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Molecularly imprinted polymers (MIP) combine the selectivity of immunoaffinity chromatography with the robustness of common solid-phase extraction in what is referred to as molecularly imprinted solid-phase extraction (MISPE). This contribution shows how MIP design may be guided by pharmacophore modeling for the example of citrinin, which is an emerging mycotoxin from cereals. The obtained pharmacophore model allowed searching public databases for a set of citrinin-mimicking molecular surrogates. Imprinted and non-imprinted polymers were subsequently obtained through bulk and core-shell polymerization in the presence of these surrogates. Evaluation of their binding ability for citrinin and structurally related ochratoxin A revealed a promising MIP derived from rhodizonic acid. A protocol for MISPE of citrinin from cereals was subsequently developed and compared to immunoaffinity chromatography with respect to clean-up efficiency and recovery.
Wiebke Derz; Melita Fleischmann; Paul W. Elsinghorst. Guiding Molecularly Imprinted Polymer Design by Pharmacophore Modeling. Molecules 2021, 26, 5101 .
AMA StyleWiebke Derz, Melita Fleischmann, Paul W. Elsinghorst. Guiding Molecularly Imprinted Polymer Design by Pharmacophore Modeling. Molecules. 2021; 26 (16):5101.
Chicago/Turabian StyleWiebke Derz; Melita Fleischmann; Paul W. Elsinghorst. 2021. "Guiding Molecularly Imprinted Polymer Design by Pharmacophore Modeling." Molecules 26, no. 16: 5101.
Mycotoxins remain a global threat to human and animal health, especially in countries lacking effective measures to detect and control contaminated commodities. As the quantification of mycotoxins usually relies on complex and expensive techniques, availability of suitable in-strumentation is often a bottle neck in reliable mycotoxin detection. As part of our research towards strategies offering widespread access to mycotoxin analysis while cutting down on costs, we present a new extraction and quantification protocol combining materials originally designed for dried blood spot analysis with stable isotope dilution analysis. Its key benefits are that extraction of mycotoxins can be carried out at remote sites and by minimally trained per-sonnel while quantification will take place in specialized central laboratories simply connected by regular, paper-based mail. As a proof of concept, aflatoxins, ochratoxin A and deoxynivalenol were extracted from cereal-based foodstuffs, fixed on paper cards for transport and successfully quantified after re-extraction by stable isotope dilution LC-MS/MS analysis. Several materials (cellu-lose/polyethylene terephthalate/glass fiber, non-treated/chemically treated) as well as possible transport and storage conditions (temperature, humidity) were evaluated. The final myco-DES (dried extract spots) protocol allows to quantify mycotoxin levels currently recognized as safe (aflatoxin B1: 2 µg/kg, ochratoxin A: 3 µg/kg, deoxynivalenol: 500 µg/kg) after a storage of up to 4 weeks under tropical climate conditions (40 °C, 75% relative humidity).
Katharina Maria Schlegel; Paul Wilhelm Elsinghorst. Myco-DES: Enabling Remote Extraction of Mycotoxins for Robust and Reliable Quantification by Stable Isotope Dilution LC–MS/MS. Analytical Chemistry 2020, 92, 5387 -5395.
AMA StyleKatharina Maria Schlegel, Paul Wilhelm Elsinghorst. Myco-DES: Enabling Remote Extraction of Mycotoxins for Robust and Reliable Quantification by Stable Isotope Dilution LC–MS/MS. Analytical Chemistry. 2020; 92 (7):5387-5395.
Chicago/Turabian StyleKatharina Maria Schlegel; Paul Wilhelm Elsinghorst. 2020. "Myco-DES: Enabling Remote Extraction of Mycotoxins for Robust and Reliable Quantification by Stable Isotope Dilution LC–MS/MS." Analytical Chemistry 92, no. 7: 5387-5395.
The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC50 values of 5.58 and 7.20 μM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).
Carina Lemke; Joscha Christmann; Jiafei Yin; José M. Alonso; Estefanía Serrano; Mourad Chioua; Lhassane Ismaili; María Angeles Martínez-Grau; Christopher D. Beadle; Tatiana Vetman; Florian M. Dato; Ulrike Bartz; Paul W. Elsinghorst; Markus Pietsch; Christa E. Müller; Isabel Iriepa; Timo Wille; José Marco-Contelles; Michael Gütschow. Chromenones as Multineurotargeting Inhibitors of Human Enzymes. ACS Omega 2019, 4, 22161 -22168.
AMA StyleCarina Lemke, Joscha Christmann, Jiafei Yin, José M. Alonso, Estefanía Serrano, Mourad Chioua, Lhassane Ismaili, María Angeles Martínez-Grau, Christopher D. Beadle, Tatiana Vetman, Florian M. Dato, Ulrike Bartz, Paul W. Elsinghorst, Markus Pietsch, Christa E. Müller, Isabel Iriepa, Timo Wille, José Marco-Contelles, Michael Gütschow. Chromenones as Multineurotargeting Inhibitors of Human Enzymes. ACS Omega. 2019; 4 (26):22161-22168.
