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Nachweis Von Xenobiotika in Alternativen Matrices Mittels Flüssigkeitschromatographie-Massenspektrometrie

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Nachweis Von Xenobiotika in Alternativen Matrices Mittels Flüssigkeitschromatographie-Massenspektrometrie NACHWEIS VON XENOBIOTIKA IN ALTERNATIVEN MATRICES MITTELS FLÜSSIGKEITSCHROMATOGRAPHIE-MASSENSPEKTROMETRIE METHODENENTWICKLUNG UND NEUE EINSATZMÖGLICHKEITEN IN DER FORENSISCHEN TOXIKOLOGIE UND KLINISCHEN CHEMIE INAUGURALDISSERTATION zur Erlangung des Doktorgrades (Dr. rer. nat.) der Fakultät für Chemie und Pharmazie der Albert-Ludwigs-Universität Freiburg im Breisgau vorgelegt von Jürgen Kempf aus Zell a. H. 2015 Die praktischen Arbeiten zur Erstellung der vorliegenden Dissertation wurden im Zeitraum von Januar 2009 bis September 2014 am Institut für Rechtsmedizin des Universitätsklinikums der Albert-Ludwigs-Universität Freiburg durchgeführt. Vorsitzender des Promotionsausschusses: Prof. Dr. Stefan Weber Referent: Prof. Dr. Rolf Schubert Betreuer der Arbeit und Korreferent: Prof. Dr. Wolfgang Weinmann Datum der Promotion: 02.02.2015 Danksagung Danksagung Laut Promotionsordnung der Universität Freiburg für die Fakultät für Chemie und Pharmazie dient die Promotion „...dem Nachweis der Befähigung zu selbständiger vertiefter wissenschaftlicher Arbeit“. Bei der hier vorliegenden Arbeit handelt es sich zwar um eine, gemäß Promotionsordnung, selbständig angefertigte vertiefte wissenschaftlich Arbeit, diese wäre jedoch ohne die Hilfe und Unterstützung zahlreicher Personen nicht möglich gewesen: Herzlich danken möchte ich Prof. Dr. Wolfgang Weinmann für die Bereitstellung eines interessanten und vielseitigen Promotionsthemas, seine Unterstützung und seinen fachlichen Rat bei der Durchführung dieser Arbeit sowie für die Freiheit, viele Ideen und Projekte nach eigenem Ermessen durchführen zu können. Herrn Prof. Dr. Auwärter möchte ich an dieser Stelle dafür danken, die Arbeit nach dem Ruf von Herrn Prof. Weinmann nach Bern unter gleichbleibenden Bedingungen in der Abteilung Forensische Toxikologie am Institut für Rechtsmedizin beenden zu können. Herrn Prof. Dr. Rolf Schubert danke ich herzlich für die Betreuung dieser Dissertation seitens der Fakultät für Chemie und Pharmazie, sein stets offenes Ohr und seinen besonnenen Umgang mit den anfänglichen formalen Problemen der Promotions- berechtigung eines Master-Abschlusses. Frau Prof. Dr. Regine Süss möchte ich danken, dass sie sich als Dritt-Prüferin für die Arbeit zur Verfügung gestellt hat. Großer Dank gilt zudem Herrn Prof. Dr. Dr. h.c. mult. Stefan Pollak für sein Einverständnis die Promotionsarbeit am Institut für Rechtsmedizin durchführen zu können sowie die großzügige finanzielle Unterstützung zahlreicher nationaler und internationaler Tagungsteilnahmen und Fortbildungen. Die vorliegende Arbeit bot Gelegenheit mit mehreren Kooperationspartnern aus anderen Instituten bzw. Kliniken sowie der Industrie zusammen zu arbeiten und so interessante Einblicke in andere Forschungs- und Arbeitsbereiche zu erhalten: Herrn Thomas Wuske von der Drägerwerk AG Lübeck, der mit seiner Anfrage zur Stabilität von Benzodiazepinen in Speichel den Stein ins Rollen brachte, sei für die Zusammenarbeit und die Bereitstellung von Realproben