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  • 1.
    Aftab, Obaid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Engskog, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Haglöf, Jakob
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Elmsjö, Albert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Arvidsson, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Hammerling, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Gustafsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    NMR spectroscopy based metabolic profiling of drug induced changes in vitro can discriminate between pharmacological classes2014Inngår i: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 54, nr 11, s. 3251-3258Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Drug induced changes in mammalian cell line models have already been extensively profiled at the systemic mRNA level and subsequently used to suggest mechanisms of action for new substances as well as to support drug repurposing, i.e. identifying new potential indications for drugs already licensed for other pharmacotherapy settings. The seminal work in this field, which includes a large database and computational algorithms for pattern matching, is known as the “Connectivity Map” (CMap). The potential of similar exercises at the metabolite level is, however, still largely unexplored. Only recently the first high throughput metabolomic assay pilot study was published, involving screening of metabolic response to a set of 56 kinase inhibitors in a 96-well format. Here we report results from a separately developed metabolic profiling assay, which leverages 1H NMR spectroscopy to the quantification of metabolic changes in the HCT116 colorectal cancer cell line, in response to each of 26 compounds. These agents are distributed across 12 different pharmacological classes covering a broad spectrum of bioactivity. Differential metabolic profiles, inferred from multivariate spectral analysis of 18 spectral bins, allowed clustering of most tested drugs according to their respective pharmacological class. A more advanced supervised analysis, involving one multivariate scattering matrix per pharmacological class and using only 3 spectral bins (three metabolites), showed even more distinct pharmacology-related cluster formations. In conclusion, this kind of relatively fast and inexpensive profiling seems to provide a promising alternative to that afforded by mRNA expression analysis, which is relatively slow and costly. As also indicated by the present pilot study, the resulting metabolic profiles do not seem to provide as information rich signatures as those obtained using systemic mRNA profiling, but the methodology holds strong promise for significant refinement.

  • 2.
    Ahlgren, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Remediation of diclofenac in a non-sterile bioreactor using the white rot fungus Trametes versicolor2015Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [en]

    From an environmental perspective, it is interesting to assess new methods for efficient removal of drugs from wastewater. The purpose of this project was to assess the possibility of using the white rot fungus Trametes versicolor  to degrade diclofenac in a lab scale bioreactor. Two methods for quantitative analysis of diclofenac were developed, using GC-MS and UHPLC-Q-TOF (C18-column). Both methods were partly validated, with regard to sensitivity, linearity, accuracy and precision, which highlighted the superiority of UHPLC-Q-TOF over GC-MS. Two HILIC columns were also assessed, but proved unsuitable for quantitative analysis of diclofenac under the used conditions. The fungal mycelia were immobilized on plastic carriers in a nutrient solution. In initial E-flask experiments, 10 mg/L diclofenac was added to an active culture and a heat-killed control of T. versicolor . Samples were analyzed, and the results from the active culture indicated a 98% removal of diclofenac after 48 hours. The lab scale bioreactor was used in a semi-continuous mode with the influent containing 10 mg/L diclofenac. Samples were collected from the effluent to monitor the concentration over 7 days. The results showed a decline in concentration to a stable level of approximately 2 mg/L. The initial experiments showed that most of the removal (85%) was due to sorption of diclofenac, but a clear difference was seen between the active and heat-killed culture. It was impossible to conclude from the bioreactor experiment if the observed removal was due to sorption or to a combination of sorption and enzymatic remediation.

  • 3.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Analysis of Caffeine in Dietary Products by Multiple Injection Capillary Electrophoresis2012Inngår i: Caffeine: Chemistry, Analysis, Function and Effects / [ed] Victor R Preedy, London: Royal Society of Chemistry, 2012, s. 154-178Kapittel i bok, del av antologi (Fagfellevurdert)
  • 4.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Analysis of somatropin by double-injection capillary-zone electrophoresis in polybrene/chondroitin sulfate a double-coated capillaries2016Inngår i: Capillary Electrophoresis of Proteins and Peptides: Methods and Protocols / [ed] Nguyet Thuy Tran, Myriam Taverna, New York: Springer-Verlag New York, 2016, s. 93-105Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Purity determination of somatropin as a recombinant protein is important to ensure its safety and quality. This is carried out by capillary zone electrophoresis in double-injection mode using polybrene/chondroitin sulfate A double-coated capillaries. Modification of the capillary wall eliminates protein-wall interactions which results in improved accuracy and precision of the determinations. In the double-injection mode two somatropin samples are analyzed within a single electrophoretic run. Prior to the second injection, the first injected plug is electrophoresed for a predetermined time period in order to adjust the inter- plug distance. Here, the principle for the separation of somatropin charge variants is described.

  • 5.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Double-injection capillary electrophoresis for the identification of analytes2014Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 35, nr 20, s. 2915-2921Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This paper presents a new approach for identifying analytes by CE. The compound to be identified is analyzed together with the corresponding reference standard during a double injection capillary electrophoretic run. The inter-plug distance is regulated by applying an electrical field over the capillary for a predetermined time period (tPE). The migration time of an analyte being exposed to the partial electrophoresis was calculated from the partial migration time (tmig(p)) as described in this paper. The identification is based on the closeness of agreement between the calculated migration time (tmig(c)) and observed migration time (tmig) of the reference standard. The validity of the derived equations was checked by analyzing several substances such as caffeine, melamine, acetyl salicylic acid, paracetamol, ibuprofen, metoprolol, naproxen, somatropin, several insulin analogs, as well as different pharmaceutical and natural products. The migration time ratios for the identified solutes varied between 0.996 and 1.006 (i.e., 1.001 ± 0.005), indicating good agreement between the observed and calculated migration times.

  • 6.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Identification of Ɛ-Caprolactam and Melamine in Polyvinyl- Pyrrolidone Powder by Double Injection Micellar Elektrokinetic Chromatography2015Inngår i: Pharmaceutica analytica acta, ISSN 2153-2435, Vol. 6, nr 11, artikkel-id 1000442Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A double-injection micellar electrokinetic chromatography (DIMEKC) method for the identification of Ɛ- caprolactam andmelamine deliberately added to povidone (polyvinylpyrrolidone) products has been developed. The separations were performedin 89 mM phosphate buffer (pH 7.4) containing 52 mM sodium dodecyl sulfate (SDS) in fused silica capillaries with UV absorptiondetection at 200 nm. The identification relied on the agreement between the calculated migration time (t mig(c) ) of the analytes andthe migration time (t mig ) of their corresponding reference standards being analysed simultaneously within a double injection run.The migration time of the analytes was calculated from the partial migration times (t mig(p) ) as described in this paper. The migrationtime ratios (t mig(c) / t mig ) varied

  • 7.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Identification of ε-caprolactam, melamine and urea in polyvinylpyrrolidone powders by micellar electrokinetic chromatography2014Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 91, s. 12-16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A sodium dodecyl sulfate micellar electrokinetic chromatography (SDS-MEKC) method for the simultaneous separation and identification of ɛ-caprolactam, melamine and urea deliberately added to polyvinylpyrrolidone (povidone) products has been developed. All samples to be analyzed contained paracetamol as an internal marker (IM). The optimized separations were performed in 50 mM phosphate buffer (pH 7.0) containing 2% (w/v) sodium dodecyl sulfate (SDS) in fused silica capillaries with UV absorption detection at 200 nm. The method was validated with respect to repeatability and intermediate precision, selectivity and robustness with satisfactory results. The relative migration times (RMT) were found to be between 0.03% and 0.13% for intra-day precision and between 0.50% and 0.60% for inter-day precision in four days. The detection limits were determined to be 1.3 (11.5 μM), 0.4 (3.5 μM) and 41 μg/ml (0.4 mM) for ɛ-caprolactam, melamine and urea, respectively.

