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  • 1.
    Balgoma, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Zelleroth, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver2020In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 16, no 1, article id 12Article in journal (Refereed)
    Abstract [en]

    Introduction: The abuse of anabolic androgenic steroids (AASs) is a source of public concern because of their adverse effects. Supratherapeutic doses of AASs are known to be hepatotoxic and regulate the lipoproteins in plasma by modifying the metabolism of lipids in the liver, which is associated with metabolic diseases. However, the effect of AASs on the profile of lipids in plasma is unknown.

    Objectives: To describe the changes in the plasma lipidome exerted by AASs and to discuss these changes in the light of previous research about AASs and de novo lipogenesis in the liver.

    Methods: We treated male Wistar rats with supratherapeutic doses of nandrolone decanoate and testosterone undecanoate. Subsequently, we isolated the blood plasma and performed lipidomics analysis by liquid chromatography-high resolution mass spectrometry.

    Results: Lipid profiling revealed a decrease of sphingolipids and glycerolipids with palmitic, palmitoleic, stearic, and oleic acids. In addition, lipid profiling revealed an increase in free fatty acids and glycerophospholipids with odd-numbered chain fatty acids and/or arachidonic acid.

    Conclusion: The lipid profile presented herein reports the imprint of AASs on the plasma lipidome, which mirrors the downregulation of de novo lipogenesis in the liver. In a broader perspective, this profile will help to understand the influence of androgens on the lipid metabolism in future studies of diseases with dysregulated lipogenesis (e.g. type 2 diabetes, fatty liver disease, and hepatocellular carcinoma).

  • 2.
    Barclay, Victoria K. H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Tyrefors, Niklas L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Johansson, I. Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Acidic transformation of nordiazepam can affect recovery estimate during trace analysis of diazepam and nordiazepam in environmental water samples by liquid chromatography-tandem mass spectrometry2019In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 411, no 17, p. 3919-3928Article in journal (Refereed)
    Abstract [en]

    In this study, a special interest was focused on the stability of diazepam and nordiazepam in aqueous samples at acidic and neutral pH. The aim of the study was to isolate and illustrate one of the many possible sources of error that can be encountered when developing and validating analytical methods. This can be of particular importance when developing multi-analyte methods where there is limited time to scrutinize the behavior of each analyte. A method was developed for the analysis of the benzodiazepines diazepam and nordiazepam in treated wastewater. The samples were extracted by solid phase extraction, using SPEC C18AR cartridges, and analyzed by the use of liquid chromatography, with a C18 stationary phase, coupled to tandem mass spectrometry. Environmental water samples are often acidified during storage to reduce the microbial degradation of the target compounds and to preserve the sample. In some cases, the samples are acidified before extraction. In this study, it was found that a chemical equilibrium between nordiazepam and a transformation product could cause inaccurately high extraction recovery values when the samples were stored at low sample pH. The stability of nordiazepam was shown to be low at pH3. Within 12days, 20% of the initial concentration of nordiazepam was transformed. Interestingly, the transformed nordiazepam was shown to be regenerated and reformed to nordiazepam during sample handling. At a sample pH of 7, diazepam and nordiazepam were stable for 12days. It was concluded that great care must be taken when acidifying water samples containing nordiazepam during storage or extraction. The storage and the extraction should be conducted at neutral pH if no internal standard is used to compensate for degradation and conversion of nordiazepam. The developed method was validated in treated wastewater and applied for the quantification of diazepam and nordiazepam in treated wastewater samples.

  • 3.
    Goldberg, Esther
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Oligonucleotide analysis with 2D-LC-MS using mixed mode column2019Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In this project method development for analysis and characterization of an oligonucleotide sample containing two major impurities was done. For this purpose UPLC was used with a RP-WAX mixed mode column with UV and/or MS detection. Initially the separation properties of a promising MS compatible mobile phase, ammonium acetate buffer (AAB), was tested in a stepwise replacement of ammonium phosphate buffer (APB) already known to separate the sample well but problematic for MS detection due to its non-volatility. Due to the insufficient separation ability of AAB, the approach of the project shifted towards using APB as a mobile phase. Here an existing method on a custom-built 2D-UPLC-MS instrument was used with RP-WAX mixed mode column in dimension 1 (D1). A C18 column was introduced to dimension 2 (D2), for desalting purposes. The 2D-LC method was developed further by placing a loop between the two columns and optimizing heartcuts for the oligonucleotide and the two impurities. With this work understanding of the loop volume and system volume affecting MS intensities in 2D-LC was obtained. With method development signal intensities from 2D-LC-MS were increased remarkably compared to initial values. However, it was not yet possible to confirm the structure of the oligonucleotide and identify the impurities due to low MS intensity, which is the final aim of the project. Further studies are needed to be able to confidently identify sample components.

