Biomedical subjects

Kathrin Schmidt

Publications and source records attributed to Kathrin Schmidt.

7 recordsLinked to original sources

PubMed2006

Root replacement using stentless valves in the small aortic root: a propensity score analysis.

BACKGROUND: Root replacement using a stentless bioprosthesis may be the optimal approach to avoid patient-prosthesis mismatch in patients with a small aortic root. Primary root replacement, however, is considered to be associated with increased surgical risk. We compared early outcome of full root replacement with a stentless bioprosthesis with that of aortic valve replacement with a stented bioprosthesis using propensity score-matching analysis. METHODS: Of 231 patients undergoing elective, first-time aortic valve replacement with a small root (< or = 22 mm), 120 patients were selected using propensity score-matching analysis. They underwent either root replacement using a 23-mm stentless bioprosthesis (stentless group, n = 60) or supra-annular aortic valve replacement using a 21-mm stented bioprosthesis (stented group, n = 60). Preoperative characteristics and frequency of concomitant operations were identical. RESULTS: Duration of operation (196 +/- 54 versus 174 +/- 49 minutes), cardiopulmonary bypass (112 +/- 36 versus 91 +/- 33 minutes), and aortic cross-clamping (76 +/- 21 versus 61 +/- 21 minutes) were significantly longer in the stentless group. However, the need for perioperative transfusion and the incidence of postoperative reexploration for bleeding (3% versus 8%) was lower, and ventilation time was shorter. Mean duration of intensive care and hospital stay were also significantly shorter (2.3 +/- 1.7 versus 4.0 +/- 3.9 days, 8.9 +/- 3.1 versus 12.4 +/- 5.7 days). In-hospital mortality was identical (5% each). No independent predictor for in-hospital mortality was identified. CONCLUSIONS: Full root replacement using a stentless bioprosthesis does not increase postoperative morbidity or mortality of aortic valve replacement and may be advantageous in patients with a small aortic root.

Aged↗

PubMed2005

Antitumor-active cobalt-alkyne complexes derived from acetylsalicylic acid: studies on the mode of drug action.

Cobalt-alkyne complexes are drugs with remarkable cytotoxicity. From the complexes tested up to now we selected the aspirin derivative [2-acetoxy-(2-propynyl)benzoate]hexacarbonyldicobalt (Co-ASS) as the lead compound. To get more insight into the mode of action, we systematically modified the alkyne ligand and determined the cytotoxic properties of the resulting cobalt complexes. Further investigations were performed on the drug lipophilicity, the cellular uptake into MCF-7 and MDA-MB 231 breast cancer cells, the DNA-binding efficacy, and the nuclear drug content. The ability to inhibit glutathione reductase and cyclooxygenase (COX) enzymes, the binding to the estrogen receptor, and the induction of apoptotic processes were examined for selected compounds. Interestingly, the most antitumor active compounds were potent COX inhibitors (COX-1 and COX-2). The presented results indicate that cobalt-alkyne complexes of the Co-ASS type, represent a new class of organometallic cytostatics with a mode of drug action in which COX inhibition probably plays a major role.

Alkynes↗

PubMed2003

Invesgations [correction investigations] on the influence of halide substituents on the estrogen receptor interaction of 2, 4, 5-tris(4-hydroxyphenyl)imidazoles.