Chicago/Turabian StyleCarina Lemke; Joscha Christmann; Jiafei Yin; José M. Alonso; Estefanía Serrano; Mourad Chioua; Lhassane Ismaili; María Angeles Martínez-Grau; Christopher D. Beadle; Tatiana Vetman; Florian M. Dato; Ulrike Bartz; Paul W. Elsinghorst; Markus Pietsch; Christa E. Müller; Isabel Iriepa; Timo Wille; José Marco-Contelles; Michael Gütschow. 2019. "Chromenones as Multineurotargeting Inhibitors of Human Enzymes." ACS Omega 4, no. 26: 22161-22168.
The use of the synthetic antioxidant ethoxyquin (1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline, EQ) as a flame retardant in fish meal transported by sea is required by international authorities to prevent self-ignition. Because of extensive carry-over within the food chain, selective and sensitive analytical methods are required for investigations on human exposure and the safety of EQ and its metabolites. Therefore, a simple, fast, and rugged liquid-chromatography (LC) method was developed for the detection of EQ and its metabolites in fish and fishery products after liquid-liquid extraction using QuEChERS. For screening purposes, a fluorescence detector was used (LC-FLD) with the EQ-analogue methoxyquin serving as an internal standard. For stable-isotope dilution analysis by liquid chromatography-tandem mass spectrometry (SIDA-LC-MS/MS), deuterated analogues of EQ and its metabolites were synthesized for the first time and allowed for sensitive quantification and thus confirmation of screening results. Both methods were validated and successfully applied to commercially available fish samples.
Andreas Kranawetvogl; Paul Wilhelm Elsinghorst. Determination of the Synthetic Antioxidant Ethoxyquin and Its Metabolites in Fish and Fishery Products Using Liquid Chromatography–Fluorescence Detection and Stable-Isotope Dilution Analysis–Liquid Chromatography–Tandem Mass Spectrometry. Journal of Agricultural and Food Chemistry 2019, 67, 6650 -6657.
AMA StyleAndreas Kranawetvogl, Paul Wilhelm Elsinghorst. Determination of the Synthetic Antioxidant Ethoxyquin and Its Metabolites in Fish and Fishery Products Using Liquid Chromatography–Fluorescence Detection and Stable-Isotope Dilution Analysis–Liquid Chromatography–Tandem Mass Spectrometry. Journal of Agricultural and Food Chemistry. 2019; 67 (23):6650-6657.
Chicago/Turabian StyleAndreas Kranawetvogl; Paul Wilhelm Elsinghorst. 2019. "Determination of the Synthetic Antioxidant Ethoxyquin and Its Metabolites in Fish and Fishery Products Using Liquid Chromatography–Fluorescence Detection and Stable-Isotope Dilution Analysis–Liquid Chromatography–Tandem Mass Spectrometry." Journal of Agricultural and Food Chemistry 67, no. 23: 6650-6657.
Analysis of ergot alkaloids remains a topic of importance and the European Food Safety Authority (EFSA) has encouraged laboratories to provide monitoring data for the further evaluation of their occurrence in food and feed. While LC-MS/MS has dominated developments in recent years, LC-FLD is still more widespread, especially in developing countries. To improve the analysis of ergot alkaloids by LC-FLD, we developed an improved protocol introducing lysergic acid diethylamide (LSD) for internal standardization. Several aspects such as the composition and pH of the extraction medium, type of sorbent and conditions applied for solid-phase extraction/clean-up, use of a keeper during final evaporation and the type of syringe filter used for filtration prior to injection were thoroughly investigated. Optimized conditions comprise extraction by ethyl acetate, methanol and 28% aqueous ammonia in combination with basic aluminum oxide for extract clean-up. Use of a keeper was found inappropriate as LC-FLD analysis was significantly affected by co-eluting keeper components. Similar observations were made with some of the investigated syringe filters, where polytetrafluoroethylene (PTFE) proved to be the most suitable. Validation and application of the optimized methodology to real samples provided limits of detection and quantification suitable for the evaluation of relevant ergot alkaloid contaminations in rye and bakery products with superior precision that was facilitated by the introduced internal standard, LSD.
Iris Holderied; Michael Rychlik; Paul W. Elsinghorst. Optimized Analysis of Ergot Alkaloids in Rye Products by Liquid Chromatography-Fluorescence Detection Applying Lysergic Acid Diethylamide as an Internal Standard. Toxins 2019, 11, 184 .
