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Olar R.,University of Bucharest | Vlaicu I.D.,University of Bucharest | Vlaicu I.D.,National Institute of Materials Physics Bucharest | Chifiriuc M.C.,University of Bucharest | And 6 more authors.
Journal of Thermal Analysis and Calorimetry | Year: 2016

Synthesis and characterization of four new Ni(II) complexes with mixed ligands have been reported in the present paper. As interest ligands, acrylate (acr) ion together with one N-donor heterocyclic ligand, namely benzimidazole (HBzIm), 2-methylbenzimidazole (2-MeBzIm), 5-methylbenzimidazole (5-MeBzIm) or 5,6-dimethylbenzimidazole (5,6-Me2BzIm), was chosen. The syntheses afforded the complexes formulated as [Ni(HBzIm)2(acr)2(H2O)]·3H2O (1), [Ni(2-MeBzIm)2(acr)2(H2O)]·1.5H2O (2), [Ni(5-MeBzIm)2(acr)2(H2O)] (3) and [Ni(5,6-Me2BzIm)2(acr)2] (4). Complexes (1) and (2) contain crystallization water molecules and coordinated water molecules, both their nature and presence being confirmed on the basis of IR spectra and thermal analysis. In contrast to above-mentioned complexes, (3) contains only coordinated water molecule, while (4) is an anhydrous compound. Based on electronic spectra and magnetic measurements, a distorted octahedral stereochemistry was proposed for all Ni(II) complexes. Acrylate ions act both as unidentate and chelate ligands in complexes (1)–(3), while in complex (4) act only as chelate ligands. All used N-donor ligands function as monodentate in all Ni(II) complexes. Biological properties of complexes (1)–(4) were evaluated against several Gram(+), Gram(−) bacterial strains and against fungus Candida albicans. © 2016 Akadémiai Kiadó, Budapest, Hungary


Olar R.,University of Bucharest | Calu L.,University of Bucharest | Calu L.,Romanian National Institute for Research and Development for Biological Sciences | Badea M.,University of Bucharest | And 9 more authors.
Journal of Thermal Analysis and Calorimetry | Year: 2016

A series of complexes of type M(pmtp)(CH3COO)2·nH2O ((1) M: Co, n = 4.5; (2) M: Ni, n = 3.5; (3) M: Cu, n = 0.5; (4) M: Zn, n = 0; pmtp: 5-phenyl-7-methyl-1,2,4-triazolo[1,5-a]pyrimidine) were synthesised by one-pot condensation. The complexes were characterized by elemental analysis, ESI–MS, IR, UV–Vis-NIR, EPR spectra, magnetic susceptibility at room temperature as well as thermogravimetric analysis. The modifications in the IR spectra of complexes are in accordance with the condensation process and indicate the triazolopyrimidine coordination as unidentate. The electronic and EPR spectra together with magnetic moments indicate an octahedral stereochemistry for paramagnetic ions, except for Cu(II) with a square pyramidal geometry. Processes such as water elimination, acetate into carbonate transformation, as well as oxidative degradation of the triazolopyrimidine derivative were evidenced during thermal decomposition. The complexes exhibited an improved antimicrobial activity in comparison with the ligand, on both planktonic and biofilm-embedded microbial cells. The best antimicrobial activity in both susceptible and resistant strains was obtained for complex (3) followed by complex (1), which can be related to both oxidation state and stereochemical versatility. At high concentrations, the Cu(II) complex exhibits both cytotoxicity on HT 29 tumour cell line and anti-inflammatory activity. © 2016 Akadémiai Kiadó, Budapest, Hungary


Silvestro L.,3S Pharmacological Consultation and Research GmbH | Gheorghe M.,Pharma Serv Intl SRL | Gheorghe M.,University of Bucharest | Iordachescu A.,Pharma Serv Intl SRL | And 4 more authors.
Analytical and Bioanalytical Chemistry | Year: 2011

A new sensitive and fast quantitative analytical method for the simultaneous determination of clopidogrel, its main metabolite clopidogrel carboxylic acid, and the newly described acyl glucuronide metabolite, in human plasma samples, is presented. The analytical procedures (plasma storage, handling, and extract storage in the autosampler) were optimized in order to avoid back-conversion; a known drawback in measurements of clopidogrel. Clopidogrel acyl glucuronide was confirmed as a major source of back-conversion to the parent drug in the presence of methanol, and thorough stability experiments were carried out to find the most appropriate conditions for an accurate analysis of clopidogrel and the two metabolites. The method was validated by assessing selectivity, sensitivity, linearity, accuracy, and precision for all three analytes, in accordance to Food and Drug Administration guidelines. Spiked quality controls in plasma as well as incurred samples were used to verify back-conversion in the selected conditions, with results meeting European Medicines Agency acceptance criteria (concentrations within 80-120% of the first reading). The method was then applied to a pharmacokinetic study, and for the first time, a pharmacokinetic curve of clopidogrel acyl glucuronide in human plasma is presented. The concentrations ranged up to 1,048.684 ng/mL, with a mean of 470.268 ng/mL, while clopidogrel had a mean C max of 1.348 ng/mL; these orders of magnitude show how much the back-conversion of this metabolite may influence clopidogrel quantification if it is not properly controlled. © 2011 Springer-Verlag.


