A single LC-tandem mass spectrometry method for the simultaneous determination of 14 antimalarial drugs and their metabolites in human plasma.

Among the various determinants of treatment response, the achievement of sufficient blood levels is essential for curing malaria. For helping us at improving our current understanding of antimalarial drugs pharmacokinetics, efficacy and toxicity, we have developed a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) requiring 200mul of plasma for the simultaneous determination of 14 antimalarial drugs and their metabolites which are the components of the current first-line combination treatments for malaria (artemether, artesunate, dihydroartemisinin, amodiaquine, N-desethyl-amodiaquine, lumefantrine, desbutyl-lumefantrine, piperaquine, pyronaridine, mefloquine, chloroquine, quinine, pyrimethamine and sulfadoxine). Plasma is purified by a combination of protein precipitation, evaporation and reconstitution in methanol/ammonium formate 20mM (pH 4.0) 1:1. Reverse-phase chromatographic separation of antimalarial drugs is obtained using a gradient elution of 20mM ammonium formate and acetonitrile both containing 0.5% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 21min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effect variability, overall process efficiency, standard addition experiments as well as antimalarials short- and long-term stability in plasma. The reactivity of endoperoxide-containing antimalarials in the presence of hemolysis was tested both in vitro and on malaria patients samples. With this method, signal intensity of artemisinin decreased by about 20% in the presence of 0.2% hemolysed red-blood cells in plasma, whereas its derivatives were essentially not affected. The method is precise (inter-day CV%: 3.1-12.6%) and sensitive (lower limits of quantification 0.15-3.0 and 0.75-5ng/ml for basic/neutral antimalarials and artemisinin derivatives, respectively). This is the first broad-range LC-MS/MS assay covering the currently in-use antimalarials. It is an improvement over previous methods in terms of convenience (a single extraction procedure for 14 major antimalarials and metabolites reducing significantly the analytical time), sensitivity, selectivity and throughput. While its main limitation is investment costs for the equipment, plasma samples can be collected in the field and kept at 4 degrees C for up to 48h before storage at -80 degrees C. It is suited to detecting the presence of drug in subjects for screening purposes and quantifying drug exposure after treatment. It may contribute to filling the current knowledge gaps in the pharmacokinetics/pharmacodynamics relationships of antimalarials and better define the therapeutic dose ranges in different patient populations.

Metal concentrations in soils around the copper smelter and surrounding industrial complex of Port Kembla, NSW, Australia

Anthropogenic emissions of metals from sources such as smelters are an international problem, but there is limited published information on emissions from Australian smelters. The objective of this study was to investigate the regional distribution of heavy metals in soils in the vicinity of the industrial complex of Port Kembla, NSW, Australia, which comprises a copper smelter, steelworks and associated industries. Soil samples (n=25) were collected at the depths of 0-5 and 5-20 cm, air dried and sieved to < 2 mm. Aqua regia extractable amounts of As, Cr, Cu, Ph and Zn were analysed by inductively coupled plasma mass spectrometry (lCP-MS) and inductively coupled plasma atomic emission spectrometry (ICP-AES). Outliers were identified from background levels by statistical methods. Mean background levels at a depth of 0-5 cm were estimated at 3.2 mg/kg As, 12 mg/kg Cr, 49 mg/kg Cu, 20 mg/kg Ph and 42 mg/kg Zn. Outliers for elevated As and Cu values were mainly present within 4 km from the Port Kembla industrial complex, but high Ph at two sites and high Zn concentrations were found at six sites up to 23 km from Port Kembla. Chromium concentrations were not anomalous close to the industrial complex. There was no significant difference of metal concentrations at depths of 0-5 and 5-20 cm, except for Ph and Zn. Copper and As concentrations in the soils are probably related to the concentrations in the parent rock. From this investigation, the extent of the contamination emanating from the Port Kembla industrial complex is limited to 1-13 km, but most likely <4 km, depending on the element; the contamination at the greater distance may not originate from the industrial complex. (C) 2003 Elsevier B.V. All rights reserved.

[Le podium du marathon de Boston, 19/4/20, de gauche à droite, Peter] Trivoulidas, Arthur Roth [et Carl] Linder : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 59159

Large scale identification of protein SUMOylation by mass spectrometry in HEK293 cells

Les fichiers qui accompagnent mon document sont des tableaux supplémentaires réalisés avec Excel (Microsoft Office), dans la version papier du mémoire ces fichiers sont sur un CD-ROM.