AMA StyleIris Holderied, Michael Rychlik, Paul W. Elsinghorst. Optimized Analysis of Ergot Alkaloids in Rye Products by Liquid Chromatography-Fluorescence Detection Applying Lysergic Acid Diethylamide as an Internal Standard. Toxins. 2019; 11 (4):184.
Chicago/Turabian StyleIris Holderied; Michael Rychlik; Paul W. Elsinghorst. 2019. "Optimized Analysis of Ergot Alkaloids in Rye Products by Liquid Chromatography-Fluorescence Detection Applying Lysergic Acid Diethylamide as an Internal Standard." Toxins 11, no. 4: 184.
Nerve agents still represent a serious threat to civilian and military personnel as demonstrated by the violent conflict in the Middle East. For verification of poisoning, covalent adducts with endogenous proteins (e.g., human serum albumin, HSA) are valuable long-term biomarkers. Accordingly, we developed a microbore liquid chromatography-electrospray ionization mass spectrometry/high-resolution mass spectrometry (μLC-ESI MS/HR MS) method for simultaneous detection of HSA-adducts with the V-type nerve agents VX, Chinese VX (CVX), and Russian VX (RVX). Following Pronase-catalyzed proteolysis, novel disulfide-adducts were detected in addition to phosphonylated tyrosine residues. Dipeptide disulfide-adducts were formed between the thiol-containing leaving group of the V-type nerve agents (2-(diisopropylamino)ethanethiol, DPAET, for VX and 2-(diethylamino)ethanethiol, DEAET, for CVX and RVX) and the free thiol group of Cys34 in HSA (DPAET-CysPro, DEAET-CysPro). We also identified tripeptide disulfide-adducts containing Cys448 (MetProCys-DPAET, MetProCys-DEAET) and to a lesser extent Cys514 (AspIleCys-DPAET, AspIleCys-DEAET). Synthetic tripeptide references were used for confirmation of the postulated structures by μLC-ESI MS/HR MS. Lower limits of detection were determined in human plasma, being nearly identical for the three V-type nerve agents, and corresponded to 1-6 μM nerve agent for tyrosine-adducts, 1-3 μM nerve agent for CysPro-adducts, and 6 μM nerve agent for MetProCys-adducts, thus covering concentrations of toxicological relevance. Characterization of proteolysis kinetics revealed stable plateaus for all adducts being reached between 60 and 90 min at 37 °C. Adduct formation kinetics were characterized by simultaneously monitoring the V-type nerve agent, its leaving group, and the corresponding disulfide dimer. Furthermore, adduct formation patterns were investigated as a function of the molar ratio of HSA to V-type nerve agent. Graphical abstract Modification of human serum albumin (HSA) by V-type nerve agents Chinese VX (CVX) and RussianVX (RVX). Various tyrosine residues (Tyr???)n (e.g. most reactive Tyr411) were phosphonylated and disulfide-adducts were formed between the thiol-containing leaving group 2-(diethylamino)ethanethiol (DEAET) and at least three cysteine residues (Cys34, Cys448 and Cys514). Pronase-mediated proteolysis produced low-molecular cleavage products including phosphonylated tyrosines, dipeptide (Cys34Pro) and tripeptide (MetProCys448, AspIleCys514) disulfide-adducts that were detected by microbore liquid chromatography-electrospray ionization mass spectrometry/high-resolution mass spectrometry (μLC-ESI MS/HR MS).
Andreas Kranawetvogl; Jim Küppers; Markus Siegert; Michael Gütschow; Franz Worek; Horst Thiermann; Paul W. Elsinghorst; Harald John. Bioanalytical verification of V-type nerve agent exposure: simultaneous detection of phosphonylated tyrosines and cysteine-containing disulfide-adducts derived from human albumin. Analytical and Bioanalytical Chemistry 2018, 410, 1463 -1474.
AMA StyleAndreas Kranawetvogl, Jim Küppers, Markus Siegert, Michael Gütschow, Franz Worek, Horst Thiermann, Paul W. Elsinghorst, Harald John. Bioanalytical verification of V-type nerve agent exposure: simultaneous detection of phosphonylated tyrosines and cysteine-containing disulfide-adducts derived from human albumin. Analytical and Bioanalytical Chemistry. 2018; 410 (5):1463-1474.
Chicago/Turabian StyleAndreas Kranawetvogl; Jim Küppers; Markus Siegert; Michael Gütschow; Franz Worek; Horst Thiermann; Paul W. Elsinghorst; Harald John. 2018. "Bioanalytical verification of V-type nerve agent exposure: simultaneous detection of phosphonylated tyrosines and cysteine-containing disulfide-adducts derived from human albumin." Analytical and Bioanalytical Chemistry 410, no. 5: 1463-1474.
