Publications by authors named "Magdalena Kowalska"

36 Publications

Paroxetine-Overview of the Molecular Mechanisms of Action.

Int J Mol Sci 2021 Feb 7;22(4). Epub 2021 Feb 7.

Department of Organic Chemistry, Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland.

In the 21st century and especially during a pandemic, the diagnosis and treatment of depression is an essential part of the daily practice of many family doctors. It mainly affects patients in the age category 15-44 years, regardless of gender. Anxiety disorders are often diagnosed in children and adolescents. Social phobias can account for up to 13% of these diagnoses. Social anxiety manifests itself in fear of negative social assessment and humiliation, which disrupts the quality of social functioning. Treatment of the above-mentioned disorders is based on psychotherapy and pharmacotherapy. Serious side effects or mortality from antidepressant drug overdose are currently rare. Recent studies indicate that paroxetine (ATC code: N06AB), belonging to the selective serotonin reuptake inhibitors, has promising therapeutic effects and is used off-label in children and adolescents. The purpose of this review is to describe the interaction of paroxetine with several molecular targets in various points of view including the basic chemical and pharmaceutical properties. The central point of the review is focused on the pharmacodynamic analysis based on the molecular mechanism of binding paroxetine to various therapeutic targets.
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http://dx.doi.org/10.3390/ijms22041662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914979PMC
February 2021

K11.1, Na1.5, and Ca1.2 Transporter Proteins as Antitarget for Drug Cardiotoxicity.

Int J Mol Sci 2020 Oct 30;21(21). Epub 2020 Oct 30.

Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland.

Safety assessment of pharmaceuticals is a rapidly developing area of pharmacy and medicine. The new advanced guidelines for testing the toxicity of compounds require specialized tools that provide information on the tested drug in a quick and reliable way. Ion channels represent the third-largest target. As mentioned in the literature, ion channels are an indispensable part of the heart's work. In this paper the most important information concerning the guidelines for cardiotoxicity testing and the way the tests are conducted has been collected. Attention has been focused on the role of selected ion channels in this process.
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http://dx.doi.org/10.3390/ijms21218099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663169PMC
October 2020

Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies.

Curr Drug Metab 2020 ;21(7):548-561

Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland.

Background: Painful peripheral neuropathy is a dose-limiting adverse effect of the antitumor drug oxaliplatin. The main symptoms of neuropathy: tactile allodynia and cold hyperalgesia, appear in more than 80% of patients on oxaliplatin therapy and are due to the overexpression of neuronal sodium channels (Navs) and neuroinflammation.

Objective: This study assessed antiallodynic and antihyperalgesic properties of two repurposed drugs with antiinflammatory and Nav-blocking properties (bromhexine and its pharmacologically active metabolite - ambroxol) in a mouse model of neuropathic pain induced by oxaliplatin. Using molecular docking techniques, we predicted targets implicated in the observed in vivo activity of bromhexine.

Methods: Oxaliplatin (a single intraperitoneal dose of 10 mg/kg) induced tactile allodynia and cold hyperalgesia in CD-1 mice and the effectiveness of single-dose or repeated-dose bromhexine and ambroxol to attenuate pain hypersensitivity was assessed in von Frey and cold plate tests. Additionally, Veber analysis and molecular docking experiments of bromhexine on mouse (m) and human (h) Nav1.6-1.9 were carried out.

Results: At the corresponding doses, ambroxol was more effective than bromhexine as an antiallodynic agent. However, at the dose of 150 mg/kg, ambroxol induced motor impairments in mice. Repeated-dose bromhexine and ambroxol partially attenuated the development of late-phase tactile allodynia in oxaliplatin-treated mice. Only 7-day administration of bromhexine attenuated the development of late-phase cold hyperalgesia. Bromhexine was predicted to be a strong inhibitor of mNav1.6, mNav1.7, mNav1.9, and hNav1.7-hNav1.9.

Conclusion: The conversion of bromhexine to other than ambroxol active metabolites should be considered when interpreting some of its in vivo effects. Nav-blocking properties of bromhexine (and previously also predicted for ambroxol) might underlie its ability to attenuate pain caused by oxaliplatin.
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http://dx.doi.org/10.2174/1389200221666200711155632DOI Listing
January 2020

Development of pancreatic acini in embryos of the grass snake Natrix natrix (Lepidosauria, Serpentes).

J Morphol 2020 01 12;281(1):110-121. Epub 2019 Nov 12.

Department of Animal Histology and Embryology, University of Silesia in Katowice, Katowice, Poland.

This study report about the differentiation of pancreatic acinar tissue in grass snake, Natrix natrix, embryos using light microscopy, transmission electron microscopy, and immuno-gold labeling. Differentiation of acinar cells in the embryonic pancreas of the grass snake is similar to that of other amniotes. Pancreatic acini occurred for the first time at Stage VIII, which is the midpoint of embryonic development. Two pattern of acinar cell differentiation were observed. The first involved formation of zymogen granules followed by cell migration from ducts. In the second, one zymogen granule was formed at the end of acinar cell differentiation. During embryonic development in the pancreatic acini of N. natrix, five types of zymogen granules were established, which correlated with the degree of their maturation and condensation. Within differentiating acini of the studied species, three types of cells were present: acinar, centroacinar, and endocrine cells. The origin of acinar cells as well as centroacinar cells in the pancreas of the studied species was the pancreatic ducts, which is similar as in other vertebrates. In the differentiating pancreatic acini of N. natrix, intermediate cells were not present. It may be related to the lack of transdifferentiation activity of acinar cells in the studied species. Amylase activity of exocrine pancreas was detected only at the end of embryonic development, which may be related to animal feeding after hatching from external sources that are rich in carbohydrates and presence of digestive enzymes in the egg yolk. Mitotic division of acinar cells was the main mechanism of expansion of acinar tissue during pancreas differentiation in the grass snake embryos.
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http://dx.doi.org/10.1002/jmor.21083DOI Listing
January 2020

The influence of cationic lipoid - 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine - on model lipid membranes.