gedankt. I Danksagung Herrn Prof. Dr. Christian Fleischhaker und Herrn PD Dr. Hans-Willi Clement der Klinik für Psychiatrie, Psychotherapie und Psychosomatik im Kindes- und Jugendalter des Universitätsklinikums Freiburg danke ich für ihre Bereitschaft, das Studienprotokoll ihrer arbeitsreichen Probandenstudie um eine Speichelnahme zu erweitern und die Möglichkeit, unter kontrollierten Bedingungen erhaltenen Realproben analysieren zu können. Herrn Prof. Dr. Dr. Jörg-Elard Otten und Frau Dr. Yvonne Schüssel aus der Klinik für Mund-, Kiefer- und Gesichtschirurgie des Universitätsklinikums Freiburg möchte ich an dieser Stelle dafür danken, dass ich durch ihre Fragestellung über den Tellerrand der reinen forensischen Analytik blicken und erste praktische Erfahrungen mit der Analyse von humaner Zahnhartsubstanz sammeln konnte. Herrn Prof. Dr. Markus Altenburger und Frau Dr. Hanna Ernst aus der Klinik für Zahnerhaltungskunde u. Parodontologie des Universitätsklinikums Freiburg danke ich für die gelungene Zusammenarbeit und die Ausdauer die nötig war, um das gemeinsame Projekt zum Thema Einlagerung von Drogen in humaner Zahnhartsubstanz erfolgreich auf den Weg zu bringen. Petra Decker, Sebastian Götz, Markus Meyer, und Birgit Schneider von der Firma Bruker Daltonik GmbH danke ich recht herzlich für die mehrjährige Kooperation auf dem Gebiet der Applikationsentwicklung, die vielen Blicke hinter die Kulissen eines Geräteherstellers und dessen „ganz normalen Wahnsinn“ sowie die vielen (außer-) fachlichen Diskussionen. Die Vier seien stellvertretend für die zahlreichen Bruker- Mitarbeiter aus Entwicklung und Service genannt, die gemeinsam den besten technischen Support den man sich für sein Projekt wünschen kann, realisiert haben. Neben den Kooperationspartnern gebührt mein Dank allen Kollegen und Mitarbeitern am Institut für Rechtsmedizin Freiburg: „Meinen“ Praktikantinnen Rebecca Kuhn, Bettina Kaiser, Anna Sandhaas und Bettina Saar sowie „meinen“ Bachelorstudenten Markus Stieglat und Laura M. Huppertz möchte ich an dieser Stelle ganz herzlich für das unglaubliche Engagement im Rahmen ihrer jeweiligen Projektarbeiten danken. Ohne euren Einsatz wären einige der Studien und Versuche nicht in diesem Umfang möglich gewesen. Großen Dank schulde ich Susanne Vogt, deren Türe jederzeit offen stand und die auch für die verzwicktesten Fragen immer ein offenes Ohr hatte. Ihre umsichtigen Antworten, Ratschläge und Ideen halfen mehr als einmal die richtige Entscheidung zu treffen. Danke, Susanne. II Danksagung Stefan Kneisel danke ich für zahlreiche Diskussionen sowie die unkomplizierte und konstruktive Zusammenarbeit beim Projekt „Nachweis synthetischer Cannabinoide in Speichel“. Annette Thierauf-Emberger möchte ich für die gemeinsame Projektarbeit, ihre Hilfe bei zahlreichen medizinischen Fragestellungen und mehreren, teils spontaner und umfangreicher Blutentnahme-Aktionen sowie ihre (nahezu) immerwährende gute Laune danken. Den Präparatoren Gaby Herzog, Thomas Rost und Wolfgang Schmidt danke ich für ihre Unterstützung bei der Entnahme von post-mortalen Proben und die jederzeit freundliche Aufnahme in ihrer Abteilung. Großer Dank geht an die gesamte Arbeitsgruppe Forensische Toxikologie, insbesondere Lisa Fischer, Florian Geyler, Raija „Böse Frau“ Hammer, Laura M. Huppertz, Jens