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Zsilla G.,Hungarian Academy of Sciences | Matyus P.,Semmelweis University | Levay G.,Chemical Works of Gedeon Richter Plc
Neurochemical Research | Year: 2010

The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D2 dopamine receptors. N-methyl-d-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D2 dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication. © 2010 Springer Science+Business Media, LLC.

Hada V.,API Research and Development | Hada V.,API Research and Development Spectroscopic Research | Dubrovay Z.,API Research and Development | Dubrovay Z.,API Research and Development Spectroscopic Research | And 5 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

In the course of developing a new, improved process at Gedeon Richter for the production of the "bisindole" alkaloids vinblastine (VLB) and vincristine (VCR), some novel VLB/VCR-related trace impurities were detected by analytical HPLC at the production site. Repeated attempts to isolate and purify these unknown impurities by preparative liquid chromatography yielded small amounts of materials whose main components were the unknown impurities, but were still contaminated with other VLB/VCR-related compounds. In spite of these difficulties, by using a combination of high-resolution (LC-)MS/MS and off-line 1D and 2D ultra high-field NMR techniques and leaning on the relevant spectroscopic data for VLB and VCR as discussed in Part 1 [1], we could unambiguously solve the structures of, and could give a complete spectral characterization for, the trace impurities. Among these, although "cyclo-VCR" (impurity-2), "[VCR]-C(16)-COOEt" (impurity-4) and "[VLB]-C(16)-COOEt" (impurity-5) are known synthetic VLB/VCR-derivatives, and "[VLB]-C(14')-OH(α)" is a known natural alkaloid (leurocolombine), they are new VLB/VCR impurities, and "[VCR]-N(4')-C(21')-iminium-salt" (impurity-3) is also a new chemical structure which provides direct proof of a hypothetic metabolic pathway of VLB/VCR. The structure determination of impurity-4 and impurity-5, and the rationalization of their origin was a particularly challenging task: since VCR is produced by the oxidation of VLB, it may be assumed that [VCR]-C(16)-COOEt (impurity-4) originates from the oxidization of [VLB]-C(16)-COOEt (impurity-5). This is consistent with the finding that [VLB]-C(16)-COOEt (impurity-5) could be detected by LC-MS/MS in the raw VLB samples in similar amounts as [VCR]-C(16)-COOEt (impurity-4) in the final VCR product. Our investigations indicate that [VLB]-C(16)-COOEt (impurity-5) does not form directly from VLB during extraction or chromatographic separation, suggesting that it may be a new natural product. © 2012 Elsevier B.V.

Gorog S.,Chemical Works of Gedeon Richter Plc
TrAC - Trends in Analytical Chemistry | Year: 2015

Identification is an important step in the quality control of drugs and the research for new drugs. First, this review discusses the identification of bulk drugs and the active ingredients in formulations, based mainly on pharmacopoeial tests. The most important methods for this purpose are infrared (IR) and, to a lesser extent, ultraviolet (UV) spectroscopy, as well as retention matching with standards using high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC). The identification of impurities and degradants is based mainly on HPLC-UV, HPLC-mass spectrometry (HPLC-MS) and nuclear magnetic resonance (NMR) spectroscopies. The above methods are also used for identification purposes in drug research. The use of MS and NMR in the research for large-molecule drugs of biotechnological origin and natural products, mainly of plant origin, with special respect to traditional Chinese (and Indian) medicines is also discussed. The review concludes with the identification aspects of the fight against counterfeit drugs. © 2014.

Gulyas B.,Karolinska Institutet | Toth M.,Karolinska Institutet | Vas A.,Chemical Works of Gedeon Richter Plc | Shchukin E.,Karolinska Institutet | And 3 more authors.
Current Radiopharmaceuticals | Year: 2012

With the main objective of comparing the prospective diagnostic power of two 11C-labelled molecular imaging biomarkers with affinity for TSPO and used for the visualisation of activated microglia after a stroke, we measured with positron emission tomography (PET) in four post-stroke patients the regional brain uptake and binding potential of [ 11C]vinpocetine and [ 11C]PK11195. Percentage standard uptake values (%SUV) and binding potential (BP ND) were used as outcome measures. The total peak brain uptake value and average global brain uptake value were higher for [ 11C]vinpocetine than for [ 11C]PK11195. The regional %SUV values were significantly higher for [ 11C]vinpocetine than for [ 11C]PK11195 in the hemispheres as well as in almost all standard brain regions. The %SUV values of [ 11C]vinpocetine were higher in the peri-infarct zone than in the ischaemic core, however, the difference did not prove to be significant. There was basically no difference in %SUV values between the ischaemic core and the peri-infarct zone for [ 11C]PK11195. The BP ND values for [ 11C]vinpocetine were higher in all standard regions than those for [ 11C]PK11195, but the difference was not significant between them. The BP ND values of [ 11C]vinpocetine were higher in the peri-infarct zone than in the ischaemic core, however, the difference did not prove to be significant. A comparative analysis of the two ligands indicates that [ 11C]vinpocetine shows a number of favourable characteristics over [ 11C]PK11195, but to demonstrate that it may serve as a prospective molecular imaging biomarker of microglia activation in post-stroke patients, further studies are required. © 2012 Bentham Science Publishers.

Fekete S.,Budapest University of Technology and Economics | Olah E.,Chemical Works of Gedeon Richter Plc | Fekete J.,Budapest University of Technology and Economics
Journal of Chromatography A | Year: 2012

Columns packed with sub-2 μm totally porous and sub-3 μm core-shell particles are very widespread nowadays to conduct fast and efficient separations. In order to carry out really fast separations, short (5. cm long) columns are very popular today. The goal of this paper is to review the recent possibilities in fast or "ultra-fast" HPLC by applying short and narrow bore columns packed with modern core-shell and very fine fully porous particles. Efficiency data obtained with these recently commercialized columns from the past few years are collected, discussed and compared in terms of potential separation time and efficiency. The reasons of the success of these columns are presented. This paper also shows that theoretically expected efficiency is sometimes compromised in practical work especially in the case of narrow bore columns. The extra-column dispersion of a given LC system can also dramatically decrease the performance of small columns. It is not possible to utilize the real efficiency of these small columns in spite of their really high intrinsic separation power. © 2011 Elsevier B.V.

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