Simultaneous analysis of five antidepressant drugs using direct injection of biofluids in a capillary restricted-access media-liquid chromatography-tandem mass spectrometry system

Direct analysis, with minimal sample pretreatment, of antidepressant drugs, fluoxetine, imipramine, desipramine, amitriptyline, and nortriptyline in biofluids was developed with a total run time of 8 min. The setup consists of two HPLC pumps, injection valve, capillary RAM-ADS-C18 pre-column and a capillary analytical C 18 column connected by means of a six-port valve in backflush mode. Detection was performed with ESI-MS/MS and only 1 mu m of sample was injected. Validation was adequately carried out using FLU-d(5) as internal standard. Calibration curves were constructed under a linear range of 1-250 ng mL(-1) in plasma, being the limit of quantification (LOQ), determined as 1 ng mL(-1), for all the analytes. With the described approach it was possible to reach a quantified mass sensitivity of 0.3 pg for each analyte (equivalent to 1.1-1.3 fmol), translating to a lower sample consumption (in the order of 103 less sample than using conventional methods). (C) 2008 Elsevier B.V. All rights reserved.

Hollow-fiber liquid-phase microextraction and gas chromatography-mass spectrometry of barbiturates in whole blood samples

Here, we present a method for measuring barbiturates (butalbital, secobarbital, pentobarbital, and phenobarbital) in whole blood samples. To accomplish these measurements, analytes were extracted by means of hollow-fiber liquid-phase microextraction in the three-phase mode. Hollow-fiber pores were filled with decanol, and a solution of sodium hydroxide (pH 13) was introduced into the lumen of the fiber (acceptor phase). The fiber was submersed in the acidified blood sample, and the system was subjected to an ultrasonic bath. After a 5 min extraction, the acceptor phase was withdrawn from the fiber and dried under a nitrogen stream. The residue was reconstituted with ethyl acetate and trimethylanilinium hydroxide. An aliquot of 1.0 mu L of this solution was injected into the gas chromatograph/mass spectrometer, with the derivatization reaction occurring in the hot injector port (flash methylation). The method proved to be simple and rapid, and only a small amount of organic solvent (decanol) was needed for extraction. The detection limit was 0.5 mu g/mL for all the analyzed barbiturates. The calibration curves were linear over the specified range (1.0 to 10.0 mu g/mL). This method was successfully applied to postmortem samples (heart blood and femoral blood) collected from three deceased persons previously exposed to barbiturates.

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 299 - Wissenschaftlicher Austausch mit Professor Hugo von Meltzl bei der Erstellung wissenschaftlicher Aufsätze zur Schopenhauerschen Philosophie

u.a.: Nachlass Schopenhauer; Eduard Grisebach; Arthur Schopenhauer;

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 298 - Dankesschreiben an den Professor Hugo von Meltzl wegen der Zusendung einer Publikation

u.a.: Versetzung an das Konsulat in Port-au-Prince; Bibliothek Schopenhauers; Eduard Grisebach; Arthur Schopenhauer;

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 301 - Mitteilung an den Professor Hugo von Meltzl über den aktuellen Stand der Zusammenstellung des Schopenhauer-Nachlasses

u.a.: Kontaktaufnahme mit David Asher in Leipzig wegen der Briefe Schopenhauers; Bitte um Anonymisierung der Autorenschaft Eduard Grisebach; Arthur Schopenhauer;

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 302 - Dankesschreiben an den Professor Hugo von Meltzl wegen der Unterstützung der Drucklegung des Schopenhauer-Nachlasses

u.a.: Recherche einer Goethe-Handschrift; Zweifel an der Handschrift Schopenhauers in der 1. Auflage der: "Ueber die vierfache Wurzel des Satzes vom zureichenden Grunde"; Kontaktaufnahme mit Professor für Philosophie Pol de Mont aus Antwerpen; Eduard Grisebach; Arthur Schopenhauer; Wilhelm Gwinner; Johann Karl Friedrich Rosenkranz;

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 300 - Mitteilung an den Professor Hugo von Meltzl über den Bearbeitungsstand seiner Bearbeitung zum Nachlass Schopenhauers

u.a.: Probleme bei der Datierung der Briefe Schopenhauers; Bitte um Anonymisierung der Autorenschaft aufgrund politischer Gründe; Eduard Grisebach; Arthur Schopenhauer;

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 303 - Rechtfertigung gegenüber Professor Hugo von Meltzl über die ausgebliebene publizistische Tätigkeit anlässlich des 100. Geburtstags Arthur Schopenhauers

u.a.: Nordamerikanische Reise; Versetzung in das Konsulat von Hawaii; Eduard Grisebach;

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 304 - Ankündigung an Professor Hugo von Meltzl wegen seiner geplanten Veröffentlichung zu "Münchhausens Reisen und Abenteuer"

u.a.: Nachlass Schopenhauer;