  • 8.
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Separation of somatropin charge variants by multiple-injection CZE with Polybrene/chondroitin sulfate A double-coated capillaries2013Inngår i: Journal of Separation Science, ISSN 1615-9306, E-ISSN 1615-9314, Vol. 36, nr 16, s. 2686-2690Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The performance of dynamic double-coated fused-silica capillaries with Polybrene and chondroitin sulfate A has been compared with uncoated fused-silica capillaries for the determination of recombinant human growth factor (somatropin) charge variants. The separations were carried out under the same electrophoretic conditions as described in the European Pharmacopoeia, i.e. at pH 6.0 and 30 degrees C. The coating significantly reduced the interactions between the proteins and the surface of the fused-silica capillary. The first five separations performed in a new bare fused-silica capillary were discarded because of very poor separation performance as a result of protein-surface interactions. There was an approximate twofold increase in the interday migration time precision (%RSD 6.5%) in the double-coated capillaries. The method was successfully transferred to a multiple CZE mode where two samples were analyzed in a single electrophoretic run. The average purity of somatropin certified reference standard was 98.0% (%RSD 0.3%) determined by using uncoated and coated capillaries.

  • 9.
    Amini, Ahmad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Lodén, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Arvidsson, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Principles for different modes of multiple-injection CZE2008Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 29, nr 19, s. 3952-3958Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This paper introduces four different modes of multiple-injection CZE (MICZE). The validity of these MICZE models was evaluated by the experimental data. Prior to the application of MICZE, the electrophoretic conditions are developed in the single-injection mode by adjusting different experimental parameters such as pH, type and concentration of buffer additives and temperature. Based on the migration time difference (tmig) between the analyte and the internal standard or injection marker, one or more MICZE modes can be employed. The injection marker is added to the sample to compensate for injection-volume fluctuations. The inter-plug distance is regulated by applying an electrical field over the capillary for a short period of time between each injection. After the final injection, the separation is completed by electrophoresis for a time period corresponding to that in the single-injection mode

  • 10.
    Amini, Ahmad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Nilsson, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Quantitative analysis of polypeptide pharmaceuticals by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry2008Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 46, nr 3, s. 411-417Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An accurate method based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has been developed for quantitative analysis of calcitonin and insulin in different commercially available pharmaceutical products. Tryptic peptides derived from these polypeptides were chemically modified at their C-terminal lysine-residues with 2-methoxy-4,5-dihydro-imidazole (light tagging) as standard and deuterated 2-methoxy-4,5-dihydro-imidazole (heavy tagging) as internal standard (IS). The heavy modified tryptic peptides (4D-Lys tag), differed by four atomic mass units from the corresponding light labelled counterparts (4H-Lys tag). The normalized peak areas (the ratio between the light and heavy tagged peptides) were used to construct a standard curve to determine the concentration of the analytes. The concentrations of calcitonin and insulin content of the analyzed pharmaceutical products were accurately determined, and less than 5% error was obtained between the present method and the manufacturer specified values. It was also found that the cysteine residues in CSNLSTCVLGK from tryptic calcitonin were converted to lanthionine by the loss of one sulfhydryl group during the labelling procedure.

  • 11.
    Amini, Ahmad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Rundlöf, Torgny
    Rönnquist, Kerstin
    Tydén, Monica
    Turunen, Taina
    Korhola, Paula
    Anette, Perolari
    A protocol for the quality assessment of illegally distributed human growth hormones with respect to identity, purity, endotoxin level and microorganism content2015Inngår i: Analytical Methods, ISSN 1759-9660, E-ISSN 1759-9679, Vol. 7, nr 20, s. 8857-8864Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Different methods based on MALDI-TOF-MS and double injection capillary zone electrophoresis (DICZE) were used for the identification and purity determination of somatropin in illegally distributed products. During the past few years, more than 200 products suspected to contain somatropin have been analysed. Some of the samples were also subjected to control microorganisms and endotoxins. The identification of somatropin was carried out by peptide mapping using trypsin as the proteolytic enzyme. A double chain peptide cross-linked via a disulfide bond was used as the signature peptide. Capillary electrophoresis in double injection mode was applied to both identification and purity determination of the samples. The identification was based on the comparison between the observed migration time of the reference standard and the calculated migration time of the analyte, being present in the second injection plug. The DICZE provides electrophoretic fingerprints of intact somatropin and the related proteins which facilitate the identification. In addition, some of these samples revealed the presence of microorganisms as well as a high level of endotoxins. Taken together, the doubtful quality of the analysed samples and the microbiological findings represent a serious threat for the consumers and public health.

  • 12.
    Barclay, Victoria K. H.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Tyrefors, Niklas L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Johansson, I. Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Trace analysis of fluoxetine and its metabolite norfluoxetine: Part I: Development of a chiral liquid chromatography-tandem mass spectrometry method for wastewater samples2011Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, nr 33, s. 5587-5596Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An enantioselective method for the determination of fluoxetine (a selective serotonin reuptake inhibitor) and its pharmacologically active metabolite norfluoxetine has been developed for raw and treated wastewater samples. The stable isotope-labeled fluoxetine and norfluoxetine were used in an extended way for extraction recovery calculations at trace level concentrations in wastewater. Wastewater samples were enriched by solid phase extraction (SPE) with Evolute CX-50 extraction cartridges. The obtained extraction recoveries ranged between 65 and 82% in raw and treated wastewater at a trace level concentration of 50 pM (15-16 ng L(-1)). The target compounds were identified by the use of chiral liquid chromatography tandem mass spectrometry (LC-MS/MS) in selected reaction monitoring (SRM) mode. The enantiomers were successfully resolved on a chiral alpha(1)-acid glycoprotein column (chiral AGP) with acetonitrile and 10 mM ammonium acetate buffer at pH 4.4 (3/97, v/v) as the mobile phase. The effects of pH, amount of organic modifier and buffer concentration in the mobile phase were investigated on the enantiomeric resolution (R(s)) of the target compounds. Enantiomeric R(s)-values above 2.0 (1.03 RSD%, n = 3) were achieved for the enantiomers of fluoxetine and norfluoxetine in all mobile phases investigated. The method was validated by assessing parameters such as cross-contamination and carryover during SPE and during LC analysis. Cross-talk effects were examined during the detection of the analytes in SRM mode. In addition, the isotopic purity of fluoxetine-d(5) and norfluoxetine-d(5) were assessed to exclude the possibility of self-contamination. The interassay precision of the chromatographic separation was excellent, with relative standard deviations (RSD) equal to or lower than 0.56 and 0.81% in raw and treated wastewaters, respectively. The method detection and quantification limits (respectively, MDL and MQL) were determined by the use of fluoxetine-d5 and norfluoxetine-d5. The MQL for the single enantiomers ranged from 12 to 14 pM (3.6-4.3 ng L(-1)) in raw wastewater and from 3 to 4 pM (0.9-1 ng L(-1)) in treated wastewater. The developed method has been employed for the quantification of (R)-fluoxetine, (S)-fluoxetine and the enantiomers of norfluoxetine in raw and treated wastewater samples to be presented in Part II of this study.