Biochim Biophys Acta Biomembr 2020 02 30;1862(2):183088. Epub 2019 Oct 30.

Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland. Electronic address:

The triesters of phosphatidylcholine as the derivatives of natural phosphatidylcholines are less cytotoxic than the other cationic lipoids, therefore they can be applied in lipofection and in drug delivery. However, a successful and effective use of these compounds requires detailed information of their mechanism of action, which is probably highly complex and multi-stages. However, the first barrier in the way to cell and thus the first side of action of these compounds is the cellular membrane. The aim of this work was to investigate the effect of one cationic lipoid, namely 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (EPOPC) on model POPC/SM/Chol = 1:1:1 membranes. The experiments were performed on monolayer and bilayer systems and they involved the surface pressure measurements, Brewster angle microscopy studies, dynamic light scattering and zeta potential measurements and the experiments with the surfactant solution and steady-state fluorescence anisotropy of DPH and TMA-DPH. Moreover, to perform the studies systematically also the properties of the binary (POPC/EPOPC, SM/EPOPC, Chol/EPOPC) and ternary (POPC/Chol/EPOPC, SM/Chol/EPOPC) model systems were investigated. The obtained results indicated that even low concentration of EPOPC alters properties and organization of model membranes. Namely, EPOPC makes the interactions in model membrane weaker and increases fluidity and permeability of the lipid system. Finally, based on these data it can be proposed that the mechanism of action of EPOPC in lipofection/drug delivery involves the modifications in membrane organization, which facilitates the incorporation of drug or other material into the cell.
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http://dx.doi.org/10.1016/j.bbamem.2019.183088DOI Listing
February 2020

Development of endocrine pancreatic islets in embryos of the grass snake Natrix natrix (Lepidosauria, Serpentes).

J Morphol 2019 01 5;280(1):103-118. Epub 2018 Dec 5.

Department of Animal Histology and Embryology, University of Silesia in Katowice, Poland.

Differentiation of the pancreatic islets in grass snake Natrix natrix embryos, was analyzed using light, transmission electron microscopy, and immuno-gold labeling. The study focuses on the origin of islets, mode of islet formation, and cell arrangement within islets. Two waves of pancreatic islet formation in grass snake embryos were described. The first wave begins just after egg laying when precursors of endocrine cells located within large cell agglomerates in the dorsal pancreatic bud differentiate. The large cell agglomerates were divided by mesenchymal cells thus forming the first islets. This mode of islet formation is described as fission. During the second wave of pancreatic islet formation which is related to the formation of the duct mantle, we observed four phases of islet formation: (a) differentiation of individual endocrine cells from the progenitor layer of duct walls (budding) and their incomplete delamination; (b) formation of two types of small groups of endocrine cells (A/D and B) in the wall of pancreatic ducts; (c) joining groups of cells emerging from neighboring ducts (fusion) and rearrangement of cells within islets; (d) differentiated pancreatic islets with characteristic arrangement of endocrine cells. Mature pancreatic islets of the grass snake contained mainly A endocrine cells. Single B and D or PP-cells were present at the periphery of the islets. This arrangement of endocrine cells within pancreatic islets of the grass snake differs from that reported from most others vertebrate species. Endocrine cells in the pancreas of grass snake embryos were also present in the walls of intralobular and intercalated ducts. At hatching, some endocrine cells were in contact with the lumen of the pancreatic ducts.
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http://dx.doi.org/10.1002/jmor.20921DOI Listing
January 2019

Peritoneal fluid stimulates neoplastic transformation of normal HEK 293 cells by high expression of pluripotent genes.

Pol J Pathol 2018;69(3):399-310

Gynecological cancers constitute a serious problem in the world. Their advanced stages are often characterized by the accumulation of ascites, which leads to spreading of cancer cells outside their primary focus. Despite progress in the treatment, prognoses are still not satisfactory. The main causes of these failures are chemoresistance, metastases and recurrences of the disease, which is influenced by, among others, the microenvironment of cancer cells. This study investigated the effect of the microenvironment, which create ascites derived from patients with ovarian and endometrial cancer to non-gynecological HEK 293 cells. The effect of the gynecological cancer microenvironment on HEK 293 cells behaviour was analysed using RT-PCR, qRT-PCR, Western blotting and functional analysis (invasion assays, hanging drop) methods. Our results suggest that the key genes for the development of cancer can be regulated by epigenetic and hypoxia-inducible factor in dependent manner. It was observed that in vitro microenvironment, which is created by cells originating from patients with gynecological cancer (ovarian cancer, endometrial cancer) is able to generate changes in HEK 293 cells by itself.
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http://dx.doi.org/10.5114/pjp.2018.79550DOI Listing
May 2019

The influence of the essential oil extracted from hops on monolayers and bilayers imitating plant pathogen bacteria membranes.

Colloids Surf B Biointerfaces 2019 Jan 19;173:672-680. Epub 2018 Oct 19.

Department of Environmental Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Kraków, Poland. Electronic address:

Many plant-derived compounds possess antimicrobial, antioxidant and even anticancer activities. Therefore, they are considered as substances that can be used instead of synthetic compounds in various applications. In this work, the essential oil from hop cones was extracted and analyzed, and then its effects on model bacteria membranes were studied to verify whether the hop essential oils could be used as ecological pesticides. The experiments involved surface pressure-area measurements, penetration studies and Brewster angle microscopy (BAM) imaging of lipid monolayers as well as hydrodynamic diameter, zeta potential, steady-state fluorescence anisotropy and Cryo-Transmission Electron Microscopy (cryo-TEM) measurements of liposomes. Finally the bactericidal tests on plant pathogen bacteria Pseudomonas syringae pv. lachrymans PCM 1410 were performed. The obtained results showed that the components of the essential oils from hop cones incorporate into lipid monolayers and bilayers and alter their fluidity. However, the observed effect is determined by the system composition, its condensation and the oil concentration. Interestingly, at a given dose, the effect of the essential oil on membranes was found to stabilize. Moreover, BAM images proved that hop oil prevents the formation of a large fraction of a condensed phase at the interface. Both the studies on model membranes as well as the in vitro tests allow one to conclude that the hop essential oil could likely be considered as the candidate to be used in agriculture as a natural pesticide.
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http://dx.doi.org/10.1016/j.colsurfb.2018.10.047DOI Listing
January 2019

Studies on the Activity of Selected Highly Lipophilic Compounds toward hGAT1 Inhibition. Part II.