Silvestro L.,3S Pharmacological Consultation and Research GmbH | Savu S.R.,3S Pharmacological Consultation and Research GmbH | Savu S.N.,Pharma Serv Intl SRL | Tudoroniu A.,Pharma Serv Intl SRL | Tarcomnicu I.,Pharma Serv Intl SRL
Biomedical Chromatography | Year: 2012

A new method for the fast simultaneous quantification of fluticasone propionate and salmeterol from plasma samples by liquid chromatography-tandem mass spectrometry, with adequate sensitivity for pharmacokinetic applications, was developed and validated. The chromatographic separation and mass-spectrometric parameters were optimized for the retention and detection of the two compounds, despite quite different structures and properties. Two columns connected in series were used, cation-exchange (Zorbax 300-SCX, 5cm×2.1mm, 5μm) and octadecyl (Discovery HSC 18, 10cm×2.1mm, 5μm). The mass-spectrometric interface was operated in negative electrospray ionization mode; high sensitivity and lesser matrix effects were obtained, permitting smaller consumption of plasma. The sample preparation was based on supported liquid-liquid extraction in 96-well format plates that provided clean samples with a simplified procedure that was suitable for automation. The method was validated according to regulatory guidelines, by assessing lower limits of quantification, selectivity, linearity, accuracy, precision, extraction recoveries and matrix effects. A comparison with two other methods for the separate determination of fluticasone propionate and salmeterol in plasma samples, previously developed by our group, is presented. The statistical evaluation of the results obtained with the three methods on a set of unknown samples from treated patients demonstrated good correlation (R 2 0.987 for fluticasone propionate and 0.967 for salmeterol). © 2011 John Wiley & Sons, Ltd.


Iordachescu A.,Pharma Serv Intl SRL | Iordachescu A.,University of Bucharest | Silvestro L.,3S Pharmacological Consultation and Research GmbH | Tudoroniu A.,Pharma Serv Intl SRL | And 2 more authors.
Chromatographia | Year: 2012

This paper presents a new analytical method with adequate sensitivity, precision, accuracy, and specificity to quantitatively determine (-)-donepezil and (+)-donepezil in plasma, at concentrations that can be expected in real samples of pharmacokinetic studies. This method combines a HPLC separation on cellulose tris (3,5-dimethylphenyl carbamate) coated on 5-lm silica-gel column known as CHIRALCEL OD-RH eluted with mobile phase consisting of acetonitrile and ammonium bicarbonate and MS-MS detection. Under the HPLC conditions used (-)-donepezil and (+)-donepezil, as well as the enantiomers of the internal standard d 7-donepezil, eluted at 5 and 6.25 min, respectively. The curve fittings were optimal for the entire calibration range (0.05-25.0 ng mL -1) with correlation coefficients (r) = 0.999 for (-)-donepezil and (r) = 0.999 for (+)-donepezil (linear regression model with 1/x 2 weighing). The assay method showed a good specificity for donepezil enantiomers, and it could be successfully applied to pharmacokinetic studies. © Springer-Verlag 2012.


Silvestro L.,3S Pharmacological Consultation and Research GmbH | Savu S.R.,3S Pharmacological Consultation and Research GmbH
Bioanalysis | Year: 2015

Solid phase-supported liquid extraction (SLE) is a technique almost 40 years old being rediscovered in the last few years due to its simplicity, optimal for automation and giving very clean extracts with minimal matrix effects when analyzed by techniques like HPLC-MS/MS, GC-MS/MS, CE-MS/MS. In the next paragraphs the evolution of SLE, according to literature, will be presented first, followed by some considerations on the SLE material now available and a typical protocol of work. To conclude, considerations based on the author's practical experiences with SLE will be done, as well as few remarks on potential future areas of SLE development. © 2015 Future Science Ltd.