  • 13.
    Barclay, Victoria K H
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Tyrefors, Niklas L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Johansson, I Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Trace analysis of fluoxetine and its metabolite norfluoxetine. Part II: Enantioselective quantification and studies of matrix effects in raw and treated wastewater by solid phase extraction and liquid chromatography-tandem mass spectrometry2012Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1227, s. 105-114Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The isotope-labeled compounds fluoxetine-d5 and norfluoxetine-d5 were used to study matrix effects caused by co-eluting compounds originating from raw and treated wastewater samples, collected in Uppsala, Sweden. The matrix effects were investigated by the determination of matrix factors (MF) and by a post-column infusion method. The matrix factors were determined to be 38–47% and 71–86% for the enantiomers of norfluoxetine-d5 and fluoxetine-d5, respectively. The influence of matrix effects when quantifying the enantiomers of the active pharmaceutical ingredient and the metabolite in wastewater samples with LC–MS/MS is discussed and methods to overcome the problem are presented. The enantiomeric concentrations of fluoxetine and its human metabolite norfluoxetine, quantified by a one-point calibration method, were 12–52 pM (3.5–16 ng L−1) in raw wastewater and 4–48 pM (1.2–15 ng L−1) in treated wastewater. Furthermore, the calculated enantiomeric fractions (EF) of the substances were found to be between 0.68 and 0.71 in both matrices. Neither the EF values for fluoxetine nor those for norfluoxetine were significantly different in the raw wastewater compared to the treated wastewater. Interestingly, the concentration of (S)-fluoxetine was found to be higher than the concentration of (R)-fluoxetine in both raw and treated wastewater. These results are different from other results presented in the literature, which shows that the relative concentrations of the enantiomers of a chiral active pharmaceutical ingredient might be significantly different in wastewater samples from different treatment systems. We report, for the first time, the concentrations of the enantiomers of norfluoxetine in wastewater samples. The concentrations of (S)-norfluoxetine were found to be higher than the concentration of (R)-norfluoxetine in the raw as well as in the treated wastewater samples.

  • 14.
    Barclay, Victoria K.H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Development of LC-MS/MS Methods for the Analysis of Chiral and Achiral Pharmaceuticals and Metabolites in Aqueous Environmental Matrices2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis describes the development of liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the trace analysis of active pharmaceutical ingredients (APIs) and their metabolites in aqueous environmental matrices. The research was focused on the development of chiral LC-MS/MS methods for the analysis of fluoxetine and metoprolol, as well as their chiral metabolites in environmental water samples. A method was also developed for the achiral compounds, diazepam and nordiazepam.

    The LC-MS/MS methods were validated by the use of the isotope-labeled compounds. As these isotope-labeled compounds were not found in the wastewater samples, the validation could be assessed at trace level concentrations in the actual matrices in which the analytes were detected.

    The analytes were extracted from the water samples using solid phase extraction methods. Different types of solid phase extraction sorbents were evaluated. Fluoxetine and norfluoxetine were extracted through the use of a mixed mode polymeric based extraction sorbent. A hydrophilic and lipophilic balanced sorbent was employed for the simultaneous extraction of metoprolol and its metabolites, the base α-hydroxymetoprolol and the acidic metabolite deaminated metoprolol. Moreover, silica based C18 extraction discs were applied for the sample preparation of diazepam and nordiazepam.

    The chromatographic separations were conducted in reversed phase LC with MS compatible mobile phases. The enantiomers of fluoxetine and norfluoxetine were simultaneously separated using the chiral stationary phase (CSP), α1-acid glycoprotein (AGP). The Chiral AGP column was also applied for the separation of the enantiomers of deaminated metoprolol. For the simultaneous separation of the metoprolol enantiomers and the four stereoisomers of α-hydroxymetoprolol, the cellobiohydrolase (CBH) protein based CSP was used. An octadecyl silica based LC column was applied for the separation of diazepam and nordiazepam.

    The analytes were detected by the use of tandem quadrupole mass spectrometry operating in selective reactive monitoring mode. High resolution MS, employing a quadrupole time-of-flight (QqTOF) mass analyzer, was utilized for the identification of an unknown compound in wastewater samples.

    The APIs and their metabolites, as well as their respective enantiomers, were quantified in raw and treated wastewater from Uppsala, Sweden along with surface water from the River Fyris in Uppsala.

    Delarbeid
    1. Trace analysis of fluoxetine and its metabolite norfluoxetine: Part I: Development of a chiral liquid chromatography-tandem mass spectrometry method for wastewater samples
    Åpne denne publikasjonen i ny fane eller vindu >>Trace analysis of fluoxetine and its metabolite norfluoxetine: Part I: Development of a chiral liquid chromatography-tandem mass spectrometry method for wastewater samples
    2011 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, nr 33, s. 5587-5596Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    An enantioselective method for the determination of fluoxetine (a selective serotonin reuptake inhibitor) and its pharmacologically active metabolite norfluoxetine has been developed for raw and treated wastewater samples. The stable isotope-labeled fluoxetine and norfluoxetine were used in an extended way for extraction recovery calculations at trace level concentrations in wastewater. Wastewater samples were enriched by solid phase extraction (SPE) with Evolute CX-50 extraction cartridges. The obtained extraction recoveries ranged between 65 and 82% in raw and treated wastewater at a trace level concentration of 50 pM (15-16 ng L(-1)). The target compounds were identified by the use of chiral liquid chromatography tandem mass spectrometry (LC-MS/MS) in selected reaction monitoring (SRM) mode. The enantiomers were successfully resolved on a chiral alpha(1)-acid glycoprotein column (chiral AGP) with acetonitrile and 10 mM ammonium acetate buffer at pH 4.4 (3/97, v/v) as the mobile phase. The effects of pH, amount of organic modifier and buffer concentration in the mobile phase were investigated on the enantiomeric resolution (R(s)) of the target compounds. Enantiomeric R(s)-values above 2.0 (1.03 RSD%, n = 3) were achieved for the enantiomers of fluoxetine and norfluoxetine in all mobile phases investigated. The method was validated by assessing parameters such as cross-contamination and carryover during SPE and during LC analysis. Cross-talk effects were examined during the detection of the analytes in SRM mode. In addition, the isotopic purity of fluoxetine-d(5) and norfluoxetine-d(5) were assessed to exclude the possibility of self-contamination. The interassay precision of the chromatographic separation was excellent, with relative standard deviations (RSD) equal to or lower than 0.56 and 0.81% in raw and treated wastewaters, respectively. The method detection and quantification limits (respectively, MDL and MQL) were determined by the use of fluoxetine-d5 and norfluoxetine-d5. The MQL for the single enantiomers ranged from 12 to 14 pM (3.6-4.3 ng L(-1)) in raw wastewater and from 3 to 4 pM (0.9-1 ng L(-1)) in treated wastewater. The developed method has been employed for the quantification of (R)-fluoxetine, (S)-fluoxetine and the enantiomers of norfluoxetine in raw and treated wastewater samples to be presented in Part II of this study.