ACS Chem Neurosci 2019 01 28;10(1):337-347. Epub 2018 Sep 28.

Department of Pharmacodynamics, Chair of Pharmacodynamics , Jagiellonian University Medical College , 9 Medyczna St. , 30-688 Krakow , Poland.

In this paper, we describe the latest results involving molecular modeling and pharmacodynamic studies of the selected highly lipophilic compounds acting by human GABA transporter 1 (hGAT1) inhibition. The chemical interaction of 17 GABA analogues with a model of hGAT1 is described using the molecular docking method. The biological role of GAT1 is related to the regulation of GABA level in the central nervous system and GAT1 inhibition plays an important role in the control of seizure threshold. To confirm that GAT1 can be also a molecular target for drugs used to treat other neurological and psychiatric diseases (e.g., pain and anxiety), in the in vivo part of this study, potential antinociceptive and anxiolytic-like properties of tiagabine, a selective GAT1 inhibitor, are described.
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http://dx.doi.org/10.1021/acschemneuro.8b00282DOI Listing
January 2019

Development of the duct system during exocrine pancreas differentiation in the grass snake Natrix natrix (Lepidosauria, Serpentes).

J Morphol 2018 06 21;279(6):724-746. Epub 2018 Feb 21.

Department of Animal Histology and Embryology, University of Silesia, Katowice, Poland.

We analyzed the development of the pancreatic ducts in grass snake Natrix natrix L. embryos with special focus on the three-dimensional (3D)-structure of the duct network, ultrastructural differentiation of ducts with attention to cell types and lumen formation. Our results indicated that the system of ducts in the embryonic pancreas of the grass snake can be divided into extralobular, intralobular, and intercalated ducts, similarly as in other vertebrate species. However, the pattern of branching was different from that in other vertebrates, which was related to the specific topography of the snake's internal organs. The process of duct remodeling in Natrix embryos began when the duct walls started to change from multilayered to single-layered and ended together with tube formation. It began in the dorsal pancreatic bud and proceeded toward the caudal direction. The lumen of pancreatic ducts differentiated by cavitation because a population of centrally located cells was cleared through cell death resembling anoikis. During embryonic development in the pancreatic duct walls of the grass snake four types of cells were present, that is, principal, endocrine, goblet, and basal cells, which is different from other vertebrate species. The principal cells were electron-dense, contained indented nuclei with abundant heterochromatin, microvilli and cilia, and were connected by interdigitations of lateral membranes and junctional complexes. The endocrine cells were electron-translucent and some of them included endocrine granules. The goblet cells were filled with large granules with nonhomogeneous, moderately electron-dense material. The basal cells were small, electron-dense, and did not reach the duct lumen.
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http://dx.doi.org/10.1002/jmor.20806DOI Listing
June 2018

Ultrastructure of endocrine pancreatic granules during pancreatic differentiation in the grass snake, Natrix natrix L. (Lepidosauria, Serpentes).

J Morphol 2018 03 17;279(3):330-348. Epub 2017 Nov 17.

Department of Animal Histology and Embryology, University of Silesia, 9 Bankowa St, Katowice, 40-007, Poland.

We used transmission electron microscopy to study the pancreatic main endocrine cell types in the embryos of the grass snake Natrix natrix L. with focus on the morphology of their secretory granules. The embryonic endocrine part of the pancreas in the grass snake contains four main types of cells (A, B, D, and PP), which is similar to other vertebrates. The B granules contained a moderately electron-dense crystalline-like core that was polygonal in shape and an electron-dense outer zone. The A granules had a spherical electron-dense eccentrically located core and a moderately electron-dense outer zone. The D granules were filled with a moderately electron-dense non-homogeneous content. The PP granules had a spherical electron-dense core with an electron translucent outer zone. Within the main types of granules (A, B, D, PP), different morphological subtypes were recognized that indicated their maturity, which may be related to the different content of these granules during the process of maturation. The sequence of pancreatic endocrine cell differentiation in grass snake embryos differs from that in many vertebrates. In the grass snake embryos, the B and D cells differentiated earlier than A and PP cells. The different sequence of endocrine cell differentiation in snakes and other vertebrates has been related to phylogenetic position and nutrition during early developmental stages.
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http://dx.doi.org/10.1002/jmor.20775DOI Listing
March 2018

Genotoxic potential of diesel exhaust particles from the combustion of first- and second-generation biodiesel fuels-the FuelHealth project.

Environ Sci Pollut Res Int 2017 Nov 9;24(31):24223-24234. Epub 2017 Sep 9.

Department of Radiobiology and Immunology, Institute of Biology, Jan Kochanowski University, 15 Swietokrzyska Str, 25-406, Kielce, Poland.

Epidemiological data indicate that exposure to diesel exhaust particles (DEPs) from traffic emissions is associated with higher risk of morbidity and mortality related to cardiovascular and pulmonary diseases, accelerated progression of atherosclerotic plaques, and possible lung cancer. While the impact of DEPs from combustion of fossil diesel fuel on human health has been extensively studied, current knowledge of DEPs from combustion of biofuels provides limited and inconsistent information about its mutagenicity and genotoxicity, as well as possible adverse health risks. The objective of the present work was to compare the genotoxicity of DEPs from combustion of two first-generation fuels, 7% fatty acid methyl esters (FAME) (B7) and 20% FAME (B20), and a second-generation 20% FAME/hydrotreated vegetable oil (SHB: synthetic hydrocarbon biofuel) fuel. Our results revealed that particulate engine emissions from each type of biodiesel fuel induced genotoxic effects in BEAS-2B and A549 cells, manifested as the increased levels of single-strand breaks, the increased frequencies of micronuclei, or the deregulated expression of genes involved in DNA damage signaling pathways. We also found that none of the tested DEPs showed the induction of oxidative DNA damage and the gamma-H2AX-detectable double-strand breaks. The most pronounced differences concerning the tested particles were observed for the induction of single-strand breaks, with the greatest genotoxicity being associated with the B7-derived DEPs. The differences in other effects between DEPs from the different biodiesel blend percentage and biodiesel feedstock were also observed, but the magnitude of these variations was limited.
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http://dx.doi.org/10.1007/s11356-017-9995-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655577PMC
November 2017

A comparative analysis of in vitro toxicity of diesel exhaust particles from combustion of 1st- and 2nd-generation biodiesel fuels in relation to their physicochemical properties-the FuelHealth project.