Chemical warfare agents represent a continuous and considerable threat to military personnel and the civilian population. Such compounds are prohibited by the Chemical Weapons Convention, to which adherence by the member states is strictly controlled. Therefore, reliable analytical methods for verification of an alleged use of banned substances are required. Accordingly, current research focuses on long-term biomarkers derived from covalent adducts with biomolecules such as proteins. Recently, we have introduced a microbore liquid chromatography/electrospray ionization high-resolution tandem mass spectrometry method allowing for the investigation of two different classes of adducts of the nerve agent VX with human serum albumin (HSA). Phosphonylated tyrosine residues and novel disulfide adducts at cysteine residues of HSA were produced by enzymatic cleavage with pronase and detected simultaneously. Notably, the thiol containing leaving group of VX (2-(diisopropylamino)ethanethiol, DPAET) formed disulfide adducts that were released as cysteine and proline containing dipeptides originating from at least two different sites of HSA. Aim of this study was to identify assumed and novel adducts of DPAET with HSA using synthetic peptide reference compounds. Two novel tripeptides were identified representing disulfide adducts with DPAET (Met-Pro-Cys-DPAET, MPC-DPAET and Asp-Ile-Cys-DPAET, DIC-DPAET). MPC-DPAET was shown to undergo partial in-source decay during electrospray ionization for MS detection thereby losing the N-terminal Met residue. This results in the more stable Pro-Cys-DPAET (PC-DPAET) dipeptide detectable as protonated ion. The limit of detection for MPC-DPAET was evaluated, revealing toxicologically relevant VX plasma concentrations. The results provide novel insights into the reactivity of VX and its endogenous targets. Copyright © 2016 John Wiley & Sons, Ltd.
Andreas Kranawetvogl; Jim Küppers; Michael Gütschow; Franz Worek; Horst Thiermann; Paul W. Elsinghorst; Harald John. Identification of novel disulfide adducts between the thiol containing leaving group of the nerve agent VX and cysteine containing tripeptides derived from human serum albumin. Drug Testing and Analysis 2017, 9, 1192 -1203.
AMA StyleAndreas Kranawetvogl, Jim Küppers, Michael Gütschow, Franz Worek, Horst Thiermann, Paul W. Elsinghorst, Harald John. Identification of novel disulfide adducts between the thiol containing leaving group of the nerve agent VX and cysteine containing tripeptides derived from human serum albumin. Drug Testing and Analysis. 2017; 9 (8):1192-1203.
Chicago/Turabian StyleAndreas Kranawetvogl; Jim Küppers; Michael Gütschow; Franz Worek; Horst Thiermann; Paul W. Elsinghorst; Harald John. 2017. "Identification of novel disulfide adducts between the thiol containing leaving group of the nerve agent VX and cysteine containing tripeptides derived from human serum albumin." Drug Testing and Analysis 9, no. 8: 1192-1203.
Highlights•A novel coumarin-derived turn-on probe for the detection of thiols with sufficient solubility in aqueous environments and excellent fluorescence characteristics.•A fluorescence-based assay for acetylcholinesterase activity as an addition to the established Ellman methodology.•Evaluation of the asymmetric sigmoidal product formation curves applying a three parameter Gompertz equation. AbstractA novel coumarin-derived thiol probe, based on the thiol-promoted cleavage of a quenching 2,4-dinitrobenzenesulfonyl group is described. The probe shows a sensitive fluorescence turn-on and sufficient solubility in aqueous environments. As a proof of concept, a new assay for AChE activity was developed as a useful addition to the established Ellman method. The observed reaction kinetics followed an asymmetric sigmoidal pattern and were successfully evaluated applying a three parameter Gompertz equation. Providing a linear relationship between the detected fluorescence formation curves and corresponding enzyme activities, this probe appears as a valuable tool for AChE activity measurements. Graphical abstract
Matthias D. Mertens; Anne Bierwisch; Tianwei Li; Michael Gütschow; Horst Thiermann; Timo Wille; Paul W. Elsinghorst. A novel fluorogenic probe for the investigation of free thiols: Application to kinetic measurements of acetylcholinesterase activity. Toxicology Letters 2016, 244, 161 -166.
AMA StyleMatthias D. Mertens, Anne Bierwisch, Tianwei Li, Michael Gütschow, Horst Thiermann, Timo Wille, Paul W. Elsinghorst. A novel fluorogenic probe for the investigation of free thiols: Application to kinetic measurements of acetylcholinesterase activity. Toxicology Letters. 2016; 244 ():161-166.
Chicago/Turabian StyleMatthias D. Mertens; Anne Bierwisch; Tianwei Li; Michael Gütschow; Horst Thiermann; Timo Wille; Paul W. Elsinghorst. 2016. "A novel fluorogenic probe for the investigation of free thiols: Application to kinetic measurements of acetylcholinesterase activity." Toxicology Letters 244, no. : 161-166.