    Emneord
    Wastewater, Solid phase extraction, Fluoxetine, Norfluoxetine, Isotope-labeled compounds, Chiral LC-MS/MS
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-158308 (URN)10.1016/j.chroma.2011.06.024 (DOI)000294031700004 ()
    Tilgjengelig fra: 2011-09-06 Laget: 2011-09-06 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    2. Trace analysis of fluoxetine and its metabolite norfluoxetine. Part II: Enantioselective quantification and studies of matrix effects in raw and treated wastewater by solid phase extraction and liquid chromatography-tandem mass spectrometry
    Åpne denne publikasjonen i ny fane eller vindu >>Trace analysis of fluoxetine and its metabolite norfluoxetine. Part II: Enantioselective quantification and studies of matrix effects in raw and treated wastewater by solid phase extraction and liquid chromatography-tandem mass spectrometry
    2012 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1227, s. 105-114Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The isotope-labeled compounds fluoxetine-d5 and norfluoxetine-d5 were used to study matrix effects caused by co-eluting compounds originating from raw and treated wastewater samples, collected in Uppsala, Sweden. The matrix effects were investigated by the determination of matrix factors (MF) and by a post-column infusion method. The matrix factors were determined to be 38–47% and 71–86% for the enantiomers of norfluoxetine-d5 and fluoxetine-d5, respectively. The influence of matrix effects when quantifying the enantiomers of the active pharmaceutical ingredient and the metabolite in wastewater samples with LC–MS/MS is discussed and methods to overcome the problem are presented. The enantiomeric concentrations of fluoxetine and its human metabolite norfluoxetine, quantified by a one-point calibration method, were 12–52 pM (3.5–16 ng L−1) in raw wastewater and 4–48 pM (1.2–15 ng L−1) in treated wastewater. Furthermore, the calculated enantiomeric fractions (EF) of the substances were found to be between 0.68 and 0.71 in both matrices. Neither the EF values for fluoxetine nor those for norfluoxetine were significantly different in the raw wastewater compared to the treated wastewater. Interestingly, the concentration of (S)-fluoxetine was found to be higher than the concentration of (R)-fluoxetine in both raw and treated wastewater. These results are different from other results presented in the literature, which shows that the relative concentrations of the enantiomers of a chiral active pharmaceutical ingredient might be significantly different in wastewater samples from different treatment systems. We report, for the first time, the concentrations of the enantiomers of norfluoxetine in wastewater samples. The concentrations of (S)-norfluoxetine were found to be higher than the concentration of (R)-norfluoxetine in the raw as well as in the treated wastewater samples.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-170511 (URN)10.1016/j.chroma.2011.12.084 (DOI)000301563700013 ()22265784 (PubMedID)
    Tilgjengelig fra: 2012-03-12 Laget: 2012-03-12 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    3. Chiral analysis of metoprolol and two of its metabolites, alpha‑hydroxymetoprolol and deaminated metoprolol, in wastewater using liquid chromatography-tandem mass spectrometry
    Åpne denne publikasjonen i ny fane eller vindu >>Chiral analysis of metoprolol and two of its metabolites, alpha‑hydroxymetoprolol and deaminated metoprolol, in wastewater using liquid chromatography-tandem mass spectrometry
    2012 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1269, nr SI, s. 208-217Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A LC–MS/MS method for the chiral separation of metoprolol and two of its main metabolites, α-hydroxymetoprolol (α-OH-Met) and deaminated metoprolol (COOH-Met), in environmental water samples has been developed. The target bases, metoprolol and α-OH-Met, as well as the acidic metabolite (COOH-Met) were extracted from water samples by a solid phase extraction method employing Oasis HLB cartridges. The extraction recoveries were ≥73% for all compounds in surface water. Four different types of chiral stationary phases were investigated for the separation of the eight stereoisomers of metoprolol and its metabolites, Chiralcel OD-H, Chirobiotic V, Chiral AGP and Chiral CBH. In the final method, the enantiomers of metoprolol and four stereoisomers of α-OH-Met were separated using Chiral CBH, the enantiomers of COOH-Met were separated employing Chiral AGP. The analytes were detected in SRM mode by triple quadrupole mass spectrometry. The method was applied for the chiral analysis of the analytes in treated wastewater samples from Uppsala, Sweden. The enantiomers and diastereoisomers of α-OH-Met were detected and analyzed in the samples. The concentrations of the three first eluting stereoisomers of α-OH-Met were between 54 and 61 pM. Interestingly, the last eluting stereoisomer was found to be present at a concentration of 151 pM at the same sampling occasion. This is, to the best of the authors’ knowledge, the first time the stereoisomers of α-OH-Met have been detected in wastewater samples. The enantiomers of metoprolol were determined to be 1.77 and 1.86 nM in the same matrix. The enantiomers of COOH-Met were not detected above the method detection limit (42 pM) in treated wastewater samples. The developed LC–MS/MS methods were validated in wastewater samples.

    HSV kategori
    Forskningsprogram
    Analytisk farmaceutisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-171547 (URN)10.1016/j.chroma.2012.09.090 (DOI)000312475300016 ()
    Tilgjengelig fra: 2012-03-21 Laget: 2012-03-21 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    4. A liquid chromatography-tandem mass spectrometry method for the trace analysis of diazepam and nordiazepam in environmental water samples. A comprehensive study of storage conditions and identification of an unknown compound.
    Åpne denne publikasjonen i ny fane eller vindu >>A liquid chromatography-tandem mass spectrometry method for the trace analysis of diazepam and nordiazepam in environmental water samples. A comprehensive study of storage conditions and identification of an unknown compound.
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-171548 (URN)
    Tilgjengelig fra: 2012-03-21 Laget: 2012-03-21 Sist oppdatert: 2018-01-12
  • 15.
    Barclay, Victoria K.H.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Tyrefors, Niklas L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Johansson, I. Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Chiral analysis of metoprolol and two of its metabolites, alpha‑hydroxymetoprolol and deaminated metoprolol, in wastewater using liquid chromatography-tandem mass spectrometry2012Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1269, nr SI, s. 208-217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A LC–MS/MS method for the chiral separation of metoprolol and two of its main metabolites, α-hydroxymetoprolol (α-OH-Met) and deaminated metoprolol (COOH-Met), in environmental water samples has been developed. The target bases, metoprolol and α-OH-Met, as well as the acidic metabolite (COOH-Met) were extracted from water samples by a solid phase extraction method employing Oasis HLB cartridges. The extraction recoveries were ≥73% for all compounds in surface water. Four different types of chiral stationary phases were investigated for the separation of the eight stereoisomers of metoprolol and its metabolites, Chiralcel OD-H, Chirobiotic V, Chiral AGP and Chiral CBH. In the final method, the enantiomers of metoprolol and four stereoisomers of α-OH-Met were separated using Chiral CBH, the enantiomers of COOH-Met were separated employing Chiral AGP. The analytes were detected in SRM mode by triple quadrupole mass spectrometry. The method was applied for the chiral analysis of the analytes in treated wastewater samples from Uppsala, Sweden. The enantiomers and diastereoisomers of α-OH-Met were detected and analyzed in the samples. The concentrations of the three first eluting stereoisomers of α-OH-Met were between 54 and 61 pM. Interestingly, the last eluting stereoisomer was found to be present at a concentration of 151 pM at the same sampling occasion. This is, to the best of the authors’ knowledge, the first time the stereoisomers of α-OH-Met have been detected in wastewater samples. The enantiomers of metoprolol were determined to be 1.77 and 1.86 nM in the same matrix. The enantiomers of COOH-Met were not detected above the method detection limit (42 pM) in treated wastewater samples. The developed LC–MS/MS methods were validated in wastewater samples.