Environ Sci Pollut Res Int 2017 Aug 3;24(23):19357-19374. Epub 2017 Jul 3.

Center for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, 16 Dorodna Str., 03-195, Warsaw, Poland.

Biodiesels represent more carbon-neutral fuels and are introduced at an increasing extent to reduce emission of greenhouse gases. However, the potential impact of different types and blend concentrations of biodiesel on the toxicity of diesel engine emissions are still relatively scarce and to some extent contradictory. The objective of the present work was to compare the toxicity of diesel exhaust particles (DEP) from combustion of two 1st-generation fuels: 7% fatty acid methyl esters (FAME; B7) and 20% FAME (B20) and a 2nd-generation 20% FAME/HVO (synthetic hydrocarbon biofuel (SHB)) fuel. Our findings indicate that particulate emissions of each type of biodiesel fuel induce cytotoxic effects in BEAS-2B and A549 cells, manifested as cell death (apoptosis or necrosis), decreased protein concentrations, intracellular ROS production, as well as increased expression of antioxidant genes and genes coding for DNA damage-response proteins. The different biodiesel blend percentages and biodiesel feedstocks led to marked differences in chemical composition of the emitted DEP. The different DEPs also displayed statistically significant differences in cytotoxicity in A549 and BEAS-2B cells, but the magnitude of these variations was limited. Overall, it seems that increasing biodiesel blend concentrations from the current 7 to 20% FAME, or substituting 1st-generation FAME biodiesel with 2nd-generation HVO biodiesel (at least below 20% blends), affects the in vitro toxicity of the emitted DEP to some extent, but the biological significance of this may be moderate.
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http://dx.doi.org/10.1007/s11356-017-9561-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556143PMC
August 2017

Photodynamic therapy in the treatment of vulvar lichen sclerosus.

Photodiagnosis Photodyn Ther 2017 Sep 17;19:135-139. Epub 2017 May 17.

Department of Gynecologic Oncology, The Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology in Warsaw, Roentgena Street 5, 02-781 Warsaw, Poland. Electronic address:

Background: Vulvar lichen sclerosus is a chronic and incurable disease that causes various unpleasant symptoms and serious consequences.

Objective: The purpose of the study was to assess the effectiveness of photodynamic therapy in the treatment of vulvar lichen sclerosus.

Methods: Participants in the study included 102 female patients aged 19-85 suffer from vulvar lichen sclerosus. The patients underwent photodynamic therapy (PDT). In the course of PDT the 5% 5- aminolevulinic acid was used in gel form. The affected areas were irradiated with a halogenic lamp PhotoDyn 501 (590-760nm) during a 10-min radiation treatment. The treatment was repeated weekly for 10 weeks.

Result: PDT has brought about a good therapeutic effect (complete or partial clinical remission), with 87.25% improvement rate in patients suffering from lichen sclerosus. The greatest vulvoscopic response was observed in the reduction of subepithelial ecchymoses and teleangiectasia (78.95%), and the reduction of erosions and fissures (70.97%). A partial remission of lichenification with hyperkeratosis was observed in 51.61% of cases. The least response was observed in the atrophic lesions reduction (improvement in 37.36% of cases).

Conclusion: Our patients suffering from vulvar lichen sclerosus demonstrated positive responses to photodynamic therapy and the treatment was well tolerated. Photodynamic therapy used to treat lichen sclerosus yields excellent cosmetic results.
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http://dx.doi.org/10.1016/j.pdpdt.2017.05.011DOI Listing
September 2017

Three-dimensional reconstruction of the embryonic pancreas in the grass snake Natrix natrix L. (Lepidosauria, Serpentes) based on histological studies.

Zoology (Jena) 2017 04 11;121:91-110. Epub 2016 Nov 11.

Department of Animal Histology and Embryology, University of Silesia, 9 Bankowa Str., 40-007 Katowice, Poland. Electronic address:

The aim of this study was to evaluate two research hypotheses: H-the embryonic pancreas in grass snakes develops in the same manner as in all previously investigated amniotes (from three buds) and its topographical localization within the adult body has no relation to its development; H-the pancreas develops in a different manner and is related to the different topography of internal organs in snakes. For the evaluation of these hypotheses we used histological methods and three-dimensional (3D) reconstructions of the position of the pancreatic buds and surrounding organs at particular developmental stages and of the final position and shape of the pancreatic gland. Our results indicate that the pancreas primordium in the grass snake is formed by only two buds - a dorsal and a ventral one - that are not connected until the end of stage II. This differs from the majority of vertebrates investigated so far. The gall bladder of the grass snake embryos is connected with the liver only by a thin cystic duct, which also differs from many other vertebrates. Our histological study also indicates a different distribution of the endocrine cells in the embryonic pancreas of the grass snake because the first endocrine cells appeared in the dorsal part of the pancreas in a region located close to the spleen. During the entire developmental period no evidence of these cells was found in the ventral part of the pancreas. The endocrine cells form elongated, large and irregular-shaped islets. They can also form structures resembling "inverted acini". Such an arrangement is characteristic of snakes only. The differentiating pancreas penetrates the ventral part of the developing spleen and divides it into three separate parts at developmental stage IX. This is unique among vertebrates. At the end of the embryonic development (stage XI), the pancreas, the spleen and the gall bladder are located in close proximity and form the so-called triad. Our results suggest that the untypical topography of the organ systems in snakes may determine the unique development of the pancreas in these animals.
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http://dx.doi.org/10.1016/j.zool.2016.11.001DOI Listing
April 2017

Ultrastructural features of the differentiating thyroid primordium in the sand lizard (Lacerta agilis L.) from the differentiation of the cellular cords to the formation of the follicular lumen.