Skatole metabolites have been considered as putative contributors to boar taint. Recently, 2-aminoacetophenone, a volatile phase I skatole metabolite, was identified in back fat samples from boars of Pietrain × Baden-Württemberg hybrid type. This paper addresses the question of the physiological origin of the observed 2-aminoacetophenone in these pigs. Microsomal fractions from nine boars were isolated, and formation of skatole metabolites was subsequently analyzed by stable-isotope dilution analysis (SIDA) using headspace solid-phase microextraction gas chromatography–mass spectrometry (HS-SPME/GC-MS). Significant breed-related differences in phase I skatole metabolism were observed, explaining the high levels of 2-aminoacetophenone in Pietrain × Baden-Württemberg hybrid type boars.
Christoph Gerlach; Paul W. Elsinghorst; Hans-Georg Schmarr; Matthias Wüst. 2-Aminoacetophenone Is the Main Volatile Phase I Skatole Metabolite in Pietrain × Baden-Württemberg Hybrid Type Boars. Journal of Agricultural and Food Chemistry 2016, 64, 1158 -1163.
AMA StyleChristoph Gerlach, Paul W. Elsinghorst, Hans-Georg Schmarr, Matthias Wüst. 2-Aminoacetophenone Is the Main Volatile Phase I Skatole Metabolite in Pietrain × Baden-Württemberg Hybrid Type Boars. Journal of Agricultural and Food Chemistry. 2016; 64 (5):1158-1163.
Chicago/Turabian StyleChristoph Gerlach; Paul W. Elsinghorst; Hans-Georg Schmarr; Matthias Wüst. 2016. "2-Aminoacetophenone Is the Main Volatile Phase I Skatole Metabolite in Pietrain × Baden-Württemberg Hybrid Type Boars." Journal of Agricultural and Food Chemistry 64, no. 5: 1158-1163.
A quick and selective analytical method was developed for the simultaneous quantitation of 2-methylimidazole, 4-methylimidazole, and 2-acetyl-4-(1,2,3,4-tetrahydroxybutyl)imidazole, which are known to be formed by Maillard reactions. The methodology reported here employs stable-isotope dilution analysis (SIDA) using 4-methylimidazole-d6 and [13C6]-2-acetyl-4-(1,2,3,4-tetrahydroxybutyl)imidazole as internal standards. It was successfully applied in a model assay to show that the addition of ammonium chloride during the manufacture of licorice promotes imidazole formation depending on the added amount of ammonium chloride without the well-known impact of present caramel food colorings. Furthermore, a monitoring assay of 29 caramel coloring-free licorice products showed that both 4-methylimidazole and 2-acetyl-4-(1,2,3,4-tetrahydroxybutyl)imidazole are endogenously generated in detectable quantities. None of the samples showed 2-methylimidazole levels above the limit of detection, 50 μg/kg.
Marion Raters; Paul W. Elsinghorst; Stephanie Goetze; Anna Dingel; Reinhard Matissek. Determination of 2-Methylimidazole, 4-Methylimidazole, and 2-Acetyl-4-(1,2,3,4-tetrahydroxybutyl)imidazole in Licorice Using High-Performance Liquid Chromatography–Tandem Mass Spectrometry Stable-Isotope Dilution Analysis. Journal of Agricultural and Food Chemistry 2015, 63, 5930 -5934.
AMA StyleMarion Raters, Paul W. Elsinghorst, Stephanie Goetze, Anna Dingel, Reinhard Matissek. Determination of 2-Methylimidazole, 4-Methylimidazole, and 2-Acetyl-4-(1,2,3,4-tetrahydroxybutyl)imidazole in Licorice Using High-Performance Liquid Chromatography–Tandem Mass Spectrometry Stable-Isotope Dilution Analysis. Journal of Agricultural and Food Chemistry. 2015; 63 (25):5930-5934.
Chicago/Turabian StyleMarion Raters; Paul W. Elsinghorst; Stephanie Goetze; Anna Dingel; Reinhard Matissek. 2015. "Determination of 2-Methylimidazole, 4-Methylimidazole, and 2-Acetyl-4-(1,2,3,4-tetrahydroxybutyl)imidazole in Licorice Using High-Performance Liquid Chromatography–Tandem Mass Spectrometry Stable-Isotope Dilution Analysis." Journal of Agricultural and Food Chemistry 63, no. 25: 5930-5934.
Intoxication by organophosphorus compounds, especially by pesticides, poses a considerable risk to the affected individual. Countermeasures involve both medical intervention by means of antidotes as well as external decontamination to reduce the risk of dermal absorption. One of the few decontamination options available is Reactive Skin Decontamination Lotion (RSDL), which was originally developed for military use. Here, we present a (31)P NMR spectroscopy based methodology to evaluate the detoxification efficacy of RSDL with respect to a series of organophosphorus pesticides and nerve agents. Kinetic analysis of the obtained NMR data provided degradation half-lives proving that RSDL is also reasonably effective against organophosphorus pesticides. Unexpected observations of different RSDL degradation patterns are presented in view of its reported oximate-catalyzed mechanism of action.