Klingele, Björn Moosmann, Renate Oßwald, Christa Pelz, Kathrin Riedy, Nadine „Cookie“ Schiesel, Sabrina Schwabe, Christine „Alberich“ Stronczek, Jessica Traber und Katrin Weber, für viele wertvolle Anregungen, stete Hilfsbereitschaft und die freundschaftliche Arbeitsatmosphäre, die wesentlich zum Gelingen dieser Arbeit beigetragen haben. III IV "So eine Arbeit wird eigentlich nie fertig, man muss sie für fertig erklären, wenn man nach der Zeit und den Umständen das Möglichste getan hat." Johann Wolfgang von Goethe V VI Publikationsliste Publikationsliste ORIGINALBEITRÄGE J. Kempf, Th. Wuske, R. Schubert, W. Weinmann Pre-analytical stability of selected benzodiazepines on a polymeric oral fluid sampling device Forensic Science International 2009 Apr 15;186(1-3):81-5. A. Thierauf, J. Kempf, M. Perdekamp, V. Auwärter, H. Gnann, A. Wohlfarth, W. Weinmann Ethylsulphate and ethylglucuronide in vitreous humor as postmortem evidence marker for ethanol consumption prior to death Forensic Science International 2011 Jul 15; 210(1-3):63-8. A. Thierauf, J. Kempf, J. Eschbach, V. Auwärter, W. Weinmann, H. Gnann A case of a distinct difference between the measured blood ethanol concentration and the concentration estimated by Widmark's equation. Medicine, Science, and the Law. 2013 Apr;53(2):96-9. C. Schneider, A. Thierauf, J. Kempf, V. Auwärter Ethanol concentration in breastmilk after the consumption of non-alcoholic beer Breastfeeding Medicine 2013 Jun;8(3):291-3 S. Kneisel, V. Auwärter, J. Kempf Analysis of 30 synthetic cannabinoids in oral fluid using liquid chromatography-electrospray ionization tandem mass spectrometry. Drug Testing and Analysis 2013 Aug; 5(8):657-69. S. Vogt, J. Kempf, J. Buttler, V. Auwärter, W. Weinmann Desalkylflurazepam found in patients’ samples after high-dose midazolam treatment Drug Testing and Analysis 2013 Sep; 5(9-10):745-7. Y. Schüssl, K. Pelz, J. Kempf, J.-E. Otten Concentrations of amoxicillin and clindamycin in teeth following a single dose of oral medication Clinical Oral Investigation 2014 Jan;18(1):35-40 L.M. Huppertz, S. Kneisel, V. Auwärter, J. Kempf A Comprehensive Library-Based, Automated Screening Procedure for 46 Synthetic Cannabinoids in Serum Employing Liquid Chromatography-Quadrupole Ion Trap Mass Spectrometry with High- Temperature Electrospray Ionization Journal of Mass Spectrometry 2014, 49, 117-127 J. Kempf, J. Traber, V. Auwärter, L.M. Huppertz ‘Psychotropics caught in a trap’ – Adopting a screening approach to specific needs Forensic Science International 2014 May 6,243C:84-89 VII Publikationsliste J. Spinner, M. Klima, J. Kempf, L.M. Huppertz, V. Auwärter, M.J. Altenburger; M.A. Neukamm Determination of drugs of abuse in bovine dentin using liquid chromatography-electrospray ionization mass spectrometry Journal of Mass Spectrometry 2014 Dec,49(12): 1306-13 T. Alderliesten, L.M.A Favie, R.W. Neijzen, V. Auwärter, C.H.A. Nijboer, R.E.J. Marges, J. Kempf, F. van Bel, F. Groenendaal Neuroprotection by argon ventilation after perinatal asphyxia: a safety study in newborn piglets PLOS ONE 9(12):e113575. Doi:101371/journal.pone.0113575 SONSTIGE VERÖFFENTLICHUNGEN J. Kempf, R. Kuhn, C. Fleischhaker, K. Schneider-Momm, W. Weinmann Detection of Methylphenidate in Serum and Oral Fluid
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