Zoology (Jena) 2016 Apr 29;119(2):97-112. Epub 2015 Dec 29.

Department of Vertebrate Biology and Conservation, University of Wroclaw, 21 Sienkiewicza Str., 50-225 Wroclaw, Poland.

The differentiation of the thyroid primordium of lacertilian species is poorly understood. The present study reports on the ultrastructural analysis of the developing thyroid primordium in the sand lizard (Lacerta agilis) during the early stages of differentiation. The early thyroid primordium of sand lizard embryos was composed of cellular cords that contained single cells with a giant lipid droplet, which were eliminated by specific autophagy (lipophagy). The follicular lumens at the periphery of the primordium differentiated even before the division of the cellular cords. When the single cells within the cords started to die through paraptosis, the adjacent cells started to polarise and junctional complexes began to form around them. After polarisation and clearing up after the formation of the lumens, the cellular cords divided into definitive follicles. The cellular cords in the central part of the primordium started to differentiate later than those at the periphery. The cellular cords divided into presumptive follicles first and only later differentiated into definitive follicles. During this process, a population of centrally located cells was removed through apoptosis to form the lumen. Although the follicular lumen in sand lizard embryos is differentiated by cavitation similar to that in the grass snake, there were very important differences during the early stages of the differentiation of the cellular cords and the formation of the thyroid follicles.
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http://dx.doi.org/10.1016/j.zool.2015.12.005DOI Listing
April 2016

Precision Test of Many-Body QED in the Be+ 2p Fine Structure Doublet Using Short-Lived Isotopes.

Phys Rev Lett 2015 Jul 13;115(3):033002. Epub 2015 Jul 13.

CERN, Physics Department, CH-1211 Geneva 23, Switzerland.

Absolute transition frequencies of the 2s 2S{1/2}→2p2P{1/2,3/2} transitions in Be^{+} were measured for the isotopes ^{7,9-12}Be. The fine structure splitting of the 2p state and its isotope dependence are extracted and compared to results of ab initio calculations using explicitly correlated basis functions, including relativistic and quantum electrodynamics effects at the order of mα(6) and mα(7) ⁢ln α. Accuracy has been improved in both the theory and experiment by 2 orders of magnitude, and good agreement is observed. This represents one of the most accurate tests of quantum electrodynamics for many-electron systems, being insensitive to nuclear uncertainties.
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http://dx.doi.org/10.1103/PhysRevLett.115.033002DOI Listing
July 2015

Defining Blood Processing Parameters for Optimal Detection of γ-H2AX Foci: A Small Blood Volume Method.

Radiat Res 2015 Jul 29;184(1):95-104. Epub 2015 Jun 29.

a  Institute of Nuclear Chemistry and Technology, Centre for Radiobiology and Biological Dosimetry, Warsaw, Poland;

Biodosimetric methods used to measure the effects of radiation are critical for estimating the health risks to irradiated individuals or populations. The direct measurement of radiation-induced γ-H2AX foci in peripheral blood lymphocytes is one approach that provides a useful end point for triage. Despite the documented advantages of the γ-H2AX assay, there is considerable variation among laboratories regarding foci formation in the same exposure conditions and cell lines. Taking this into account, the goal of our study was to evaluate the influence of different blood processing parameters on the frequency of γ-H2AX foci and optimize a small blood volume protocol for the γ-H2AX assay, which simulates the finger prick blood collection method. We found that the type of fixative, temperature and blood processing time markedly affect the results of the γ-H2AX assay. In addition, we propose a protocol for the γ-H2AX assay that may serve as a potential guideline in the event of large-scale radiation incidents.
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http://dx.doi.org/10.1667/RR13897.1DOI Listing
July 2015

The influence of tea tree oil (Melaleuca alternifolia) on fluconazole activity against fluconazole-resistant Candida albicans strains.

Biomed Res Int 2015 4;2015:590470. Epub 2015 Feb 4.

Department of Microbiology and Immunology, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland.

The aim of this study was to evaluate the activity of fluconazole against 32 clinical strains of fluconazole-resistant Candida albicans, and C. albicans ATCC 10231 reference strain, after their exposure to sublethal concentrations of tea tree oil (TTO) or its main bioactive component terpinen-4-ol. For all tested fluconazole-resistant C. albicans strains TTO and terpinen-4-ol minimal inhibitory concentrations (MICs) were low, ranging from 0.06% to 0.5%. The 24-hour exposure of fluconazole-resistant C. albicans strains to fluconazole with sublethal dose of TTO enhanced fluconazole activity against these strains. Overall, 62.5% of isolates were classified as susceptible, 25.0% exhibited intermediate susceptibility, and 12.5% were resistant. For all of the tested clinical strains the fluconazole MIC decreased from an average of 244.0 μg/mL to an average of 38.46 μg/mL, and the fluconazole minimal fungicidal concentrations (MFC) decreased from an average of 254.67 μg/mL to an average of 66.62 μg/mL. Terpinen-4-ol was found to be more active than TTO, and strongly enhanced fluconazole activity against fluconazole-resistant C. albicans strains. The results of this study demonstrate that combining natural substances such as TTO and conventional drug such as fluconazole, may help treat difficult yeast infections.
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http://dx.doi.org/10.1155/2015/590470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334616PMC
November 2015

Billion-fold enhancement in sensitivity of nuclear magnetic resonance spectroscopy for magnesium ions in solution.

Chemphyschem 2014 Dec 9;15(18):3929-32. Epub 2014 Oct 9.

CERN, 1211 Genève 23 (Switzerland).