Paul W. Elsinghorst; Franz Worek; Marianne Koller. Detoxification of organophosphorus pesticides and nerve agents through RSDL: Efficacy evaluation by 31P NMR spectroscopy. Toxicology Letters 2015, 233, 207 -213.
AMA StylePaul W. Elsinghorst, Franz Worek, Marianne Koller. Detoxification of organophosphorus pesticides and nerve agents through RSDL: Efficacy evaluation by 31P NMR spectroscopy. Toxicology Letters. 2015; 233 (2):207-213.
Chicago/Turabian StylePaul W. Elsinghorst; Franz Worek; Marianne Koller. 2015. "Detoxification of organophosphorus pesticides and nerve agents through RSDL: Efficacy evaluation by 31P NMR spectroscopy." Toxicology Letters 233, no. 2: 207-213.
Highly toxic organophosphorus (OP) nerve agents are well characterized regarding chemical, biological and toxicological properties and the effectiveness of standard atropine and oxime therapy. Open literature data on the key nerve agent precursor methylphosphonic difluoride (DF) are scarce. To fill this gap the reactions of DF and its main degradation product methylphosphonofluoridic acid (MF) with human acetylcholinesterase (AChE) and the oximes obidoxime, HI-6 and 2-PAM were investigated in vitro. DF and MF were found to be weak inhibitors of human AChE being at least five orders less potent compared to the nerve agent sarin. Incubation of human AChE with millimolar DF and MF and subsequent addition of obidoxime and HI-6 resulted in a concentration-dependent decrease of AChE activity. This effect was not observed when incubating highly diluted AChE with oximes. The most likely explanation for this phenomenon is an inhibitory effect of phosphonyloximes formed by direct reaction of DF or MF with obidoxime and HI-6. These data indicate that high DF doses, resulting in millimolar blood and tissue DF/MF concentrations, are necessary to induce cholinergic signs and that under these conditions treatment with obidoxime and HI-6 may even worsen the poisoning.
Franz Worek; Paul Elsinghorst; Marianne Koller; Horst Thiermann. Reactions of methylphosphonic difluoride with human acetylcholinesterase and oximes – Possible therapeutic implications. Toxicology Letters 2014, 231, 92 -98.
AMA StyleFranz Worek, Paul Elsinghorst, Marianne Koller, Horst Thiermann. Reactions of methylphosphonic difluoride with human acetylcholinesterase and oximes – Possible therapeutic implications. Toxicology Letters. 2014; 231 (1):92-98.
Chicago/Turabian StyleFranz Worek; Paul Elsinghorst; Marianne Koller; Horst Thiermann. 2014. "Reactions of methylphosphonic difluoride with human acetylcholinesterase and oximes – Possible therapeutic implications." Toxicology Letters 231, no. 1: 92-98.
Paul W. Elsinghorst; Marion Raters; Anna Dingel; Jochen Fischer; Reinhard Matissek. Correction to Synthesis and Application of 13C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings. Journal of Agricultural and Food Chemistry 2014, 62, 9056 -9056.
AMA StylePaul W. Elsinghorst, Marion Raters, Anna Dingel, Jochen Fischer, Reinhard Matissek. Correction to Synthesis and Application of 13C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings. Journal of Agricultural and Food Chemistry. 2014; 62 (36):9056-9056.
Chicago/Turabian StylePaul W. Elsinghorst; Marion Raters; Anna Dingel; Jochen Fischer; Reinhard Matissek. 2014. "Correction to Synthesis and Application of 13C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings." Journal of Agricultural and Food Chemistry 62, no. 36: 9056-9056.
Jochen Fischer; Christoph Gerlach; Lisa Meier-Dinkel; Paul W. Elsinghorst; Peter Boeker; Hans-Georg Schmarr; Matthias Wüst. 2-Aminoacetophenone — A hepatic skatole metabolite as a potential contributor to boar taint. Food Research International 2014, 62, 35 -42.
AMA StyleJochen Fischer, Christoph Gerlach, Lisa Meier-Dinkel, Paul W. Elsinghorst, Peter Boeker, Hans-Georg Schmarr, Matthias Wüst. 2-Aminoacetophenone — A hepatic skatole metabolite as a potential contributor to boar taint. Food Research International. 2014; 62 ():35-42.
Chicago/Turabian StyleJochen Fischer; Christoph Gerlach; Lisa Meier-Dinkel; Paul W. Elsinghorst; Peter Boeker; Hans-Georg Schmarr; Matthias Wüst. 2014. "2-Aminoacetophenone — A hepatic skatole metabolite as a potential contributor to boar taint." Food Research International 62, no. : 35-42.