  • 16.
    Basic, Almedina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Insulin Amyloid Formation: Effects of additives and environmental factors encountered during production scale HPLC purification2016Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [en]

    Insulin is a peptide hormone that regulates blood sugar levels and is used to treat diabetes. In acidic buffers, high temperature, and at high concentration, insulin aggregates to form insoluble amyloid fibrils. This is problematic in industrial production of insulin, where aggregation during HPLC purification results in clogged columns and reduced separation capacity. Insulin amyloid formation has mainly been studied at low pH (~2); the influence of protein concentration, organic modifiers, and excess surfaces and particles at intermediate (~4) or neutral pH is less clear, albeit highly relevant to understand insulin fibrillation in industrial production settings. To address this, Thioflavin-T (ThT) fluorescence was used to study insulin fibrillation under different experimental conditions in vitro.Moreover, insulin solubility and thermodynamic stability was determined across a range of relevant solution pH using spectroscopic techniques, including circular dichroism. The main conclusions of this work are that insulin aggregation is faster at low and neutral pH, whereas aggregation is slower in the intermediate range between pH 4 and 6. Further, increasing amounts of ethanol or isopropanol has a retarding effect on fibril formation at concentrations up to 30% (v/v). Presence of hydrophobic silica particles enhance insulin fibrillation, which explains the observations of this adverse reaction during HPLC purifications. Also, this work concludes that the stability of insulins secondary structure is unaffected by pH.

    This project has given insight into how insulin aggregation could be avoided and has thereby enabled further work for new ideas on how clogged columns could be restored by dissolving insulin aggregates.

  • 17.
    Bekiroglu, Somer
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Myrberg, Olle
    Ostman, Kristina
    Ek, Marianne
    Arvidsson, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Rundlöf, Torgny
    Hakkarainen, Birgit
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Validation of a quantitative NMR method for suspected counterfeit products exemplified on determination of benzethonium chloride in grapefruit seed extracts2008Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 47, nr 4-5, s. 958-961Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A H-1-nuclear magnetic resonance (NMR) spectroscopy method for quantitative determination of benzethonium chloride (BTC) as a constituent of grapefruit seed extract was developed. The method was validated, assessing its specificity, linearity, range, and precision, as well as accuracy, limit of quantification and robustness. The method includes quantification using an internal reference standard, 1,3,5-trimethoxybenzene, and regarded as simple, rapid, and easy to implement. A commercial grapefruit seed extract was studied and the experiments were performed on spectrometers operating at two different fields, 300 and 600 MHz for proton frequencies, the former with a broad band (BB) probe and the latter equipped with both a BB probe and a CryoProbe (TM). The concentration average for the product sample was 78.0, 77.8 and 78.4 mg/ml using the 300 BB probe, the 600 MHz BB probe and CryoProbe (TM), respectively. The standard deviation and relative standard deviation (R.S.D., in parenthesis) for the average concentrations was 0.2 (0.3%), 0.3 (0.4%) and 0.3 mg/ml (0.4%), respectively.

  • 18. Bergman, E
    et al.
    Lundahl, A
    Forsell, P
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Knutson, L
    Lennernäs, H
    The effect of gemfibrozil on the biliary excretion of rosuvastatin in pig and man2009Konferansepaper (Annet vitenskapelig)
  • 19. Bergman, E
    et al.
    Lundahl, A
    Forsell, P
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Knutson, L
    Lennernäs, H
    The hepatobiliary disposition of rosuvastatin in pigs and the impact of concomitant dosing with cyclosporine.2009Konferansepaper (Annet vitenskapelig)
  • 20. Bergman, E
    et al.
    Sjödin, E
    Forsell, P
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Knutson, L
    Lennernäs, H
    The biliary excretion of rosuvastatin and gemfibrozil in healthy humans2008Konferansepaper (Annet vitenskapelig)
  • 21. Bergman, E
    et al.
    Sjödin, E
    Forsell, P
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Knutson, L
    Lennernäs, H
    The biliary excretion of rosuvastatin and gemfibrozil in healthy humans2008Konferansepaper (Annet vitenskapelig)
  • 22.
    Bergman, Ebba
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The Effect of Acute Administration of Rifampicin and Imatinib on the Enterohepatic Transport of Rosuvastatin In Vivo2010Inngår i: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, nr 8, s. 558-568Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hepatobiliary transporters efficiently shunt rosuvastatin from the blood stream, into the hepatocyte, followed by transporter-mediated excretion into the bile ducts. This study aimed at investigating the contribution of sinusoidal versus canalicular transport on the pharmacokinetics of an intrajejunal dose of 80mg rosuvastatin in pigs (control group, n=2+6). The transport inhibitors, rifampicin (20mg/kg, n6) and imatinib (14mg/kg, n6), were administered as 2-h long intravenous infusions. Plasma samples were withdrawn from the portal and hepatic vein simultaneously during 5h along with bile sample collection. Rifampicin reduced the hepatic extraction of rosuvastatin by 35% and the area under the curve in the hepatic vein compartment increased by a factor of 6.3 (95% confidence intervals (CI): 3.132, P value <0.01). The increase in the portal vein compartment was less pronounced than in the hepatic vein, 2.0-fold (95% CI: 1.13.8, P value <0.05), suggesting that the inhibition was predominantly located in the liver rather than in the intestine and suggesting inhibition if sinusoidal transport. In contrast, no effect on the pharmacokinetics of rosuvastatin was observed following concomitant administration with imatinib possibly due to insufficient concentration of the inhibitor inside the hepatocyte. Rifampicin significantly affected the hepatobiliary transport of rosuvastatin, however imatinib did not alter the plasma exposure of rosuvastatin.

  • 23.
    Bergman, Ebba
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lundahl, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Fridblom, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Knutson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The Enterohepatic Disposition of Rosuvastatin in Pigs and The Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil2009Inngår i: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, nr 12, s. 2349-2358Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The hepatobiliary transport and local disposition of rosuvastatin in pig was investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. 80 mg rosuvastatin was administered as an intrajejunal bolus dose in Treatments I, II and III (TI, TII, and TIII, respectively; n=6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a two hour intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In Treatment IV (TIV, n=4) was 5.9 mg rosuvastatin administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH) and femoral veins and bile from the common hepatic duct. The biliary recovery of the administered rosuvastatin dose was 9.0±3.5% and 35.7±15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as the median AUCbile/AUCVH ratio was 1770 (1640-11300) in TI. Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC50-values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI; 0.89±0.06, TII; 0.46±0.13) and increased the AUCVP and AUCVH by 1.6 and 9.1-fold, respectively. In addition, the biliary exposure and fe, bile were reduced by ≈50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the OATP-family, rather than canalicular transporters.

  • 24. Bjornstad, Kristian
    et al.
    Åberg, Annica Tevell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Kalb, Suzanne R.
    Wang, Dongxia
    Barr, John R.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Validation of the Endopep-MS method for qualitative detection of active botulinum neurotoxins in human and chicken serum2014Inngår i: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 406, nr 28, s. 7149-7161Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Botulinum neurotoxins (BoNTs) are highly toxic proteases produced by anaerobic bacteria. Traditionally, a mouse bioassay (MBA) has been used for detection of BoNTs, but for a long time, laboratories have worked with alternative methods for their detection. One of the most promising in vitro methods is a combination of an enzymatic and mass spectrometric assay called Endopep-MS. However, no comprehensive validation of the method has been presented. The main purpose of this work was to perform a validation for the qualitative analysis of BoNT-A, B, C, C/D, D, D/C, and F in serum. The limit of detection (LOD), selectivity, precision, stability in matrix and solution, and correlation with the MBA were evaluated. The LOD was equal to or even better than that of the MBA for BoNT-A, B, D/C, E, and F. Furthermore, Endopep-MS was for the first time successfully used to differentiate between BoNT-C and D and their mosaics C/D and D/C by different combinations of antibodies and target peptides. In addition, sequential antibody capture was presented as a new way to multiplex the method when only a small sample volume is available. In the comparison with the MBA, all the samples analyzed were positive for BoNT-C/D with both methods. These results indicate that the Endopep-MS method is a valid alternative to the MBA as the gold standard for BoNT detection based on its sensitivity, selectivity, and speed and that it does not require experimental animals.