β-nuclear magnetic resonance (NMR) spectroscopy is highly sensitive compared to conventional NMR spectroscopy, and may be applied for several elements across the periodic table. β-NMR has previously been successfully applied in the fields of nuclear and solid-state physics. In this work, β-NMR is applied, for the first time, to record an NMR spectrum for a species in solution. (31)Mg β-NMR spectra are measured for as few as 10(7) magnesium ions in ionic liquid (EMIM-Ac) within minutes, as a prototypical test case. Resonances are observed at 3882.9 and 3887.2 kHz in an external field of 0.3 T. The key achievement of the current work is to demonstrate that β-NMR is applicable for the analysis of species in solution, and thus represents a novel spectroscopic technique for use in general chemistry and potentially in biochemistry.
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http://dx.doi.org/10.1002/cphc.201402619DOI Listing
December 2014

Association of N-(pyridin-2-yl),N'-substituted ureas with 2-amino-1,8-naphthyridines and benzoates: NMR and quantum chemical studies of the substituent effect on complexation.

J Org Chem 2013 Aug 24;78(15):7582-93. Epub 2013 Jul 24.

Faculty of Chemical Technology and Engineering, University of Technology and Life Sciences, Seminaryjna 3, PL-85-326 Bydgoszcz, Poland.

Association of four N-(pyridin-2-yl),N'-R(1)-ureas (R(1) = ethyl, n-butyl, phenyl, and tert-butyl) with substituted 2-amino-1,8-naphthyridines and benzoates were studied by (1)H NMR spectroscopic titrations and quantum chemical calculations. The benzoates and 2-amino-1,8-naphthyridines were selected as representatives of double and triple hydrogen bonding counterparts, respectively. The classical substituent effect on the association was studied. A prerequisite and a crucial step for the complex formation was the breaking of the intramolecular hydrogen bond in urea derivatives. The QTAIM calculation method was employed to explain the hydrogen bonding within complexes. In the case of benzoates carrying an electron-donating substituent the experimental findings were explained by the formation of two complexes. These observations were rationalized by the electronic repulsions between atoms in a close proximity and further verified by calculations. Single-crystal X-ray diffraction was used to confirm the structure of studied ureas in the crystalline state. These results are in line with the solution studies of self-association of ureas.
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http://dx.doi.org/10.1021/jo4011393DOI Listing
August 2013

[Difficulties in the diagnosis of the first symptoms of brain tumors prehospital delay diagnosis].

Pol Merkur Lekarski 2012 Dec;33(198):317-21

Centrum Medycznego Kształcenia Podyplomowego, Klinika Neurologii i Epileptologii, Samodzielny Publiczny Szpital Kliniczny, Warszawa.

Unlabelled: The nervous system tumors pose a current challenge to modern medicine. Diagnosis, established at an early stage of tumor development, increases the chance of the use of radical therapeutic methods, which is associated with better prognosis. The preferred method of treatment of brain tumors is the surgical treatment. Success of this therapy depends on the possibility of the radical removal of neoplastic tissue. The aim of the study was to evaluate the type and duration of clinical symptoms, which were the cause for hospitalization, prehospital diagnostics and possibilities of the use the methods of treatment giving the chance for cure at the time of diagnosis of the neoplastic process within central nervous system.

Material And Methods: A retrospective analysis of medical records of 56 patients, hospitalized in 2009-2010 at the Department of Neurology and Epileptology, The Medical Centre of Postgraduate Education in Warsaw. The basis for the diagnosis were the results of two-phase neuroimaging studies. The whole results were analyzed statistically to looking for a correlation between the duration of symptoms prior to hospitalization, their nature and the proposed treatment.

Results: Draws attention to the young age of analyzed patients (mean age 67 years). The most common symptoms were disturbances of consciousness or behavioral changes (37% patients), limb weakness and sensory disturbances (37%) and speech disorders (30%). Other, commonly reported nonspecific symptoms were: somnolence, deterioration of everyday functioning, fatigue and malaise. In the group of the 56 patients with confirmed tumor, 14 (25%) were urgently admitted to our Department, 13 (23%) arrived first to the general practitioner practice. Unfortunately, 29 (52%) out of 56 patients did not arrived to the outpatient physician, despite the first discomfort feelings. They got at a later time directly to the hospital emergency room. In most cases the proposed treatment was neurosurgical operation (n = 19, 35%), whereas radiotherapy was suggested to 4 patients (8%), and palliative treatment in the form of radiation therapy to the whole area of the brain (n = 11, 20%) and of the spine (n = 1) to 12 people. We did not find a statistically significant correlation in our study.

Conclusions: Nonspecific symptoms that may be the only manifestation of proliferative disease within the central nervous system, should attract particular oncology attention, otherwise the diagnosis may be delayed. Advancement of the disease at the moment of establishment of the diagnosis does not allow for the use of causal treatment.
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December 2012

Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB-1020: implications for treatment of attention-deficit hyperactivity disorder.

Synapse 2012 Jun 22;66(6):522-32. Epub 2012 Feb 22.

Euthymics Bioscience Inc., Thorndike St Suite S1-3, Cambridge, MA 02141, USA.

We report on the pharmacological, behavioral, and neurochemical characterization of a novel dual norepinephrine (NE)/dopamine (DA) transporter inhibitor EB-1020 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane HCl). EB-1020 preferentially inhibited monoamine reuptake in cloned cell lines transfected with human transporters with IC₅₀ values of 6 and 38, respectively, for NE and DA transporters. In microdialysis studies, EB-1020 markedly increased NE, and DA concentrations levels in rat prefrontal cortex in vivo with peak increases of 375 and 300%, respectively with the greatest effects on NE, and also increased DA extracellular concentrations in the striatum to 400% of baseline concentrations. Behavioral studies demonstrated that EB-1020 dose-dependently decreased immobility in the mouse tail suspension test of depression to 13% of control levels, and did not stimulate locomotor activity in adult rats in the optimal dose range. EB-1020 dose-dependently inhibited locomotor hyperactivity in juvenile rats lesioned with the neurotoxin 6-hydroxydopamine (100 μg intracisternally) as neonates; a well-established animal model for attention-deficit hyperactivity disorder (ADHD). These data suggest that EB-1020 mediates its actions by stimulating NE and DA neurotransmission, which are typically impaired in ADHD.
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http://dx.doi.org/10.1002/syn.21538DOI Listing
June 2012

2-Acylamino-6-pyridones: breaking of an intramolecular hydrogen bond by self-association and complexation with double and triple hydrogen bonding counterparts. Uncommon steric effect on intermolecular interactions.