  • 4.
    Ida, Björs
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Development of separation method for analysis of oligonucleotides using LC-UV/MS2018Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction

    Oligonucleotides are short nucleic acid chains, usually 19-27mer long. They bind to their corresponding chain, making a specific inhibition possible. In pharmaceuticals, this can be used to inhibit the expression of a gene or protein of interest. Oligonucleotides are usually analyzed based on separation using both hydrophobic and ion-exchange properties. In this project, the possibility to use a mixed-mode column to separate these oligonucleotides and their impurities were explored.

    Method

    Liquid chromatography is used as the separation method and the method of detection is both mass spectrometry and UV. Three different columns are evaluated; C18, DNAPac RP, and mixed-mode RP/WAX.

    Results and discussion

    Different compositions of mobile phases and gradients are evaluated based on a literature study. Triethylamine, triethylammonium acetate, ammonium formate, hexafluoroisopropanol is used along with both methanol and acetonitrile. Phosphate buffer is evaluated on LC-UV. The results from the C18 column displays a good separation of the oligonucleotides, whilst the DNAPac RP is not as sufficient using the same mobile phases. The mixed-mode column provides good separation and selectivity using phosphate buffer and UV detection.

    Conclusion

    Mixed-mode column has the potential to be used for separation of oligonucleotides and one future focus would be to make the mobile phase compatible with mass spectrometry. Phosphate buffer and UV detection seems to be the go-to mobile phase using mixed-mode column even though MS is a more powerful tool for the characterization and identification of oligonucleotides. This provides a hint about the challenge in making the mobile phase MS compatible.

  • 5.
    Lindell Jonsson, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Erngren, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Medical Product Agency.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Exploring Radiation Response in Two Head and Neck Squamous Carcinoma Cell Lines Through Metabolic Profiling2019In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, article id 825Article in journal (Refereed)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) is the sixth most common form of cancer worldwide. Radiotherapy, with or without surgery, represents the major approach to curative treatment. However, not all tumors are equally sensitive to irradiation. It is therefore of interest to apply newer system biology approaches (e.g., metabolic profiling) in squamous cancer cells with different radiosensitivities in order to provide new insights on the mechanisms of radiation response. In this study, two cultured HNSCC cell lines from the same donor, UM-SCC-74A and UM-SCC-74B, were first genotyped using Short Tandem Repeat (STR), and assessed for radiation response by the means of clonogenic survival and growth inhibition assays. Thereafter, cells were cultured, irradiated and collected for subsequent metabolic profiling analyses using liquid chromatography-mass spectrometry (LC-MS). STR verified the similarity of UM-SCC-74A and UM-SCC-74B cells, and three independent assays proved UM-SCC-74B to be clearly more radioresistant than UM-SCC-74A. The LC-MS metabolic profiling demonstrated significant differences in the intracellular metabolome of the two cell lines before irradiation, as well as significant alterations after irradiation. The most important differences between the two cell lines before irradiation were connected to nicotinic acid and nicotinamide metabolism and purine metabolism. In the more radiosensitive UM-SCC-74A cells, the most significant alterations after irradiation were linked to tryptophan metabolism. In the more radioresistant UM-SCC-74B cells, the major alterations after irradiation were connected to nicotinic acid and nicotinamide metabolism, purine metabolism, the methionine cycle as well as the serine, and glycine metabolism. The data suggest that the more radioresistant cell line UM-SCC-74B altered the metabolism to control redox-status, manage DNA-repair, and change DNA methylation after irradiation. This provides new insights on the mechanisms of radiation response, which may aid future identification of biomarkers associated with radioresistance of cancer cells.

  • 6.
    Paul, Prasanta
    et al.
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N 2,Herestr 49,PB 923, B-3000 Leuven, Belgium.
    Reynaert, Josephine
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N 2,Herestr 49,PB 923, B-3000 Leuven, Belgium.
    Sänger - van de Griend, Cari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Kantisto BV, Callenburglaan 22, NL-3742 MV Baarn, Netherlands.
    Adams, Erwin
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N 2,Herestr 49,PB 923, B-3000 Leuven, Belgium.
    Van Schepdael, Ann
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N 2,Herestr 49,PB 923, B-3000 Leuven, Belgium.
    Development and Validation of a CE Method for the Determination of Tetracyclines with Capacitively Coupled Contactless Conductivity Detection2019In: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 82, no 9, p. 1395-1403Article in journal (Refereed)
    Abstract [en]