  • 25. Björnstad, Kristian
    et al.
    Tevell Åberg, Annica
    Kalb, Suzanne
    Wang, Dongxia
    Barr, John R.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Validation of the endopep-MS method for qualitative detection of active botulinum neurotoxins in human or chicken serum2014Konferansepaper (Annet vitenskapelig)
  • 26. Breadmore, Michael C.
    et al.
    Sänger van de Griend, Cari E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    In-capillary sample concentration in CE2014Inngår i: LC GC North America, ISSN 1527-5949, E-ISSN 1939-1889, Vol. 32, nr 3, s. 174-186Artikkel i tidsskrift (Fagfellevurdert)
  • 27.
    Carlsson, Ylva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Non-aquoeus capillary electrophoretic separation of enantiomeric amines with (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid as chiral counter ion2001Inngår i: Journal of Chromatography A, ISSN 0021-9673, Vol. 922, nr 1-2, s. 303-311Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    (2)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid [(2)-DIKGA] has been introduced as a chiral counter ion innon-aqueous capillary electrophoresis. High enantioresolutions (R $3) were obtained for amines, e.g., pronethalol, labetalol Sand bambuterol. Methanol containing NaOH and (2)-DIKGA was used as the background electrolyte. The counter ionconcentration and the nature of the injection medium were found to affect the chiral separation. Covalent coating of thefused-silica capillary reduced the electro-osmotic flow resulting in improved enantioresolutions.

  • 28.
    Colombo, Stefano
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Brisander, Magnus
    Haglöf, Jakob
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Sjövall, Peter
    Andersson, Per
    Østergaard, Jesper
    Malmsten, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Matrix effects in nilotinib formulations with pH-responsive polymer produced by carbon dioxide-mediated precipitation2015Inngår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 494, nr 1, s. 205-217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Factors determining the pH-controlled dissolution kinetics of nilotinib formulations with the pH-titrable polymer hydroxypropyl methylcellulose phthalate, obtained by carbon dioxide-mediated precipitation, were mechanistically examined in acid and neutral environment. The matrix effect, modulating the drug dissolution, was characterized with a battery of physicochemical methodologies, including ToF-SIMS for surface composition, SAXS/WAXS and modulated DSC for crystallization characterization, and simultaneous UV-imaging and Raman spectroscopy for monitoring the dissolution process in detail. The hybrid particle formulations investigated consisted of amorphous nilotinib embedded in a polymer matrix in single continuous phase, displaying extended retained amorphicity also under wet conditions. It was demonstrated by Raman and FTIR spectroscopy that the efficient drug dispersion and amorphization in the polymer matrix were mediated by hydrogen bonding between the drug and the phthalate groups on the polymer. Simultaneous Raman and UV-imaging studies of the effect of drug load on the swelling and dissolution of the polymer matrix revealed that high nilotinib load prevented matrix swelling on passage from acid to neutral pH, thereby preventing re-precipitation and re-crystallization of incorporated nilotinib. These findings provide a mechanistic foundation of formulation development of nilotinib and other protein kinase inhibitors, which are now witnessing an intense therapeutic and industrial attention due to the difficulty in formulating these compounds so that efficient oral bioavailability is reached.

  • 29.
    Dubbelboer, Ilse R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lilienberg, Elsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Piquette-Miller, Micheline
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs2014Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, nr 4, s. 1301-1313Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX. The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and its active metabolite doxorubicinol (DOXol) were analyzed using UPLC-MS/MS. A multi-compartment model was developed to describe the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol was observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.

  • 30. Durgaryan, Andranik
    et al.
    Rundlöf, Torgny
    Lavén, Martin
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Identification of human chorionic gonadotropin hormone in illegally distributed products by MALDI-TOF mass spectrometry and double-injection capillary zone electrophoresis2016Inngår i: Analytical Methods, ISSN 1759-9660, E-ISSN 1759-9679, Vol. 8, nr 21, s. 4188-4196Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This paper describes two complementary methods, based on peptide-mass fingerprinting (PMF) using MALDI-TOF mass spectrometry and double injection capillary zone electrophoresis for identification of human chorionic gonadotropin (hCG). The identification was performed by determining the amino acid composition and comparing measured mass spectra with those predicted in silico. Capillary zone electrophoresis in double injection mode (DICZE) was used to confirm the identity of the protein. In DICZE, the identification was performed by analyzing illegal samples together with the corresponding reference standard during a double injection capillary zone electrophoretic run. The identification was based on the closeness of agreement between the calculated migration time (t(mig(c))) and the observed migration time (tmig) of the reference standard. Furthermore, the DICZE method provides the possibility to compare the electrophoretic separation patterns of the native reference standard and the target analyte. The inner surface of the capillary was dynamically coated with putrescine, present in the BGE at 8.2 mM, to improve the separation. The CZE analyses revealed that the protein consisted of at least ten glycosylated isoforms.

  • 31. Ekstrand, C.
    et al.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Gabrielsson, J.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Kallings, P.
    Olsen, L.
    Ingvast-Larsson, C.
    Plasma concentration-dependent suppression of endogenous hydrocortisone in the horse after intramuscular administration of dexamethasone-21-isonicotinate2015Inngår i: Journal of Veterinary Pharmacology and Therapeutics, ISSN 0140-7783, E-ISSN 1365-2885, Vol. 38, nr 3, s. 235-242Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Detection times and screening limits (SL) are methods used to ensure that the performance of horses in equestrian sports is not altered by drugs. Drug concentration-response relationship and knowledge of concentration-time profiles in both plasma and urine are required. In this study, dexamethasone plasma and urine concentration-time profiles were investigated. Endogenous hydrocortisone plasma concentrations and their relationship to dexamethasone plasma concentrations were also explored. A single dose of dexamethasone-21-isonicotinate suspension (0.03mg/kg) was administered intramuscularly to six horses. Plasma was analysed for dexamethasone and hydrocortisone and urine for dexamethasone, using UPLC-MS/MS. Dexamethasone was quantifiable in plasma for 8.3 +/- 2.9days (LLOQ: 0.025g/L) and in urine for 9.8 +/- 3.1days (LLOQ: 0.15g/L). Maximum observed dexamethasone concentration in plasma was 0.61 +/- 0.12g/L and in urine 4.2 +/- 0.9g/L. Terminal plasma half-life was 38.7 +/- 19h. Hydrocortisone was significantly suppressed for 140h. The plasma half-life of hydrocortisone was 2.7 +/- 1.3h. Dexamethasone potency, efficacy and sigmoidicity factor for hydrocortisone suppression were 0.06 +/- 0.04g/L, 0.95 +/- 0.04 and 6.2 +/- 4.6, respectively. Hydrocortisone suppression relates to the plasma concentration of dexamethasone. Thus, determination of irrelevant plasma concentrations and SL is possible. Future research will determine whether hydrocortisone suppression can be used as a biomarker of the clinical effect of dexamethasone.

