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Deak V.,University of Pécs | Lukacs R.,University of Pécs | Buzas Z.,Institute of Genetics | Buzas Z.,National Institute of Pharmacy | And 5 more authors.
Journal of Bacteriology | Year: 2010

Genes encoding the tail proteins of the temperate phage 16-3 of the symbiotic nitrogen-fixing bacterium Sinorhizobium meliloti 41 have been identified. First, a new host range gene, designated hII, was localized by using missense mutations. The corresponding protein was shown to be identical to the 85-kDa tail protein by determining its N-terminal sequence. Electron microscopic analysis showed that phage 16-3 possesses an icosahedral head and a long, noncontractile tail characteristic of the Siphoviridae. By using a lysogenic S. meliloti 41 strain, mutants with insertions in the putative tail region of the genome were constructed and virion morphology was examined after induction of the lytic cycle. Insertions in ORF017, ORF018a, ORF020, ORF021, the previously described h gene, and hII resulted in uninfectious head particles lacking tail structures, suggesting that the majority of the genes in this region are essential for tail formation. By using different bacterial mutants, it was also shown that not only the RkpM and RkpY proteins but also the RkpZ protein of the host takes part in the formation of the phage receptor. Results for the host range phage mutants and the receptor mutant bacteria suggest that the HII tail protein interacts with the capsular polysaccharide of the host and that the tail protein encoded by the original h gene recognizes a proteinaceous receptor. Copyright © 2010, American Society for Microbiology. All Rights Reserved.


Jankovics P.,National Institute of Pharmacy | Varadi A.,Semmelweis University | Tolgyesi L.,Eötvös Loránd University | Tolgyesi L.,Kromat Ltd. Co. | And 3 more authors.
Forensic Science International | Year: 2012

3-Naphthoyl- and 3-phenylacetylindoles represent a group of substances of cannabimimetic activity with affinities - strongly influenced by their functional groups - to cannabinoid receptors CB1 and CB2. Some of them have been described as ingredients of herbal blends also known as "smart products" by several research groups. Recently further cannabimimetic substances possessing new chemical structures like benzoylindoles and adamantoylindoles have emerged. In Hungary, two powder samples were seized by the authorities and identified as 1-pentyl-3-(2-iodobenzoyl)indole (AM-679) and 1-pentyl-3-(1-adamantoyl)indole. Structure elucidation was carried out by LC-UV-MS/MS, LC-TOF-MS, GC-MS and NMR. The benzoylindole AM-679 is a known agonist of cannabinoid receptors while the adamantoylindole derivative also carries chemical features typical for cannabimimetics. It is thus assumed that both substances might be detected in "smart products" in the future. © 2011 Elsevier Ireland Ltd.


Sobor M.,National Institute of Pharmacy | Sobor M.,Semmelweis University | Timar J.,Semmelweis University | Riba P.,Semmelweis University | And 5 more authors.
Pharmacology Biochemistry and Behavior | Year: 2010

Opioids impair the maternal behaviour of rats. The effect of morphine on maternal behaviour in dams treated chronically with morphine during the whole pregnancy and lactation has not been analysed systematically. The aim of the present study was to investigate the possible differences in the disruptive effect of morphine on maternal behaviour following morphine challenges between dams treated chronically with saline or morphine during gestation and postpartum. The antinociceptive action of morphine was also studied in dams. The disruptive effect of morphine on maternal behaviour was not changed as the postpartum period passed. The duration of this effect of morphine lasted for about 2. h. The dose-dependent disruptive effect of acute doses of morphine on maternal behaviour was more marked in the morphine-treated dams, than in the saline-treated ones, indicating a tendency for sensitisation to this effect. A trend for tolerance was observed to the antinociceptive effect of morphine in animals treated daily with morphine during the entire gestational and lactation periods; however, this difference did not reach statistical significance. Our experimental protocol might be a predictive model of human opioid abuse. Sensitisation to the impairing effect of opiates on maternal behaviour may explain why a mother abusing heroin neglects her baby even if she does not experience euphoria. © 2010 Elsevier Inc.


Adori C.,Semmelweis University | Zelena D.,Hungarian Academy of Sciences | Timar J.,Semmelweis University | Gyarmati Z.,Semmelweis University | And 8 more authors.
Behavioural Brain Research | Year: 2010

