Publications by authors named "Constanta Dulea"

4 Publications

  • Page 1 of 1

Synthesis and Structural Investigation of New Bio-Relevant Complexes of Lanthanides with 5-Hydroxyflavone: DNA Binding and Protein Interaction Studies.

Molecules 2016 Dec 16;21(12). Epub 2016 Dec 16.

Department of General and Inorganic Chemistry, Faculty of Pharmacy, "Carol Davila" University of Medicine and Pharmacy, 6 Traian Vuia Str., 020956 Bucharest, Romania.

In the present work, we attempted to develop new metal coordination complexes of the natural flavonoid 5-hydroxyflavone with Sm(III), Eu(III), Gd(III), Tb(III). The resultant hydroxo complexes have been characterized by a variety of spectroscopic techniques, including fluorescence, FT-IR, UV-Vis, EPR and mass spectral studies. The general chemical formula of the complexes is [Ln(CH₉O₃)₃(OH)₂(H₂O)]·H₂O, where Ln is the lanthanide cation and x = 0 for Sm(III), x = 1 for Eu(III), Gd(III), Tb(III) and = 0 for Sm(III), Gd(III), Tb(III), = 1 for Eu(III), respectively. The proposed structures of the complexes were optimized by DFT calculations. Theoretical calculations and experimental determinations sustain the proposed structures of the hydroxo complexes, with two molecules of 5-hydroxyflavone acting as monoanionic bidentate chelate ligands. The interaction of the complexes with calf thymus DNA has been explored by fluorescence titration and UV-Vis absorption binding studies, and revealed that the synthesized complexes interact with DNA with binding constants (K) ~ 10⁴. Human serum albumin (HSA) and transferrin (Tf) binding studies have also been performed by fluorescence titration techniques (fluorescence quenching studies, synchronous fluorescence spectra). The apparent association constants (K) and thermodynamic parameters have been calculated from the fluorescence quenching experiment at 299 K, 308 K, and 318 K. The quenching curves indicate that the complexes bind to HSA with smaller affinity than the ligand, but to Tf with higher binding affinities than the ligand.
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http://dx.doi.org/10.3390/molecules21121737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273368PMC
December 2016

Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatography-mass spectrometry and ion mobility mass spectrometry.

Anal Bioanal Chem 2013 Oct 16;405(25):8295-310. Epub 2013 Aug 16.

3S-Pharmacological Consultation and Research GmbH, Koenigsbergerstrasse 1, 27243, Harpstedt, Germany,

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.
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http://dx.doi.org/10.1007/s00216-013-7237-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777223PMC
October 2013

Development and validation of an HPLC-MS/MS method to determine clopidogrel in human plasma. Use of incurred samples to test back-conversion.

J Chromatogr B Analyt Technol Biomed Life Sci 2010 Nov 1;878(30):3134-42. Epub 2010 Oct 1.

3S-Pharmacological Consultation & Research GmbH, Koenigsbergerstrasse 1, 27243 Harpstedt, Germany.

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 x 2.1 mm, 5 μm), Ascentis Express C8 (10 cm x 2.1 mm, 2.7 μm) and Ascentis Express RP Amide (10 cm x 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.
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http://dx.doi.org/10.1016/j.jchromb.2010.09.022DOI Listing
November 2010

Development and application of a high-performance liquid chromatography-mass spectrometry method to determine alendronate in human urine.

J Chromatogr A 2007 Aug 19;1160(1-2):21-33. Epub 2007 Apr 19.

Pharma Serv International SRL, 52 Sabinelor Street, 5th District, 050853 Bucharest, Romania.

Despite the high potential offered by electrospray ionization on highly polar compounds like biphosphonates, few applications have been developed. High-performance liquid chromatography (HPLC) separation methods suitable for such molecules cannot be used in tandem with mass spectrometry (MS) due to high non-volatile salt content; at the same time the sample preparation, in biological fluids, is also a challenging problem. In the past ion-pair chromatography was mainly used in the case of HPLC-MS of biphosphonates, but no application to quantitative pharmacokinetic (PK) studies has been presented. In this study, after preliminary tests with ion-pair chromatography showing a poor sensitivity, a combined derivatization of the amino group and the biphosphonate has been developed and tested in a PK study. Using this analytical approach we were able to fully validate the quantitation of alendronate in the range of 6.667-4860.0 ng/ml in urine (sample volume 2.0 ml); each analytical run was 5.0 min long. The sensitivity achieved permitted a correct evaluation of the alendronate urinary excretion over the full period of urine collection. Sample preparation despite its complexity permitted to process and analyze up to 200 samples in a working day.
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http://dx.doi.org/10.1016/j.chroma.2007.04.020DOI Listing
August 2007