  • 32.
    Ekstrand, C.
    et al.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Div Pharmacol & Toxicol, SE-75007 Uppsala, Sweden..
    Ingvast-Larsson, C.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Div Pharmacol & Toxicol, SE-75007 Uppsala, Sweden..
    Olsen, L.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Div Pharmacol & Toxicol, SE-75007 Uppsala, Sweden..
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala, Sweden..
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala, Sweden..
    Gabrielsson, J.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Div Pharmacol & Toxicol, SE-75007 Uppsala, Sweden..
    A quantitative approach to analysing cortisol response in the horse2016Inngår i: Journal of Veterinary Pharmacology and Therapeutics, ISSN 0140-7783, E-ISSN 1365-2885, Vol. 39, nr 3, s. 255-263Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cortisol response to glucocorticoid intervention has, in spite of several studies in horses, not been fully characterized with regard to the determinants of onset, intensity and duration of response. Therefore, dexamethasone and cortisol response data were collected in a study applying a constant rate infusion regimen of dexamethasone (0.17, 1.7 and 17g/kg) to six Standardbreds. Plasma was analysed for dexamethasone and cortisol concentrations using UHPLC-MS/MS. Dexamethasone displayed linear kinetics within the concentration range studied. A turnover model of oscillatory behaviour accurately mimicked cortisol data. The mean baseline concentration range was 34-57g/L, the fractional turnover rate 0.47-1.5 1/h, the amplitude parameter 6.8-24g/L, the maximum inhibitory capacity 0.77-0.97, the drug potency 6-65ng/L and the sigmoidicity factor 0.7-30. This analysis provided a better understanding of the time course of the cortisol response in horses. This includes baseline variability within and between horses and determinants of the equilibrium concentration-response relationship. The analysis also challenged a protocol for a dexamethasone suppression test design and indicated future improvement to increase the predictability of the test.

  • 33. Ekstrand, Carl
    et al.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Falkenö, Ulrika
    Gabrielsson, Johan
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Kallings, Peter
    Olsén, Lena
    Tvedten, Harold
    Ingvast-Larsson, Carina
    Additional evidence for dexamethasone screening limits2014Konferansepaper (Annet vitenskapelig)
  • 34.
    Ekstrand, Carl
    et al.
    Swedish Univ Agr Sci, Div Pharmacol & Toxicol, Dept Biomed & Vet Publ Hlth, POB 7028, S-75007 Uppsala, Sweden.
    Ingvast-Larsson, Carina
    Swedish Univ Agr Sci, Div Pharmacol & Toxicol, Dept Biomed & Vet Publ Hlth, POB 7028, S-75007 Uppsala, Sweden.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi. Natl Vet Inst, Dept Chem Environm & Feed Hyg, Uppsala, Sweden.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi. Natl Vet Inst, Dept Chem Environm & Feed Hyg, Uppsala, Sweden.
    Olsen, Lena
    Swedish Univ Agr Sci, Div Pharmacol & Toxicol, Dept Biomed & Vet Publ Hlth, POB 7028, S-75007 Uppsala, Sweden;Swedish Univ Agr Sci, Div Vet Nursing, Dept Clin Sci, Uppsala, Sweden.
    Cetirizine per os: exposure and antihistamine effect in the dog2018Inngår i: Acta Veterinaria Scandinavica, ISSN 1751-0147, E-ISSN 1751-0147, Vol. 60, artikkel-id 77Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundCetirizine is an antihistamine used in dogs, but plasma concentrations in relation to effect after oral administration are not well studied. This study investigated cetirizine exposure and the plasma cetirizine concentration-antihistamine response relation in the dog following oral administration of cetirizine.ResultsEight Beagle dogs were included in a cross-over study consisting of two treatments. In treatment one, cetirizine 2-4mg/kg was administered per os once daily for 3days. The other treatment served as a control. Wheal diameter induced by intra-dermal histamine injections served as response-biomarker. Cetirizine plasma concentration was quantified by UHPLC-MS/MS. Median (range) cetirizine plasma terminal half-life was 10h (7.9-16.5). Cetirizine significantly inhibited wheal formation compared with the premedication baseline. Maximum inhibition of wheal formation after treatment with cetirizine per os was 100% compared with premedication wheal diameter. The median (range) IC50-value for reduction in wheal area was 0.33 mu g/mL (0.07-0.45). The median (range) value for the sigmoidicity factor was 1.8 (0.8-3.5). A behavioral study was also conducted and revealed no adverse effects, such as sedation.ConclusionThe results indicate that a once-daily dosing regimen of 2-4mg/kg cetirizine per os clearly provides a sufficient antihistamine effect. Based on this experimental protocol, cetirizine may be an option to treat histamine-mediated inflammation in the dog based on this experimental protocol but additional clinical studies are required.

  • 35. Ekstrand, Carl
    et al.
    Ingvast-Larsson, Carina
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Olsén, Lena
    Antihistamine effect of cetirizine after oral administrator in the dog2015Konferansepaper (Annet vitenskapelig)
  • 36. Ekstrand, Carl
    et al.
    Ingvast-Larsson, Carina
    Olsén, Lena
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Gabrielsson, Johan
    A quantitative approach to analysing hydrocortisone response in the horse2015Konferansepaper (Annet vitenskapelig)
  • 37.
    El Deeb, Sami
    et al.
    TU Braunschweig, Inst Med & Pharmaceut Chem, D-38106 Braunschweig, Germany..
    Waetzig, Hermann
    TU Braunschweig, Inst Med & Pharmaceut Chem, D-38106 Braunschweig, Germany..
    El-Hady, Deia Abd
    Univ Jeddah, Dept Chem, Fac Sci, Jeddah, Saudi Arabia.;Assiut Univ, Dept Chem, Fac Sci, Assiut, Egypt..
    Sänger-van de Griend, Cari
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi. Kantisto BV, Baarn, Netherlands.;Univ Tasmania, Australian Ctr Res Separat Sci ACROSS, Sch Chem, Hobart, Tas, Australia..
    Scriba, Gerhard K. E.
    Univ Jena, Sch Pharm, Dept Pharmaceut Med Chem, Jena, Germany..
    Recent advances in capillary electrophoretic migration techniques for pharmaceutical analysis (2013-2015)2016Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 37, nr 12, s. 1591-1608Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    This review updates and follows-up a previous review by highlighting recent advancements regarding capillary electromigration methodologies and applications in pharmaceutical analysis. General approaches such as quality by design as well as sample injection methods and detection sensitivity are discussed. The separation and analysis of drug-related substances, chiral CE, and chiral CE-MS in addition to the determination of physicochemical constants are addressed. The advantages of applying affinity capillary electrophoresis in studying receptor-ligand interactions are highlighted. Finally, current aspects related to the analysis of biopharmaceuticals are reviewed. The present review covers the literature between January 2013 and December 2015.

  • 38. El Deeb, Sami
    et al.
    Wätzig, Hermann
    Abd El-Hady, Deia
    Albishri, Hassan M.
    Sänger - van de Griend, Cari
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Scriba, Gerhard K. E.
    Recent advances in capillary electrophoretic migration techniques for pharmaceutical analysis2014Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 35, nr 1, s. 170-189Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Since the introduction about 30 years ago, CE techniques have gained a significant impact in pharmaceutical analysis. The present review covers recent advances and applications of CE for the analysis of pharmaceuticals. Both small molecules and biomolecules such as proteins are considered. The applications range from the determination of drug-related substances to the analysis of counterions and the determination of physicochemical parameters. Furthermore, general considerations of CE methods in pharmaceutical analysis are described.