The recreational party drug "ecstasy" (3,4-methylenedioxymethamphetamine MDMA) is particularly popular among young adults who are in the childbearing age and thus there is a substantial risk of prenatal MDMA exposure. We applied an intermittent treatment protocol with an early first injection on pregnant Wistar rats (15 mg/kg MDMA s.c. on the E4, E11 and E18 days of gestation) to examine the potential physiological, endocrine and behavioral effects on adult male and female offspring. Prenatal MDMA-treatment provoked reduced body weight of offspring from the birth as far as the adulthood. Adult MDMA-offspring had a reduced blood-glucose concentration and hematocrit, altered relative spleen and thymus weight, had lower performance on wire suspension test and on the first trial of rotarod test. In contrast, no alteration in the locomotor activity was found. Anxiety and depression related behavioral parameters in elevated plus maze, sucrose preference or forced swimming tests were normal. MDMA-offspring had elevated concentration of the ACTH-precursor proopiomelanocortin and male MDMA-offspring exhibited elevated blood corticosterone concentration. No significant alteration was detected in the serotonergic marker tryptophan-hydroxylase and the catcholaminergic marker tyrosine-hydroxylase immunoreactive fiber densities in MDMA-offspring. The mothers exhibited reduced densities of serotonergic but not catecholaminergic fibers after the MDMA treatment. Our findings suggest that an intermittent prenatal MDMA exposure with an early first injection and a relatively low cumulative dose provokes mild but significant alterations in physical-physiological parameters and reduces motor skill learning in adulthood. In contrast, these adult offspring do not produce anxiety or depression like behavior. © 2009 Elsevier B.V. All rights reserved.


Jankovics P.,National Institute of Pharmacy | Varadi A.,Semmelweis University | Tolgyesi L.,Eötvös Loránd University | Tolgyesi L.,Kromat Ltd. Co. | And 3 more authors.
Forensic Science International | Year: 2011

A fast and simple LC-MS/MS method was developed for screening mephedrone, butylone, methylenedioxypyrovalerone (MDPV), flephedrone, methylone and methedrone in bulk powder samples. Samples were separated on a reverse phase column using gradient elution with mixtures of water, acetonitrile and formic acid. After optimization a limit of detection of about 2ngmL-1 was achieved using multiple reaction monitoring (MRM) mode. Total run time was less than 8min. Typical fragmentation characteristics of the studied compounds are discussed. The method was successfully applied to several unknown bulk powder samples seized by the Hungarian Customs and Finance Guard. One of the samples contained the new designer drug 4'-methylethcathinone (4-MEC), which was identified and characterized by LC-MS/MS, NMR, FT-IR and LC-TOF-MS techniques. The method is also deemed to be applicable for the screening of simple dosage forms such as tablets and capsules. © 2011 Elsevier Ireland Ltd.


Timar J.,Semmelweis University | Sobor M.,Semmelweis University | Sobor M.,National Institute of Pharmacy | Kiraly K.P.,Semmelweis University | And 5 more authors.
Behavioural Pharmacology | Year: 2010

This study investigated the behavioural consequences of peri, pre and postnatal morphine (MO) exposure in rats. From gestational day 1 dams were treated with either saline or MO subcutaneously once a day (5mg/kg on the first 2 days, 10mg/kg subsequently). Spontaneous locomotor activity in a new environment (habituation) and antinociceptive effects of MO were measured separately in male and female pups after weaning and also in late adolescence or adulthood. The rewarding effect of MO was assessed by conditioned place preference in adult animals. Both exposure-induced and sex differences were observed. A significant delay in habituation to a new environment and decreased sensitivity to the antinociceptive effect of MO were found in male offspring of MO-treated dams. In contrast, the place preference induced by MO was enhanced in the MO-exposed adult animals and this effect was more marked in females. Prenatal exposure to MO resulted in more marked changes than the postnatal exposure through maternal milk. The results indicate that a medium MO dose administered once-daily results in long-term consequences in offspring and may make them more vulnerable to MO abuse in adulthood. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Jankovics P.,Catholic University of Leuven | Jankovics P.,Semmelweis University | Jankovics P.,National Institute of Pharmacy | Chopra S.,Catholic University of Leuven | And 7 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2015

The analysis of highly polar (often charged) compounds which lack a strong UV absorbing chromophore is really challenging. Despite the numerous analytical methods published, the demand for a simple, robust and cheap technique for their analysis still persists. Here, reversed phase (RP) liquid chromatography (LC) with capacitively coupled contactless conductivity detection (C4D) was explored for the first time as a possible method for separation and detection of various aminoglycoside (AMG) antibiotics which were taken as typical test compounds: tobramycin (TOB), spectinomycin, streptomycin, amikacin, kanamycin A and kanamycin B. C4D was performed using a commercially available as well as a laboratory made cell. As ion-pairing reagents (IPR) four perfluorinated carboxylic acids were used: pentafluoropropionic acid, heptafluorobutyric acid, nonafluoropentanoic acid (NFPA) and pentadecafluorooctanoic acid (PDFOA). 0.125mM NFPA-acetonitrile (ACN) (90:10) or 0.125mM PDFOA-ACN (70:30) as mobile phases were suitable to detect TOB with reasonable retention times. However, NFPA was preferred for practical reasons. Its applicable concentration range in the mobile phase was strongly restricted by loss of chromatographic performance at lower levels and excessive background conductivity at higher levels. Overall repeatability and robustness of the method were rather poor which was explained by the relatively low IPR levels. Selectivity between the tested AMGs was mainly influenced by the number of protonated amino groups per molecule making it impossible to separate compounds of equal net charges. Problems encountered with gradient elution, hydrophilic interaction liquid chromatography (HILIC) and separation at high pH without IPRs are also discussed. © 2014 Elsevier B.V..