J Org Chem 2012 Feb 2;77(4):1653-62. Epub 2012 Feb 2.

Faculty of Chemical Technology and Engineering, University of Technology and Life Sciences, Seminaryjna 3, PL-85-326 Bydgoszcz, Poland.

2-Acylamino-6-pyridones (acyl = RCO, where R = Me, Et, i-Pr, t-Bu, and 1-adamantyl) were previously characterized by X-ray diffractometry and solid-state NMR techniques by us. One of these compounds was used recently in organocatalysis. The series is now studied in solution and by computational methods recommended for noncovalent interactions (DFT/M05). These compounds showed interesting behavior during dilution and titration experiments monitored by (1)H NMR. 2-Acylamino-6-pyridones change their conformation at higher concentrations, forming double hydrogen-bonded dimers and trimers in which an uncommon steric effect is observed. To the best of our knowledge, this is the first example of such behavior of hydrogen-bonded molecules. Heterocomplexation of the studied compounds happens via double or triple hydrogen bonding, depending on the properties of the counterpart. The computation data support and explain the effects observed experimentally, including the tautomeric, closed/open form equilibrium and intermolecular interaction preferences.
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http://dx.doi.org/10.1021/jo201800uDOI Listing
February 2012

Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity.

Synapse 2012 May 15;66(5):435-44. Epub 2012 Feb 15.

Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland.

Major depressive disorder is a prevalent disease, and current pharmacotherapy is considered to be inadequate. It has been hypothesized that a triple reuptake inhibitor (TRI) that activates dopamine (DA) neurotransmission in addition to serotonin and norepinephrine (NE) circuitries may result in enhanced antidepressant effects. Here, we investigated the pharmacological effects of a serotonin-preferring TRI-amitifadine (EB-1010, formerly DOV 21947). The effects of amitifadine (10 mg/kg ip.) on extracellular concentrations of monoamines and their metabolites in rat brain regions were investigated using the in vivo microdialysis technique. The effects of amitifadine on locomotor activity and stereotyped behavior were also evaluated. A major metabolite of amitifadine, the 2-lactam compound, was investigated for inhibition of monoamine uptake processes. Amitifadine markedly and persistently increased extracellular concentrations of serotonin, NE, and DA in prefrontal cortex. The extracellular concentrations of DA were also increased in the DA-rich areas striatum and nucleus accumbens. The extracellular concentrations of the metabolites of serotonin, 5-hydroxyindoleacetic acid, and DA, 3,4-dihydroxyphenylacetic and homovanillic acid, were also markedly decreased in brain regions. Amitifadine did not increase locomotor activity or stereotypical behaviors over a broad dose range. The lactam metabolite of amitifadine weakly inhibited monoamine uptake. Thus, amitifadine increased extracellular concentrations of serotonin, NE, and DA, consistent with TRI. Although amitifadine significantly increased DA in the nucleus accumbens, it did not induce locomotor hyperactivity or stereotypical behaviors. The enhancement of serotonin, NE, and DA in rat brain regions associated with depression suggest that amitifadine may have novel antidepressant activity.
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http://dx.doi.org/10.1002/syn.21531DOI Listing
May 2012

Neuroprotective potential of mGluR5 antagonist MTEP: effects on kainate-induced excitotoxicity in the rat hippocampus.

Pharmacol Rep 2010 Nov-Dec;62(6):1051-61

Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.

Extensive research into glutamate receptors in the central nervous system has shown important role of metabotropic glutamate receptors (mGluR) as potential targets for neuroprotective drugs. The aim of the present study was to investigate neuroprotective potential of the highly selective mGlu5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) against kainate (KA)-induced excitotoxicity in vivo. Our attention was focused mainly on the effectiveness of delayed treatment. In order to evoke neuronal injury, rats were unilaterally injected with kainic acid (KA; 2.5 nmol/1 μl) into the CA1 region of the hippocampus. MTEP (1, 5 or 10 nmol/1 μl) was administered into CA1 30 min, 1, 3 and 6 h after KA. Additionally, other rats were injected intraperitoneally (i.p.) with MTEP in a dose of 1 mg/kg, once daily for 7 days. The first injection of MTEP was 1 h after KA. Seven days after treatment, the brains were taken out and analyzed histologically to estimate the total number of neurons in CA region of dorsal hippocampus using stereological methods. The study was also aimed at determining a possible influence of MTEP on neuronal glutamate release induced by KA in the hippocampus, using microdialysis method. The obtained results showed that MTEP had neuroprotective effect after both intrahippocampal and intraperitoneal injection. It was found that MTEP could prevent excitotoxic neuronal damage even when it was applied 1-6 h after the toxin. Moreover, it was observed that MTEP significantly reduced the KA-induced glutamate release in the hippocampus. It seems to play a role in mediating neuroprotective effects of MTEP.
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http://dx.doi.org/10.1016/s1734-1140(10)70367-4DOI Listing
August 2011

Chronic treatment with zinc and antidepressants induces enhancement of presynaptic/extracellular zinc concentration in the rat prefrontal cortex.

Amino Acids 2011 Jan 9;40(1):249-58. Epub 2010 Jun 9.

Institute of Pharmacology, Polish Academy of Sciences and Center of Excellence in Neuropsychopharmacology, Smętna 12, 31-343, Kraków, Poland.

