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Seeding Multi-omic Improvement of AppleBilbrey, Emma A. January 2020 (has links)
No description available.
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Development and validation of an ultrafiltration-UHPLC-MS/MS method for the quantification of unbound Beta-Lactam antibiotics cefotaxime, piperacillin, cloxacillin and flucloxacillin in plasma / Utveckling och validering av en UHPLC-MS/MS-metod med ultrafiltrering för kvantifiering av icke-proteinbunden beta-lactam-antibiotika cefotaxim, piperacillin, kloxacillin och flukloxacillin i plasmaClarin, Leona January 2020 (has links)
Kritiskt sjuka patienter med infektioner är en börda för sjukvården och 70 % av alla patienter på intensivvårdsavdelningar är ordinerade antibiotika. Antibiotika binder till proteiner i blodet, men enbart den icke-proteinbundna (fria) fraktionen kan diffundera över kapillära membran och binda till receptorer. Standardproteinbindningsgrad för olika antibiotika har utvecklats från studier på friska frivilliga och doseringen av läkemedlen är anpassade därefter. Den totala koncentrationen av antibiotika i patienters blod är vanligen representativ för den farmakologiska effekten. Dock kan vissa sjukdomar påverka proteinbindningsgraden vilket resulterar i en större eller mindre mängd fria antibiotika i blodcirkulationen. Det här kan i sin tur resultera i toxicitet eller otillräcklig effekt av läkemedlet. Syftet med det här projektet var att utveckla en analytisk metod för att bestämma den fria koncentrationen av Beta-Lactam antibiotikan cefotaxim, flukloxacillin, kloxacillin och piperacillin i plasma. En metod utvecklades med ultrafiltrering för extraktion av den fria fraktionen och högupplösande vätskekromatografi och tandem masspektrometri, UHPLC-MS/MS, för kvantifiering av analyterna. Metoden validerades delvis enligt den Europeiska Läkemedelsmyndighetens riktlinjer för bioanalytisk metodvalidering. / Infections in critically ill patients are a problem for the healthcare system and at any one time, 70 % of all intensive care unit (ICU) patients are treated with antibiotics. Antibiotics bind to proteins in the blood, but only unbound drug can diffuse over capillary membranes and bind to the targeted receptor. Standard protein binding percentages for antibiotics have been developed from studies on healthy volunteers and dosing regimens for patients are adapted accordingly. The determination of the total concentration of antibiotics in patients’ blood samples is, based on the standard percentages, ordinarily representative for the pharmacological effect of the antibiotic. However, certain conditions that are common in critically ill patients can alter protein binding percentages, resulting in a larger or smaller unbound fraction. This in turn can result in toxicity or therapeutic failure. The aim of this project was to develop an analytical method for the determination of the unbound concentration of the Beta-Lactam antibiotics cefotaxime, flucloxacillin, cloxacillin and piperacillin in plasma. A method was successfully developed using ultrafiltration for the extraction of unbound analytes and ultra high performance liquid chromatography tandem mass spectrometry, UHPLC-MS/MS, for their quantification. The method was partly validated according to the European Medicines Agency’s guidelines on bioanalytical method validation.
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Structural Characterization and Quantitative Analysis by Interfacing Liquid Chromatography and/or Ion Mobility Separation with Multi-Dimensional Mass SpectrometrySolak, Nilüfer 21 May 2010 (has links)
No description available.
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Analysis of Wastewater Samples for the Detection of Contaminating DrugsDwyer, Emily 15 May 2023 (has links)
No description available.