    In this study, a simple and robust capillary electrophoresis method with capacitively coupled contactless conductivity detection ((CD)-D-4) is developed for the determination of the tetracycline antibiotics (1) tetracycline, (2) chlortetracycline and (3) oxytetracycline. An uncoated, fused silica capillary (60.2 cm long, 75 mu m i.d.) and a solution of 50 mM tris(hydroxymethyl) aminomethane, 50 mM l-histidine and 5 mM methyl-beta-cyclodextrin, without pH adjustment (pH 8.76), was used as background electrolyte. Electrophoresis at + 25 kV showed a rapid analysis with sufficient resolution among the three antibiotics in the order of tetracycline, chlortetracycline and oxytetracycline. Successive inter-injection rinsing (20 psi) of the capillary ensured intra- and inter-day repeatability (0.9-2.2% RSD and 2.0-4.5% RSD, respectively, for relative peak areas). The method showed satisfactory performance in terms of selectivity, accuracy (99.3-101.4%) and linearity (R-2 = 0.999). Finally, the method was applied to commercial samples of tetracycline, oxytetracycline and chlortetracycline. This method can be applied for rapid quality control in developing countries in particular, and across the globe in general.

  • 7.
    Pirttilä, Kristian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pierre, Pernilla Videhult
    Karolinska Inst, Div Audiol, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    An LCMS-based untargeted metabolomics protocol for cochlear perilymph: highlighting metabolic effects of hydrogen gas on the inner ear of noise exposed Guinea pigs2019In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 15, no 10, article id 138Article in journal (Refereed)
    Abstract [en]

    Introduction

    Noise-induced hearing loss (NIHL) is an increasing problem in society and accounts for a third of all cases of acquired hearing loss. NIHL is caused by formation of reactive oxygen species (ROS) in the cochlea causing oxidative stress. Hydrogen gas (H-2) can alleviate the damage caused by oxidative stress and can be easily administered through inhalation.

    Objectives

    To present a protocol for untargeted metabolomics of guinea pig perilymph and investigate the effect of H-2 administration on the perilymph metabolome of noise exposed guinea pigs.

    Methods

    The left ear of guinea pigs were exposed to hazardous impulse noise only (Noise, n = 10), noise and H-2 (Noise + H2, n = 10), only H-2 (H2, n = 4), or untreated (Control, n = 2). Scala tympani perilymph was sampled from the cochlea of both ears. The polar component of the perilymph metabolome was analyzed using a HILIC-UHPLC-Q-TOF-MS-based untargeted metabolomics protocol. Multivariate data analysis (MVDA) was performed separately for the exposed- and unexposed ear.

    Results

    MVDA allowed separation of groups Noise and Noise + H2 in both the exposed and unexposed ear and yielded 15 metabolites with differentiating relative abundances. Seven were found in both exposed and unexposed ear data and included two osmoprotectants. Eight metabolites were unique to the unexposed ear and included a number of short-chain acylcarnitines.

    Conclusions

    A HILIC-UHPLC-Q-TOF-MS-based protocol for untargeted metabolomics of perilymph is presented and shown to be fit-for-purpose. We found a clear difference in the perilymph metabolome of noise exposed guinea pigs with and without H-2 treatment.

  • 8.
    Roos, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dahlgren, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 387-395Article in journal (Refereed)
    Abstract [en]

    Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.

  • 9.
    Stenholm, Åke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. GE Healthcare Biosci AB, Bjorkgatan 30, SE-75184 Uppsala, Sweden.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala, Sweden.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Med Prod Agcy, Uppsala, Sweden.
    Pettersson, Curt E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Removal of diclofenac from a non-sterile aqueous system using Trametes versicolor with an emphasis on adsorption and biodegradation mechanisms2019In: Environmental technology, ISSN 0959-3330, E-ISSN 1479-487X, Vol. 40, no 19, p. 2460-2472Article in journal (Refereed)
    Abstract [en]

    This paper describes the search for procedures through which the xenobiotic pollutant diclofenac can be removed from non-sterile aquatic systems. Specifically, adsorption to solid supports (carriers) in combination with biodegradation by non-immobilized and immobilized white rot fungus Trametes versicolor were investigated. Batch experiments using polyurethane foam (PUF)-carriers resulted in 99.9% diclofenac removal after 4 h, with monolayer adsorption of diclofenac to carrier and glass surfaces accounting for most of the diclofenac decrease. Enzymatic reactions contributed less, accounting for approximately < 0.5% of this decrease. In bioreactor experiments using PUF-carriers, an initial 100% removal was achieved with biodegradation contributing approximately 7%. In batch experiments that utilized polyethylene-carriers with negligible immobilization of Trametes versicolor, a 98% total diclofenac removal was achieved after one week, with a biodegradation contribution of approximately 14%. Five novel enzyme-catalyzed biodegradation products were tentatively identified in the batch-wise and bioreactor experiments using full scan ultra-high-performance liquid chromatography-quadrupole/time of flight mass spectrometry. Both reduction and oxidation products were found, with the contents estimated to be at µg L-1 concentration levels.