Previously, we reported on the synthesis and estrogen receptor (ER) interaction of imidazoles, which had to be 1-alkyl-4, 5-bis(2-halo-4-hydroxyphenyl) substituted for a high relative binding affinity (RBA >1 %). This led to the assumption that a shielding of the polar heterocyclic system is a prerequisite for ER binding. In continuation of this study we synthesized 2, 4, 5-tris(4-hydroxyphenyl)imidazoles with Cl-or F-atoms in the ortho-positions of the aromatic rings and evaluated whether they mediate sufficient hydrophobicity for ER interaction. 2-(2, 6-Dichloro-3/4-hydroxyphenyl)-4, 5-bis(2-halo-4-hydroxyphenyl)imidazoles were synthesized by reaction of the respective methoxy-substituted benzil with either the 2, 6-dichloro-4-methoxy-or the 2, 6-dichloro-3-methoxybenzaldehyde in ammonium acetate solution. The required ether cleavage was performed subsequently with BBr(3). In the competition experiment with [(3)H]estradiol the imidazoles with the a C2-standing (2, 6-dichloro-4-hydroxyphenyl) ring showed an RBA >0.02 %, but did not activate the luciferase gene in estrogen receptor positive MCF-7-2a breast cancer cells stably transfected with the plasmid ERE(wtc)luc. In the test for antagonistic potency only the 2-(2, 6-dichloro-4-hydroxyphenyl)-4, 5-bis(4-hydroxyphenyl)imidazole 3 antagonized the effects of 1 nM estradiol slightly. From these data, it can be concluded that a C2-standing 2, 6-dichloro-4-hydroxyphenyl ring is not appropriate to optimize the ER interaction of 4, 5-(4-hydroxyphenyl)imidazoles.

Antineoplastic Agents↗

PubMed2002

(4R,5S)/(4S,5R)-4,5-Bis(4-hydroxyphenyl)-2-imidazolines: ligands for the estrogen receptor with a novel binding mode.

(4R,5S)/(4S,5R)-4,5-Bis(4-hydroxyphenyl)-2-imidazolines 1-7 were synthesized by the reaction of the methoxy-substituted (1R,2S)/(1S,2R)-1,2-diarylethylenediamines 1b-7b with triethyl orthoformate and subsequent ether cleavage with BBr(3). All compounds were tested for estrogen receptor (ER) binding in a competition experiment with [(3)H]-estradiol and for gene activation in a luciferase assay using ER positive MCF-7-2a breast cancer cells stably transfected with the plasmid ERE(wtc)luc. The relative binding affinities of the 2-imidazolines were very low (RBA < 0.1%). Nevertheless, 4-7 possessed full agonistic activity in the luciferase assay. The relative transcription potency increased in the order 5 (2,2'-I) < 6 (2,6-Cl(2), 2'-F) < 4 (2,2'-Cl) < 7 (2,6-Cl(2), 2'-Cl). These data together with spectroscopic and molecular modeling studies were used to investigate the preferred binding mode adopted by the imidazoline ligands. The 1,2-diarylethane pharmacophor takes a Z-stilbene-like structure with pseudoaxially oriented phenyl rings at the planar heterocyclic ring. Because of this unusual spatial structure, the (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines have to be assigned to a second class of estrogenically active compounds (type II estrogens). In contrast to type I estrogens, e.g., estradiol (E2), diethylstilbestrol (DES), and meso-hexestrol (HES), which are connected to His 524 in the binding site, type II estrogens are very likely H-bonded to Asp 351 in a hydrophobic side pocket.

Animals↗

PubMed2002

Synthesis, structural evaluation, and estrogen receptor interaction of 2,3-diarylpiperazines.