2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI) is observed as a minor contaminant in caramel food colourings (E 150c). Feeding experiments with rodents have revealed a significant lymphopenic effect that has been linked to the presence of THI in these food colourings. Pyridoxal kinase inhibition by THI has been suggested, but not demonstrated, as a mode of action as it leads to lowered levels of pyridoxal-5'-phosphate, which are known to cause lymphopenia. Recently, THI was also shown to inhibit sphingosine-1-phosphate lyase causing comparable immunosuppressive effects and derivatives of THI are being developed for the treatment of rheumatoid arthritis in humans. Interestingly, sphingosine-1-phosphate lyase activity depends on pyridoxal-5'-phosphate, which in turn is provided by pyridoxal kinase. This report shows that THI does inhibit pyridoxal kinase with competitive and mixed-type non-competitive behaviour towards its two substrates, pyridoxal and ATP, respectively. The corresponding inhibition constants are in the low millimolar range.
Paul Elsinghorst; Martino Luigi di Salvo; Alessia Parroni; Roberto Contestabile. Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI). Journal of Enzyme Inhibition and Medicinal Chemistry 2014, 30, 336 -340.
AMA StylePaul Elsinghorst, Martino Luigi di Salvo, Alessia Parroni, Roberto Contestabile. Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI). Journal of Enzyme Inhibition and Medicinal Chemistry. 2014; 30 (2):336-340.
Chicago/Turabian StylePaul Elsinghorst; Martino Luigi di Salvo; Alessia Parroni; Roberto Contestabile. 2014. "Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)." Journal of Enzyme Inhibition and Medicinal Chemistry 30, no. 2: 336-340.
The continuous application of organophosphate pesticides in developing countries, in addition to the remaining stock piles of chemical warfare nerve agents and their possible use is a significant threat to the public. Yet, today's options for a treatment of organophosphorus poisonings are still inadequate. This article provides a concise overview of current and future research trying to improve both prophylaxis and treatment of organophosphorus intoxications. The authors provide a summary of current oxime therapy and highlight several new concepts to overcome existing gaps. This overview of therapeutic options is accompanied by two sections on cyclodextrins, related compounds and bioscavengers, which may be used for either prophylaxis or treatment. For both groups, the authors review current drug design and screening approaches, the resulting developments and future challenges. While the search for one multipotent oxime has been a fruitless endeavor, combination of multiple oximes with complemental and systemic reactivity appears as a valuable concept. Development of potential scavengers, be it cyclodextrins or bioscavengers, is still hampered by insufficient efficacy of these compounds. Future strategies will aim at improving their catalytic efficacy while minimizing immunogenicity.
Paul Wilhelm Elsinghorst; Franz Worek; Horst Thiermann; Timo Wille. Drug development for the management of organophosphorus poisoning. Expert Opinion on Drug Discovery 2013, 8, 1467 -1477.
AMA StylePaul Wilhelm Elsinghorst, Franz Worek, Horst Thiermann, Timo Wille. Drug development for the management of organophosphorus poisoning. Expert Opinion on Drug Discovery. 2013; 8 (12):1467-1477.
Chicago/Turabian StylePaul Wilhelm Elsinghorst; Franz Worek; Horst Thiermann; Timo Wille. 2013. "Drug development for the management of organophosphorus poisoning." Expert Opinion on Drug Discovery 8, no. 12: 1467-1477.
2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI) is a minor toxic contaminant observed in caramel food colorings and was shown to exert immunosuppressant activity when fed to rodents. Because of this toxicity, maximum levels of THI in caramel food colorings have been defined by international and European authorities. Several reports of THI analysis using external standardization have been published for liquid foods such as beers and soft drinks. However, no suitable internal standard has yet been described allowing THI analysis in more complex samples. In this paper we describe the preparation of a labeled [13C6]THI analogue and its application for the successful validation of the first stable isotope dilution assay (SIDA) of THI in caramel food colorings. A brief survey of THI levels in commercially available caramel class III (E 150c) and IV (E 150d) food colorings is also included, corroborating that THI occurs only in caramel class III food colorings.
Paul W. Elsinghorst; Marion Raters; Anna Dingel; Jochen Fischer; Reinhard Matissek. Synthesis and Application of 13C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings. Journal of Agricultural and Food Chemistry 2013, 61, 7494 -7499.
AMA StylePaul W. Elsinghorst, Marion Raters, Anna Dingel, Jochen Fischer, Reinhard Matissek. Synthesis and Application of 13C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings. Journal of Agricultural and Food Chemistry. 2013; 61 (31):7494-7499.
Chicago/Turabian StylePaul W. Elsinghorst; Marion Raters; Anna Dingel; Jochen Fischer; Reinhard Matissek. 2013. "Synthesis and Application of 13C-Labeled 2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI), an Immunosuppressant Observed in Caramel Food Colorings." Journal of Agricultural and Food Chemistry 61, no. 31: 7494-7499.