Silvestro L.,3S Pharmacological Consultation and Research GmbH | Gheorghe M.C.,Pharma Serv Intl SRL | Tarcomnicu I.,3S Pharmacological Consultation and Research GmbH | Savu S.,3S Pharmacological Consultation and Research GmbH | And 3 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2010

Quantitative methods using LC-MS/MS allow achievement of adequate sensitivity for pharmacokinetic studies with clopidogrel; three such methods, with LLOQs as low as 5. pg/mL, were developed and fully validated according to the well established FDA 2001 guidelines. The chromatographic separations were performed on reversed phase columns Ascentis RP-Amide (15. cm × 2.1. mm, 5 μm), Ascentis Express C8 (10. cm × 2.1. mm, 2.7 μm) and Ascentis Express RP Amide (10. cm × 2.1. mm, 2.7 μm), respectively. Positive electrospray ionization in MRM mode was employed for the detection and a deuterated analogue (d3-clopidogrel) was used as internal standard. Linearity, precision, extraction recovery, matrix effects and stability tests on blank plasma spiked with clopidogrel and stored in different conditions met the acceptance criteria. During the analysis of the real samples from the first pharmacokinetic study, a significant increase (>100%) of the measured clopidogrel concentrations in the extracts kept in the autosampler at 10 °C was observed. Investigations led to the conclusion that most probably a back-conversion of one or more of the clopidogrel metabolites is occurring. The next methods were optimized in order to minimize this back-conversion. After a series of experiments, the adjustment of the sample preparation (e.g. processing at low temperature and introducing a clean-up step on Supelco HybridSPE-Precipitation cartridges) has proven to be the most effective in order to improve the stability of the extracts. Incurred samples of real subjects were successfully used in the validation of the last two analytical methods to evaluate the back-conversion, while tests using only the known metabolites could not detect this important problem. © 2010 Elsevier B.V.


Silvestro L.,3S Pharmacological Consultation and Research GmbH | Tarcomnicu I.,Pharma Serv Intl SRL | Dulea C.,Pharma Serv Intl SRL | Attili N.R.B.N.,Pharma Serv Intl SRL | And 3 more authors.
Analytical and Bioanalytical Chemistry | Year: 2013

Diosmin is a flavonoid often administered in the treatment of chronic venous insufficiency, hemorrhoids, and related affections. Diosmin is rapidly hydrolized in the intestine to its aglicone, diosmetin, which is further metabolized to conjugates. In this study, the development and validations of three new methods for the determination of diosmetin, free and after enzymatic deconjugation, and of its potential glucuronide metabolites, diosmetin-3-O-glucuronide, diosmetin-7-O-glucuronide, and diosmetin-3,7-O- glucuronide from human plasma and urine are presented. First, the quantification of diosmetin, free and after deconjugation, was carried out by high-performance liquid chromatography coupled with tandem mass spectrometry, on an Ascentis RP-Amide column (150 × 2.1 mm, 5 μm), in reversed-phase conditions, after enzymatic digestion. Then glucuronide metabolites from plasma were separated by micro-liquid chromatography coupled with tandem mass spectrometry on a HALO C18 (50 × 0.3 mm, 2.7 μm, 90 Å) column, after solid-phase extraction. Finally, glucuronides from urine were measured using a Discovery HSF5 (100 × 2.1 mm, 5 μm) column, after simple dilution with mobile phase. The methods were validated by assessing linearity, accuracy, precision, low limit of quantification, selectivity, extraction recovery, stability, and matrix effects; results in agreement with regulatory (Food and Drug Administration and European Medicines Agency) guidelines acceptance criteria were obtained in all cases. The methods were applied to a pharmacokinetic study with diosmin (450 mg orally administered tablets). The mean C max of diosmetin in plasma was 6,049.3 ± 5,548.6 pg/mL. A very good correlation between measured diosmetin and glucuronide metabolites concentrations was obtained. Diosmetin-3-O-glucuronide was identified as a major circulating metabolite of diosmetin in plasma and in urine, and this finding was confirmed by supplementary experiments with differential ion-mobility mass spectrometry. © 2013 The Author(s).


PubMed | 3S Pharmacological Consultation and Research GmbH
Type: Journal Article | Journal: Biomedical chromatography : BMC | Year: 2012

A new method for the fast simultaneous quantification of fluticasone propionate and salmeterol from plasma samples by liquid chromatography-tandem mass spectrometry, with adequate sensitivity for pharmacokinetic applications, was developed and validated. The chromatographic separation and mass-spectrometric parameters were optimized for the retention and detection of the two compounds, despite quite different structures and properties. Two columns connected in series were used, cation-exchange (Zorbax 300-SCX, 5 cm x 2.1 mm, 5 m) and octadecyl (Discovery HSC, 10 cm x 2.1 mm, 5 m). The mass-spectrometric interface was operated in negative electrospray ionization mode; high sensitivity and lesser matrix effects were obtained, permitting smaller consumption of plasma. The sample preparation was based on supported liquid-liquid extraction in 96-well format plates that provided clean samples with a simplified procedure that was suitable for automation. The method was validated according to regulatory guidelines, by assessing lower limits of quantification, selectivity, linearity, accuracy, precision, extraction recoveries and matrix effects. A comparison with two other methods for the separate determination of fluticasone propionate and salmeterol in plasma samples, previously developed by our group, is presented. The statistical evaluation of the results obtained with the three methods on a set of unknown samples from treated patients demonstrated good correlation (R 0.987 for fluticasone propionate and 0.967 for salmeterol).

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