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Characterization of Drug Release from Mesoporous SiO2-Based Membranes with Variable Pore Structure and GeometryBaumann, Frank, Paul, Theresa, Wassersleben, Susan, Regenthal, Ralf, Enke, Dirk, Aigner, Achim 31 August 2023 (has links)
Transdermal drug delivery systems (TDDSs) play important roles in therapy due to distinct
advantages over other forms and types of drug application. While common TDDS patches mainly
consist of polymeric matrices so far, inorganic carriers show numerous advantages such as high
mechanical stability, possible re-use and re-loading of drugs, and a broad chemical compatibility with
therapeutically relevant compounds and chemical enhancers. Mesoporous glasses can be prepared
in different monolithic shapes, and offer a particularly wide range of possible pore volumes, pore
diameters, and specific surface areas. Further, they show high loading capacities and favorable
physical, technical, and biological properties. Here, we explored for the first time monolithic SiO2-
based carriers as sustained release systems of therapeutic drugs. In an ideally stirred vessel as model
system, we systematically analyzed the influence of pore diameter, pore volume, and the dimensions
of glass monoliths on the loading and sustained release of different drugs, including anastrozole,
xylazine, imiquimod, levetiracetam, and flunixin. Through multilinear regression, we calculated
the influence of different parameters on drug loading and diffusion coefficients. The systematic
variation of the mesoporous glass properties revealed pore volumes and drug loading concentrations,
but not pore diameter or pore surface area as important parameters of drug loading and release
kinetics. Other relevant effectors include the occurrence of lateral diffusion within the carrier and
drug-specific properties such as adsorption. The structure–property relationships derived from our
data will allow further fine-tuning of the systems according to their desired properties as TDDS, thus
guiding towards optimal systems for their use in transdermal drug applications
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The development of cellular metabolomic platforms and their applicationsFei, Fan January 2016 (has links)
In this thesis, an analytical platform was designed and applied to various in vitro bacterial and eukaryotic cell cultures. An extraction and an analytical protocol were developed for comprehensive and simultaneous analysis of both lipid and polar metabolites for intra- and extracellular metabolomics using HILIC-LC-TOF-MS. This analytical platform was applied to four diverse research questions such as the effect of oxygen environment on growth, the interplay between gene expression and metabolism, metabolic changes that occur with age, and PAH toxicity. Specifically: (i) the effect of oxygen on the growth, physiology and metabolism of the Gram positive Streptococcus intermedius were investigated by comprehensive intra- and extracellular metabolomes and transcriptome. (ii) Metabolic insights into the role of the multipartite genome of the Gram negative bacteria Sinorhizobium meliloti and its metabolic preferences in a nutritionally complex environment. (iii) Age-associated metabolic dysregulation in murine bone marrow-derived macrophages during bacterial lipopolysaccharide-induced inflammation. (iv) Comprehensive intracellular metabolomic profiles of Sinorhizobium meliloti to sub-lethal exposure of individual or mixtures of polycyclic aromatic hydrocarbon revealed additive and dose-dependent effects. This thesis has demonstrated the versatility of the designed analytical platform and its use for diverse research in cell biology. / Thesis / Doctor of Philosophy (PhD)
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Validation of an LC-MS/MS Method to Quantify the New TRPC6 Inhibitor SH045 (Larixyl N-methylcarbamate) and Its Application in an Exploratory Pharmacokinetic Study in MiceChai, Xiao-Ning, Ludwig, Friedrich-Alexander, Müglitz, Anne, Schaefer, Michael, Yin, Hai-Yan, Brust, Peter, Regenthal, Ralf, Krügel, Ute 08 May 2023 (has links)
TRPC6 (transient receptor potential cation channels; canonical subfamily C, member 6) is widespread localized in mammalian tissues like kidney and lung and associated with progressive proteinuria and pathophysiological pulmonary alterations, e.g., reperfusion edema or lung fibrosis. However, the understanding of TRPC6 channelopathies is still at the beginning stages. Recently, by chemical diversification of (+)-larixol originating from Larix decidua resin traditionally used for inhalation, its methylcarbamate congener, named SH045, was obtained and identified in functional assays as a highly potent, subtype-selective inhibitor of TRPC6. To pave the way for use of SH045 in animal disease models, this study aimed at developing a capable bioanalytical method and to provide exploratory pharmacokinetic data for this promising derivative. According to international guidelines, a robust and selective LC-MS/MS method based on MRM detection in positive ion mode was established and validated for quantification of SH045 in mice plasma, whereby linearity and accuracy were demonstrated for the range of 2–1600 ng/mL. Applying this method, the plasma concentration time course of SH045 following single intraperitoneal administration (20 mg/kg body weight) revealed a short half-life of 1.3 h. However, the pharmacological profile of SH045 is promising, as five hours after administration, plasma levels still remained sufficiently higher than published low nanomolar IC50 values. Summarizing, the LC-MS/MS method and exploratory pharmacokinetic data provide essential prerequisites for experimental pharmacological TRPC6 modulation and translational treatment of TRPC6 channelopathies.