  • 10.
    Sänger–van de Griend, Cari E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    CE‐SDS method development, validation, and best practice—An overview2019In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 40, no 18-19, p. 2361-2374Article in journal (Refereed)
    Abstract [en]

    CE-SDS has been implemented in the biopharmaceutical industry and is being used for the characterization of therapeutic proteins in most Biological License Applications currently submitted. An overview is presented on the separation mechanism, methodology, and good working practices/best practices. The CE-SDS platform method development and validation are discussed and typical scientifically and regulatory issues and troubleshooting situations are highlighted.

  • 11.
    van Tricht, Ewoud
    et al.
    Janssen Vaccines & Prevent, Pharmaceut & Analyt Dev, Leiden, Netherlands.
    Geurink, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Janssen Vaccines & Prevent, Pharmaceut & Analyt Dev, Leiden, Netherlands.
    Galindo Garre, Francisca
    Janssen Vaccines & Prevent, Pharmaceut & Analyt Dev, Leiden, Netherlands.
    Schenning, Martijn
    Janssen Vaccines & Prevent, Pharmaceut & Analyt Dev, Leiden, Netherlands.
    Backus, Harold
    Janssen Vaccines & Prevent, Pharmaceut & Analyt Dev, Leiden, Netherlands.
    Germano, Marta
    Janssen Vaccines & Prevent, Pharmaceut & Analyt Dev, Leiden, Netherlands.
    Somsen, Govert W
    Vrije Univ Amsterdam, Div BioMol Anal, Amsterdam Inst Mol Med & Syst, Amsterdam, Netherlands.
    Sänger – van de Griend, Cari E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Kantisto BV, Baarn, Netherlands.
    Implementation of at-line capillary zone electrophoresis for fast and reliable determination of adenovirus concentrations in vaccine manufacturing2019In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 40, no 18-19, p. 2277-2284Article in journal (Refereed)
    Abstract [en]

    A CZE method was validated and implemented for fast and accurate in-process determination of adenovirus concentrations of downstream process samples obtained during manufacturing of adenovirus vector-based vaccines. An analytical-quality-by-design approach was embraced for method development, method implementation, and method maintenance. CZE provided separation of adenovirus particles from sample matrix components, such as cell debris, residual DNA and proteins. The intermediate precision of the virus particle concentration was 6.9% RSD and the relative bias was 2.3%. In comparison, the CZE method is intended to replace a quantitative polymerase chain reaction method which requires three replicates in three analytical runs to achieve an intermediate precision of 8.1% RSD. Given that, in addition, the time from sampling till reporting results of the CZE method was less than 2 h, whereas quantitative polymerase chain reaction requires 3 days, it follows that the CZE method enables faster processing times in downstream processing.

  • 12.
    Westerinen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Optimization of a Methodology for Cell Based Untargeted Metabolomics with UHPLC-Q-ToF-MS2020Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Metabolomics is the study of small molecules (molecular weight < 1500 Da) in a biological system and can provide relevant information about endpoints of biochemical pathways by establishing metabolic profiles for different sample cohorts and comparing these through multivariate data analysis. The aim of this thesis was to establish and test a suitable methodology for cell-based untargeted metabolomics, utilizing UHPLC-MS. Two different system setups were established, using one C18 column and one HILIC column. Parameter optimization was carried out with a reference solution, containing a diverse set, with regards to their physical and chemical properties, of seven substances. Cultured HCT 116 cells were chosen as model system. Three different sample preparation procedures were evaluated, based on number of detected unique markers and relative degree of reproducibility. Two of the procedures were based on liquid extraction, Dual Layer Fractionation (DLF) and Consecutive Extraction (CE), and the third was a dilution (DI) of the cell samples. The HILIC system did not achieve an adequate number of detected unique markers for any of the sample preparation procedures and further optimization is required. For the C18 system, CE proved to have the highest degree of reproducibility, while retrieving the next greatest set of detected unique markers.

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