  • 39.
    Elhamili, Anisa
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Wetterhall, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Puerta, Angel
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Westerlund, Douglas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    The effect of sample salt additives on capillary electrophoresis analysis of intact proteins using surface modified capillaries.2009Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1216, nr 17, s. 3613-3620Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effect of adding alkali salts to protein samples for capillary electrophoretic (CE) analysis of intact proteins was studied. A high degree of peak stacking, even for large proteins, was found to occur when alkali salts were added to the sample. The addition of salt to the protein sample promotes a strong improvement in the peak efficiency of individual proteins giving up to 2.1 x 10(6) apparent plates/m. The concentration of salt required in the sample to reach optimal peak efficiency show dependency on both the molecular weight and molar concentration of the protein. However, adding salt will, at a sufficiently high concentration, cause a mixture of proteins to co-migrate to one very sharp peak. The observed sample stacking effect was obtained with a number of different surface modified silica capillaries indicating a general phenomenon and not surface coating specific.

  • 40. Elmongy, Hatem
    et al.
    Ahmed, Hytham
    Wahbi, Abdel-Aziz
    Amini, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi. Swedish Drug Agency, Uppsala, Sweden.
    Colmsjö, Anders
    Abdel-Rehim, Mohamed
    Determination of metoprolol enantiomers in human plasma and saliva samples utilizing microextraction by packed sorbent and liquid chromatography-tandem mass spectrometry2016Inngår i: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 30, nr 8, s. 1309-1317Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A sensitive, accurate and reliable bioanalytical method for the enantioselective determination of metoprolol in plasma and saliva samples utilizing liquid chromatography-electrospray ionization tandem mass spectrometry was developed and validated. Human plasma and saliva samples were pretreated by microextraction by packed sorbent (MEPS) prior to analysis. A new MEPS syringe form with two inputs was used. Metoprolol enantiomers and internal standard pentycaine (IS) were eluted from MEPS sorbent using isopropanol after removal of matrix interferences using aliquots of 5% methanol in water. Complete separation of metoprolol enantiomers was achieved on a Cellulose-SB column (150 × 4.6 mm, 5 μm) using isocratic elution with mobile phase 0.1% ammonium hydroxide in hexane-isopropanol (80:20, v/v) with a flow rate of 0.8 mL/min. A post-column solvent-assisted ionization was applied to enhance metoprolol ionization signal in positive mode monitoring (+ES) using 0.5% formic acid in isopropanol at a flow rate of 0.2 mL/min. The total chromatographic run time was 10 min for each injection. The detection of metoprolol in plasma and saliva samples was performed using triple quadrupole tandem mass spectrometer in +ES under the following mass transitions: m/z 268.08 → 72.09 for metoprolol and m/z 303.3 → 154.3 for IS. The linearity range was 2.5-500 ng/mL for both R- and S-metoprolol in plasma and saliva. The limits of detection and quantitation for both enantiomers were 0.5 and 2.5 ng/mL respectively, in both matrices (plasma and saliva). The intra- and inter-day precisions were presented in terms of RSD values for replicate analysis of quality control samples and were <5%; the accuracy of determinations varied from 96 to 99%. The method was able to determine the therapeutic levels of metoprolol enantiomers in both human plasma and saliva samples successfully, which can aid in therapeutic drug monitoring in clinical laboratories.

  • 41.
    Elmsjö, Albert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Selectivity in NMR and LC-MS Metabolomics: The Importance of Sample Preparation and Separation, and how to Measure Selectivity in LC-MS Metabolomics.2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Until now, most metabolomics protocols have been optimized towards high sample throughput and high metabolite coverage, parameters considered to be highly important for identifying influenced biological pathways and to generate as many potential biomarkers as possible. From an analytical point of view this can be troubling, as neither sample throughput nor the number of signals relates to actual quality of the detected signals/metabolites. However, a method’s selectivity for a specific signal/metabolite is often closely associated to the quality of that signal, yet this is a parameter often neglected in metabolomics.

    This thesis demonstrates the importance of considering selectivity when developing NMR and LC-MS metabolomics methods, and introduces a novel approach for measuring chromatographic and signal selectivity in LC-MS metabolomics.

    Selectivity for various sample preparations and HILIC stationary phases was compared. The choice of sample preparation affected the selectivity in both NMR and LC-MS. For the stationary phases, selectivity differences related primarily to retention differences of unwanted matrix components, e.g. inorganic salts or glycerophospholipids. Metabolites co-eluting with these matrix components often showed an incorrect quantitative signal, due to an influenced ionization efficiency and/or adduct formation.

    A novel approach for measuring selectivity in LC-MS metabolomics has been introduced. By dividing the intensity of each feature (a unique mass at a specific retention time) with the total intensity of the co-eluting features, a ratio representing the combined chromatographic (amount of co-elution) and signal (e.g. in-source fragmentation) selectivity is acquired. The calculated co-feature ratios have successfully been used to compare the selectivity of sample preparations and HILIC stationary phases.

    In conclusion, standard approaches in metabolomics research might be unwise, as each metabolomics investigation is often unique.  The methods used should be adapted for the research question at hand, primarily based on any key metabolites, as well as the type of sample to be analyzed. Increased selectivity, through proper choice of analytical methods, may reduce the risks of matrix-associated effects and thereby reduce the false positive and false negative discovery rate of any metabolomics investigation.

    Delarbeid
    1. The cyanobacterial amino acid beta-N-methylamino-L-alanine perturbs the intermediary metabolism in neonatal rats
    Åpne denne publikasjonen i ny fane eller vindu >>The cyanobacterial amino acid beta-N-methylamino-L-alanine perturbs the intermediary metabolism in neonatal rats
    Vise andre…
    2013 (engelsk)Inngår i: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 49, nr 5, s. 905-919, artikkel-id 10.1007/s00726-017-2391-8Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The neurotoxic amino acid β-N-methylamino-l-alanine (BMAA) is produced by most cyanobacteria. BMAA is considered as a potential health threat because of its putative role in neurodegenerative diseases. We have previously observed cognitive disturbances and morphological brain changes in adult rodents exposed to BMAA during the development. The aim of this study was to characterize changes of major intermediary metabolites in serum following neonatal exposure to BMAA using a non-targeted metabolomic approach. NMR spectroscopy was used to obtain serum metabolic profiles from neonatal rats exposed to BMAA (40, 150, 460mg/kg) or vehicle on postnatal days 9-10. Multivariate data analysis of binned NMR data indicated metabolic pattern differences between the different treatment groups. In particular five metabolites, d-glucose, lactate, 3-hydroxybutyrate, creatine and acetate, were changed in serum of BMAA-treated neonatal rats. These metabolites are associated with changes in energy metabolism and amino acid metabolism. Further statistical analysis disclosed that all the identified serum metabolites in the lowest dose group were significantly (p<0.05) decreased. The neonatal rat model used in this study is so far the only animal model that displays significant biochemical and behavioral effects after a low short-term dose of BMAA. The demonstrated perturbation of intermediary metabolism may contribute to BMAA-induced developmental changes that result in long-term effects on adult brain function.

    Emneord
    β-N-methylamino-L-alanine, cyanobacteria, energy metabolism, neurotoxin, metabolomics, NMR
    HSV kategori
    Forskningsprogram
    Analytisk farmaceutisk kemi; Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-205735 (URN)10.1016/j.tox.2013.07.010 (DOI)000327005300002 ()23886855 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council Formas
    Tilgjengelig fra: 2013-08-22 Laget: 2013-08-22 Sist oppdatert: 2019-08-12
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