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In Vitro and In Silico Antimalarial Evaluation of FM-AZ, a New Artemisinin DerivativeTsamesidis, Ioannis, Mousavizadeh, Farnoush, Egwu, Chinedu O., Amanatidou, Dionysia, Pantaleo, Antonella, Benoit-Vical, Françoise, Reybier, Karine, Giannis, Athanassios 02 June 2023 (has links)
Artemisinin-based Combination Therapies (ACTs) are currently the frontline treatment against Plasmodium falciparum malaria, but parasite resistance to artemisinin (ART) and its derivatives, core components of ACTs, is spreading in the Mekong countries. In this study, we report the synthesis of several novel artemisinin derivatives and evaluate their in vitro and in silico capacity to counteract Plasmodium falciparum artemisinin resistance. Furthermore, recognizing that the malaria parasite devotes considerable resources to minimizing the oxidative stress that it creates during its rapid consumption of hemoglobin and the release of heme, we sought to explore whether further augmentation of this oxidative toxicity might constitute an important addition to artemisinins. The present report demonstrates, in vitro, that FM-AZ, a newly synthesized artemisinin derivative, has a lower IC50 than artemisinin in P. falciparum and a rapid action in killing the parasites. The docking studies for important parasite protein targets, PfATP6 and PfHDP, complemented the in vitro results, explaining the superior IC50 values of FM-AZ in comparison with ART obtained for the ART-resistant strain. However, cross-resistance between FM-AZ and artemisinins was evidenced in vitro
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Composition of Intracellular and Cell Wall-Bound Phlorotannin Fractions in Fucoid Algae Indicates Specific Functions of These Metabolites Dependent on the Chemical StructureBirkemeyer, Claudia, Lemesheva, Valeriya, Billig, Susan, Tarakhovskaya, Elena 20 April 2023 (has links)
Accumulation of biologically active metabolites is a specific feature of plant biochemistry, directing the use of plants in numerous applications in the pharmaceutical and food industries. Among these substances, the plethora of phenolic compounds has attracted particular interest among researchers. Here, we report on new findings in phlorotannin research, a large group of multifunctional phenolic substances, produced in brown algae. Comprehensive LC-MS profiling of three algal species allowed us to depict the complex pattern of this structurally diverse compound group across different tissues and subcellular compartments. We compiled more than 30 different phlorotannin series in one sample and used accurate mass spectrometry to assign tentative structures to the observed ions based on the confirmed sum formulas. From that, we found that acetylation, hydroxylation, and oxidation are likely to be the most common in vivo modifications to phlorotannins. Using an alternative data mining strategy to cope with extensive coelution and structural isomers, we quantitatively compared the intensity of different phlorotannin series in species, tissues, and subcellular compartments to learn more about their physiological functions. The structure and intra-thallus profiles of cell wall-bound phlorotannins were studied here for the first time. We suggest that one of the major dibenzodioxin-type phlorotannin series may exclusively target integration into the cell wall of fucoid algae.
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Sphingomyelins Prevent Propagation of Lipid Peroxidation—LC-MS/MS Evaluation of Inhibition MechanismsColiva, Giulia, Lange, Mike, Colombo, Simone, Chervet, Jean-Pierre, Domingues, M. Rosario, Fedorova, Maria 20 April 2023 (has links)
Free radical driven lipid peroxidation is a chain reaction which can lead to oxidative degradation of biological membranes. Propagation vs. termination rates of peroxidation in biological membranes are determined by a variety of factors including fatty acyl chain composition, presence of antioxidants, as well as biophysical properties of mono- or bilayers. Sphingomyelins (SMs), a class of sphingophospholipids, were previously described to inhibit lipid oxidation most probably via the formation of H-bond network within membranes. To address the “antioxidant” potential of SMs, we performed LC-MS/MS analysis of model SM/glycerophosphatidylcholine (PC) liposomes with different SM fraction after induction of radical driven lipid peroxidation. Increasing SM fraction led to a strong suppression of lipid peroxidation. Electrochemical oxidation of non-liposomal SMs eliminated the observed effect, indicating the importance of membrane structure for inhibition of peroxidation propagation. High resolution MS analysis of lipid peroxidation products (LPPs) observed in in vitro oxidized SM/PC liposomes allowed to identify and relatively quantify SM- and PC-derived LPPs. Moreover, mapping quantified LPPs to the known pathways of lipid peroxidation allowed to demonstrate significant decrease in mono-hydroxy(epoxy) LPPs relative to mono-keto derivatives in SM-rich liposomes. The results presented here illustrate an important property of SMs in biological membranes, acting as “biophysical antioxidant”. Furthermore, a ratio between mono-keto/mono-hydroxy(epoxy) oxidized species can be used as a marker of lipid peroxidation propagation in the presence of different antioxidants.
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