To develop novel estrogen receptor (ER) ligands, ring-fused derivatives of the hormonally active (1R,2S)/(1S,2R)-1-(2-chloro-4-hydroxyphenyl)-2-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine 4b were synthesized. (2R,3S)/(2S,3R)-2-(2-Chloro-4-hydroxyphenyl)-3-(2,6-dichloro-4-hydroxyphenyl)piperazine 4 induced ligand-dependent gene expression in MCF-7-2a cells, stably transfected with the plasmid ERE(wtc)luc and was therefore used as a lead structure. The influence of the substitution pattern in the aromatic rings (4-OH (1), 2-F,4-OH (2), 2-Cl,4-OH (3), 2,6-Cl2,3-OH (5), and 2,6-Cl2,4-OH (6)) and the effect of N-ethyl chains on the ER binding and activation of gene expression were studied. The synthesis started from the respective methoxy-substituted (1R,2S)/(1S,2R)-configurated 1,2-diarylethylenediamines 6b to 4b, which were reacted with dimethyl oxalate in order to get 5,6-diarylpiperazine-2,3-diones. Reduction with BH3*tetrahydrofuran and ether cleavage with BBr3 yielded the piperazines 1-6. The N-alkylation of the piperazines 1a-3a, which was employed for obtaining compounds 7-11, was succeeded by acetic anhydride followed by reduction and ether cleavage. Nuclear magnetic resonance (NMR) spectroscopical studies revealed a synclinal conformation of the 1,2-diarylethane pharmacophore and a preference of the substituents at the heterocyclic ring for an equatorial position. This spatial structure prevents an interaction with the ER analogously to that of estradiol (E2). Therefore, the piperazines can displace E2 from its binding site only to a very small extent. Only the N-ethyl (8) and N,N'-diethyl (11) derivatives of piperazine 3 showed relative binding affinity values > 0.1% (8, 0.42%, and 11, 0.17%). Nevertheless, ER-mediated gene activation was verified for the piperazines 4 (20%), 6 (73%), 7 (34%), 8 (74%), and 11 (37%) (concentration, 1 microM; E2, 100% activation) on the MCF-7-2a cell line. O-methylation led to completely inactive compounds and showed the necessity of H bridges from the piperazines to the ER for activating gene expression.

Animals↗

PubMed2002

Synthesis, structural evaluation, and estrogen receptor interaction of 4,5-bis(4-hydroxyphenyl)imidazoles.

4,5-Bis(4-hydroxyphenyl)imidazoles with 2,2'-H (1),2,2'-F (2),2,2'-Cl (3), and 2,2'6-Cl (4) substituents in the aromatic rings were synthesized by oxidation of the respective methoxy-substituted (R,S)/(S,R)-4,5-diaryl-2-imidazolines with MnO2 and subsequent ether cleavage with BBr3. N-alkylation of 1 and 3 with ethyl iodide yielded the compounds 5 and 6. The imidazoles were characterized by NMR spectroscopy and tested for estrogen receptor binding in a competition experiment with [3H]estradiol using calf uterine cytosol. Gene activation was verified in a luciferase assay using estrogen receptor positive MCF-7-2a cells stably transfected with the plasmid ERE(wtc)luc. All halide substituted imidazoles competed with estradiol for the binding site at the estrogen receptor. The N-ethyl derivative 6 showed the highest relative binding affinity of 1.26 %. Treatment of MCF-7-2a cells, however, did not lead to gene activation. The relative activation of 6 amounted only to 10% at 1 microM compared to E2 (100%).

Binding, Competitive↗

PubMed2002

Automated extraction of genomic DNA from medically important yeast species and filamentous fungi by using the MagNA Pure LC system.

A fully automated assay was established for the extraction of DNA from clinically important fungi by using the MagNA Pure LC instrument. The test was evaluated by DNA isolation from 23 species of yeast and filamentous fungi and by extractions (n = 28) of serially diluted Aspergillus fumigatus conidia (10(5) to 0 CFU/ml). Additionally, DNA from 67 clinical specimens was extracted and compared to the manual protocol. The detection limit of the MagNA Pure LC assay of 10 CFU corresponded to the sensitivity when DNA was extracted manually; in 9 of 28 runs, we could achieve a higher sensitivity of 1 CFU/ml blood, which was found to be significant (p <or= 0.004). DNA from all fungal species analyzed could be extracted and amplified by real-time PCR. Negative controls from all MagNA Pure isolations remained negative. Sixty-three clinical samples showed identical results by both methods, whereas in 4 of 67 samples, discordant results were obtained. Thus, the MagNA Pure LC technique offers a fast protocol for automated DNA isolation from numerous fungi, revealing high sensitivity and purity.

DNA, Fungal↗