Clopidogrel has been applied in antiplatelet therapy since 1998 and is the thienopyridine with the largest clinical experience. By 2011, clopidogrel (Plavix(®)) was the second top-selling drug in the world. Following complete patent expiry in 2012/2013 its use is expected to grow even further from generics entering the market. Prefaced by a brief description of clopidogrel metabolism, this review analyzes analytical methods addressing the quantification of clopidogrel and its metabolites in biological samples. Techniques that have been applied to analyze human plasma or serum are predominantly LC-MS and LC-MS/MS. The lowest level of clopidogrel quantification that has been achieved is 5pg/mL, the shortest runtime is 1.5min and almost 100% recovery has been reported using solid-phase extraction for sample preparation.
Paul W. Elsinghorst. Quantitative determination of clopidogrel and its metabolites in biological samples: A mini-review. Journal of Chromatography B 2013, 917-918, 48 -52.
AMA StylePaul W. Elsinghorst. Quantitative determination of clopidogrel and its metabolites in biological samples: A mini-review. Journal of Chromatography B. 2013; 917-918 ():48-52.
Chicago/Turabian StylePaul W. Elsinghorst. 2013. "Quantitative determination of clopidogrel and its metabolites in biological samples: A mini-review." Journal of Chromatography B 917-918, no. : 48-52.
A novel SIDA–DI–SPME–GC/MS procedure for the quantitation of skatole in pork meat juice was developed and validated as a substitute for back fat sample analysis. System suitability was evaluated by determining the correlation between skatole concentrations in a subset of 38 paired meat juice and back fat samples selected from 90 fattened boars. High correlation was observed between both matrices and conclusions about the partitioning of skatole as well as of androstenone between fat and lean compartments in vivo were drawn.
Jochen Fischer; Detert Brinkmann; Paul Elsinghorst; Matthias Wüst. Determination of the boar taint compound skatole in meat juice by means of stable isotope dilution analysis–direct immersion–solid phase microextraction–gas chromatography/mass spectrometry. Meat Science 2012, 91, 261 -265.
AMA StyleJochen Fischer, Detert Brinkmann, Paul Elsinghorst, Matthias Wüst. Determination of the boar taint compound skatole in meat juice by means of stable isotope dilution analysis–direct immersion–solid phase microextraction–gas chromatography/mass spectrometry. Meat Science. 2012; 91 (3):261-265.
Chicago/Turabian StyleJochen Fischer; Detert Brinkmann; Paul Elsinghorst; Matthias Wüst. 2012. "Determination of the boar taint compound skatole in meat juice by means of stable isotope dilution analysis–direct immersion–solid phase microextraction–gas chromatography/mass spectrometry." Meat Science 91, no. 3: 261-265.
The occurrence of orthosteric and allosteric binding sites is a characteristic common feature of several acetylcholine- binding proteins, like acetylcholinesterase or the nicotinic and muscarinic acetylcholine receptors. These proteins are involved in a number of neurological disorders, such as Alzheimer's disease, and represent important therapeutic targets for the development of heterodimeric ligands addressing both of their binding sites. Among the pharmacophores, which have been combined in such heterodimers, the tetrahydroacridine derivative tacrine has attracted particular interest. This review discusses the chemistry behind the linker connection of tacrine to other pharmacophores and summarizes the types of linkers established to date. Especially, the development of a hydrazide linker for tacrine-derived heterodimers is highlighted by applications in the inhibition of cholinesterases, the bivalent binding to nicotinic and muscarinic acetylcholine receptors, as well as the histochemical imaging of acetylcholinesterase and amyloid-β.
Paul W. Elsinghorst; Wolfgang Härtig; Daniela Gündisch; Klaus Mohr; Christian Tränkle; Michael Gütschow. A hydrazide linker strategy for heterobivalent compounds as ortho- and allosteric ligands of acetylcholine-binding proteins. Current Topics in Medicinal Chemistry 2011, 11, 2731 -2748.
AMA StylePaul W. Elsinghorst, Wolfgang Härtig, Daniela Gündisch, Klaus Mohr, Christian Tränkle, Michael Gütschow. A hydrazide linker strategy for heterobivalent compounds as ortho- and allosteric ligands of acetylcholine-binding proteins. Current Topics in Medicinal Chemistry. 2011; 11 (22):2731-2748.
Chicago/Turabian StylePaul W. Elsinghorst; Wolfgang Härtig; Daniela Gündisch; Klaus Mohr; Christian Tränkle; Michael Gütschow. 2011. "A hydrazide linker strategy for heterobivalent compounds as ortho- and allosteric ligands of acetylcholine-binding proteins." Current Topics in Medicinal Chemistry 11, no. 22: 2731-2748.