Blanchaert B.,Catholic University of Leuven | Poderos Jorge E.,Catholic University of Leuven | Jankovics P.,Semmelweis University | Jankovics P.,National Institute of Pharmacy | And 2 more authors.
Chromatographia | Year: 2013

The development of a simple reversed phase ion pair liquid chromatographic method for the assay of kanamycin A has been described. Because of the lack of a UV chromophore in the structure of kanamycin A, borate complexation was used to allow direct UV detection at 205 nm. Three columns were evaluated in this study: Zorbax Extend C18 (4.6 mm × 250 mm; 5 μm), XBridge C18 (4.6 mm × 250 mm; 5 μm) and apHera C18 (4.6 mm × 250 mm; 5 μm). The mobile phase was a mixture of 0.1 M disodium tetraborate (pH 9.0) and water (20:80, v/v) supplemented with 0.5 g L-1 sodium octanesulphonate. Final chromatographic conditions were achieved on the XBridge column at 50 C. The method was validated according to ICH guidelines and applied to a commercially available sample. It is much faster and more specific than the current microbiological assay prescribed in the European Pharmacopoeia. No expensive equipment is necessary to perform this assay making it a viable replacement. © 2013 Springer-Verlag Berlin Heidelberg.


Jankovics P.,National Institute of Pharmacy | Lohner S.,National Institute of Pharmacy | Darcsi A.,Semmelweis University | Nemeth-Palotas J.,National Institute of Pharmacy | Beni S.,Semmelweis University
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

A new derivative of vardenafil was detected in an alleged herbal dietary supplement and identified as 2-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)phenyl)-5-methyl-7-propyl-imidazo[1,5-f][1,2,4]triazin-4(3. H)-thione. Structure elucidation was carried out by LC-UV-MS/MS and NMR. Results obtained with high resolution MS and IR spectroscopy confirmed the proposed chemical structure. The compound was distinguished from hydroxyvardenafil, a second active substance identified in the same product, by the conversion of the oxo group to a thio group on the imidazo-triazin moiety. Hydroxythiovardenafil was therefore suggested as a proprietary name for the new molecule. This is the first paper to describe a thio-analog of vardenafil in a commercially available product. © 2012 Elsevier B.V.


Vergallo C.,University of Salento | Dini L.,University of Salento | Szamosvolgyi Z.,National Institute of Pharmacy | Tenuzzo B.A.,University of Salento | And 3 more authors.
PLoS ONE | Year: 2013

The effect of inhomogeneous static magnetic field (SMF)-exposure on the production of different cytokines from human peripheral blood mononuclear cells (PMBC), i.e., lymphocytes and macrophages, was tested in vitro. Some cultures were activated with lipopolysaccharide (LPS) at time point -3 h and were either left alone (positive control) or exposed to SMF continuously from 0 until 6, 18, or 24 h. The secretion of interleukin IL-6, IL-8, tumor necrosis factor TNF-α, and IL-10 was tested by ELISA. SMF-exposure caused visible morphological changes on macrophages as well as on lymphocytes, and also seemed to be toxic to lymphocytes ([36.58; 41.52]%, 0.308≤p≤0.444), but not to macrophages (<1.43%, p≥0.987). Analysis of concentrations showed a significantly reduced production of pro-inflammatory cytokines IL-6, IL-8, and TNF-α from macrophages compared to negative control ([56.78; 87.52]%, p = 0.031) and IL-6 compared to positive control ([45.15; 56.03]%, p = 0.035). The production of anti-inflammatory cytokine IL-10 from macrophages and from lymphocytes was enhanced compared to negative control, significantly from lymphocytes ([-183.62; -28.75]%, p = 0.042). The secretion of IL-6 from lymphocytes was significantly decreased compared to positive control ([-115.15; -26.84]%, p = 0.039). This massive in vitro evidence supports the hypotheses that SMF-exposure (i) is harmful to lymphocytes in itself, (ii) suppresses the release of pro-inflammatory cytokines IL-6, IL-8, and TNF-α, and (iii) assists the production of anti-inflammatory cytokine IL-10; thus providing a background mechanism of the earlier in vivo demonstrated anti-inflammatory effects of SMF-exposure. © 2013 Vergallo et al.

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