Zinc exhibits antidepressant-like activity in preclinical tests/models. Moreover, zinc homeostasis is implicated in the pathophysiology of affective disorders. The aim of the present study was to examine the effect of chronic zinc, citalopram and imipramine intraperitoneal administration on the presynaptic and extracellular zinc concentration in the rat prefrontal cortex and hippocampus. We used two methods: zinc-selenium histochemistry (which images the pool of presynaptic-vesicle zinc) and anodic stripping voltammetry (ASV) for zinc determination in microdialysate (which assays the extracellular zinc concentration). We report that chronic (14 ×) zinc (hydroaspartate, 10 and 65 mg/kg) and citalopram (20 mg/kg) administration increased the pool of presynaptic zinc (by 34, 50 and 37%, respectively) in the rat prefrontal cortex. The 21% increase induced by imipramine (20 mg/kg) was marginally significant. Likewise, zinc (hydroaspartate, 65 mg/kg), citalopram and imipramine increased the extracellular zinc (although with a different pattern: time point, area under the curve and/or basal level) in this brain region. Furthermore, zinc induced an increase in presynaptic (by 65%) and extracellular zinc (by 90%) in the hippocampus, while both citalopram and imipramine did not. These results indicate that all of the treatments increase presynaptic/extracellular zinc concentrations in the rat prefrontal cortex, which may then contribute to their antidepressant mechanisms. Alterations induced by zinc (but not antidepressants) administration in the hippocampus may be related to specific zinc mechanisms. All the data (previous and present) on the effect of antidepressant treatments on the presynaptic/extracellular zinc concentrations suggest the involvement of this biometal presynaptic/synaptic homeostasis in the antidepressant mechanism(s).
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http://dx.doi.org/10.1007/s00726-010-0641-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016009PMC
January 2011

Effect of adenosine A(2A) receptor antagonists on L-DOPA-induced hydroxyl radical formation in rat striatum.

Neurotox Res 2009 Feb 5;15(2):155-66. Epub 2009 Mar 5.

Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, Kraków 31-343, Poland.

A(2A) adenosine receptor antagonists have been proposed as a new therapy for Parkinson's disease (PD). Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A(2A) adenosine receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on L: -3,4-dihydroxyphenylalanine (L: -DOPA)-induced hydroxyl radical generation using in vivo microdialysis in the striatum of freely moving rats. L: -DOPA (100 mg/kg; in the presence of benserazide, 50 mg/kg) given acutely or repeatedly for 14 days generated a high level of hydroxyl radicals, measured by HPLC with electrochemical detection, as the product of their reaction with p-hydroxybenzoic acid (PBA). CSC (1 mg/kg) and ZM 241385 (3 mg/kg) decreased haloperidol (0.5 mg/kg)-induced catalepsy, while at low doses of 0.1 and 0.3 mg/kg, respectively, they did not display an effect. CSC (1 and 5 mg/kg) and ZM 241385 (3 and 9 mg/kg) given acutely, or CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly, increased the production of hydroxyl radicals in dialysates from rat striatum. Both acute and repeated administration of CSC (0.1 and 1 mg/kg) and ZM 241385 (3 mg/kg) decreased L: -DOPA-induced generation of hydroxyl radicals. However, a high single dose of either CSC (5 mg/kg) and ZM 241385 (9 mg/kg) markedly potentiated the effect of L: -DOPA on hydroxyl radical production. The increase in hydroxyl radical production by acute and chronic injection of CSC and ZM 241385 may be related to the increased release of dopamine (DA) and its metabolism in striatal dialysates. Similarly, increased DA release following a single high dose of CSC or ZM 241385 appears to be responsible for augmentation of L: -DOPA-induced hydroxyl radical formation. Conversely, the inhibition of L: -DOPA-induced production of hydroxyl radical by single and repeated low doses of CSC or repeated low doses of ZM 241385 may be related to reduced DA metabolism. Summing up, A(2A) antagonists, used as a supplement of L: -DOPA therapy, depending on the dose used, may have a beneficial or adverse effect on ongoing neurodegenerative processes and accompanying oxidative stress.
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http://dx.doi.org/10.1007/s12640-009-9016-2DOI Listing
February 2009

Preclinical evaluation of the abuse potential of the analgesic bicifadine.

J Pharmacol Exp Ther 2009 Jul 8;330(1):236-48. Epub 2009 Apr 8.

Virginia Commonwealth University, Department of Pharmacology/Toxicology, P.O. Box 980613, Richmond, VA 23298-0613, USA.

The abuse liability of the analgesic bicifadine was investigated in animal models used to predict the abuse potential of psychostimulants in humans. Bicifadine, cocaine, d-amphetamine, bupropion, and desipramine were evaluated for the production of cocaine-like discriminative stimulus effects in rats. Cocaine, d-amphetamine, and bupropion dose-dependently and fully substituted for cocaine. Bicifadine and desipramine produced a maximum mean cocaine-lever selection of 80 and 69%, respectively, but doses yielding peak substitution strongly suppressed response rates. Microdialysis studies in normal waking rats indicated that d-amphetamine increased dopamine levels in the nucleus accumbens and striatum to a much greater degree than bicifadine, but bicifadine increased 5-hydroxytryptamine levels in the nucleus accumbens and striatum more than d-amphetamine. Bicifadine was also tested for intravenous self-administration in rhesus monkeys experienced with cocaine administration. Reinforcing effects of bicifadine were observed in only two of four subjects, whereas cocaine, d-amphetamine, and bupropion served as reinforcers in all four monkeys. When evaluated under a progressive ratio procedure, no dose of bicifadine maintained responding to the extent of cocaine, d-amphetamine, or bupropion. The discriminative stimulus effects associated with bicifadine were similar, but not identical, to those of psychostimulants. Although bicifadine maintained self-administration behavior in some subjects, its reinforcing efficacy was very low relative to cocaine, d-amphetamine, and bupropion. These results are consistent with the microdialysis findings of lower dopamine levels and higher 5-hydroxytryptamine levels after administration of bicifadine relative to d-amphetamine. Overall, the current findings support a low abuse potential of bicifadine, more resembling that of antidepressants than psychostimulants.
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http://dx.doi.org/10.1124/jpet.109.150540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202431PMC
July 2009