associated with these endosomal compartments at this time. In contrast, by the termination of inflammation, by D5, caveolin-1 was found to be associated with late endosomal marker, Rab7 and entirely degraded from the system. Despite the limitations of an in vivo system, our results provide both morphological and biochemical data about the endosomal compartments involved in the internalization of TRII upon inflammatory stimuli. Furthermore, our study implies the possible role of caveola-mediated endocytosis in the attenuation of TGF- signaling and highlight the significance of endosomal compartments via which caveolae might meet the classical endocytic pathway under in vivo inflammatory conditions.


Lenkey N.,Hungarian Academy of Sciences | Karoly R.,Hungarian Academy of Sciences | Lukacs P.,Hungarian Academy of Sciences | Vizi E.S.,Hungarian Academy of Sciences | And 3 more authors.
PLoS ONE | Year: 2010

Background: There is only one established drug binding site on sodium channels. However, drug binding of sodium channels shows extreme promiscuity: ~25% of investigated drugs have been found to potently inhibit sodium channels. The structural diversity of these molecules suggests that they may not share the binding site, and/or the mode of action. Our goal was to attempt classification of sodium channel inhibitors by measuring multiple properties of inhibition in electrophysiology experiments. We also aimed to investigate if different properties of inhibition correlate with specific chemical properties of the compounds. Methodology/Principal Findings: A comparative electrophysiological study of 35 compounds, including classic sodium channel inhibitors (anticonvulsants, antiarrhythmics and local anesthetics), as well as antidepressants, antipsychotics and neuroprotective agents, was carried out using rNav1.2 expressing HEK-293 cells and the QPatch automatic patch-clamp instrument. In the multi-dimensional space defined by the eight properties of inhibition (resting and inactivated affinity, potency, reversibility, time constants of onset and offset, use-dependence and state-dependence), at least three distinct types of inhibition could be identified; these probably reflect distinct modes of action. The compounds were clustered similarly in the multi-dimensional space defined by relevant chemical properties, including measures of lipophilicity, aromaticity, molecular size, polarity and electric charge. Drugs of the same therapeutic indication typically belonged to the same type. We identified chemical properties, which were important in determining specific properties of inhibition. State-dependence correlated with lipophilicity, the ratio of the neutral form of molecules, and aromaticity: We noticed that the highly state dependent inhibitors had at least two aromatic rings, logP>4.0, and pKa<8.0. Conclusions/Significance: The correlations of inhibition properties both with chemical properties and therapeutic profiles would not have been evident through the sole determination of IC50; therefore, recording multiple properties of inhibition may allow improved prediction of therapeutic usefulness. © 2010 Lenkey et al.


Balogh P.,Semmelweis University | Szabo A.,Semmelweis University | Katz S.,Semmelweis University | Liko I.,Pharmacology and Drug Safety Research | And 2 more authors.
PLoS ONE | Year: 2013

Transformation of epithelial cells into connective tissue cells (epithelial-mesenchymal transition, EMT) is a complex mechanism involved in tumor metastasis, and in normal embryogenesis, while type II EMT is mainly associated with inflammatory events and tissue regenaration. In this study we examined type II EMT at the ultrastructural and molecular level during the inflammatory process induced by Freund's adjuvant treatment in rat mesenteric mesothelial cells. We found that upon the inflammatory stimulus mesothelial cells lost contact with the basal lamina and with each other, and were transformed into spindle-shaped cells. These morphological changes were accompanied by release of interleukins IL-1alpha, -1beta and IL-6 and by secretion of transforming growth factor beta (TGF-β) into the peritoneal cavity. Mesothelial cells also expressed estrogen receptor alpha (ER-α) as shown by immunolabeling at the light and electron microscopical levels, as well as by quantitative RT-PCR. The mRNA level of ER-α showed an inverse correlation with the secretion of TGF-β. At the cellular and subcellular levels ER-α was colocalized with the coat protein caveolin-1 and was found in the plasma membrane of mesothelial cells, in caveolae close to multivesicular bodies (MVBs) or in the membrane of these organelles, suggesting that ER-α is internalized via caveola-mediated endocytosis during inflammation. We found asymmetric, thickened, electron dense areas on the limiting membrane of MVBs (MVB plaques) indicating that these sites may serve as platforms for collecting and organizing regulatory proteins. Our morphological observations and biochemical data can contribute to form a potential model whereby ER-α and its caveola-mediated endocytosis might play role in TGF-β induced type II EMT in vivo. © 2013 Balogh et al.


Tarnawa I.,Pharmacology and Drug Safety Research
Drugs of the Future | Year: 2012

Increased neuronal activity and/or excitability in particular regions of the peripheral or central nervous system is associated with a great variety of diseases, like chronic pain, epilepsy, neurodegenerative disorders and several psychiatric conditions. Abnormal overfunctioning of volt-age- gated sodium channels frequently underlies these disease states. Developing agents selectively targeting sodium channel subtypes involved in a particular disease is an attractive idea, since their use could be associated with a lower risk of side effects. Currently available drugs targeting sodium channels, however, are nonselective regarding channel subtypes and still have some preference towards diseased neurons because their actions are channel state dependent. They preferentially inhibit channels in the open or inactivated states, which are located abundantly on overactive cells. New results, reviewed in this paper, provide a deeper understanding of the role of sodium channels in the pathomechanism of neuropsychiatric disorders, as well as the interaction of sodium channel inhibitors with their binding sites on the channel. This knowledge, together with a considerable advancement in drug screening technologies, holds the promise that sodium channel inhibitors with improved therapeutic and side effect profiles can be developed. Copyright © 2012 Prous Science, S.A.U. or its licensors. All rights reserved.

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