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  • 51. Eriksson, H
    et al.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knutson, L
    Dickinson, P
    Lennernäs, H
    Intestinal and liver CYP3A4-mediated metabolism of R/S-verapamil in pigs2008Conference paper (Other academic)
  • 52. Fornstedt, Torgny
    et al.
    Forssén, Patrik
    Westerlund, Douglas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    System peaks and their impact in liquid chromatography2016In: TrAC. Trends in analytical chemistry, ISSN 0165-9936, E-ISSN 1879-3142, Vol. 81, p. 42-50Article, review/survey (Refereed)
    Abstract [en]

    A sample injected into a chromatographic system can generate extra peaks, called “system peaks”, which in general are undetectable. However, for small analytical injections, solute zones eluting with a system zone will often give strongly deformed solute peaks. But, if a solute zone is eluted in a particular region of the system zone it will instead be strongly compressed and well-shaped. For overloaded solute injections, another type of complex band deformation may take place due to large system peaks. This review will present results related to system peak distortions of both small analytical peaks and large preparative ones. Guidelines will be given on how to avoid unwanted distortions and how to utilize the distortions for increased detectability in analytical chromatography, or enhanced production rate in preparative chromatography. The works reviewed here were mainly made by Georges Guiochon, and some of his close colleagues, and is dedicated to his memory.

  • 53.
    Fransson, Anette E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kisiel, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Pirttilä, Kristian
    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.
    Videhult Pierre, Pernilla
    Division of Audiology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig2017In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 11, article id 280Article in journal (Refereed)
    Abstract [en]

    Introduction: Permanent hearing loss and tinnitus as side-effects from treatment with the anticancer drug cisplatin is a clinical problem. Ototoxicity may be reduced by co-administration of an otoprotective agent, but the results in humans have so far been modest.

    Aim: The present preclinical in vivo study aimed to explore the protective efficacy of hydrogen (H2) inhalation on ototoxicity induced by intravenous cisplatin.

    Materials and Methods: Albino guinea pigs were divided into four groups. The Cispt (n = 11) and Cispt+H2 (n = 11) groups were given intravenous cisplatin (8 mg/kg b.w., injection rate 0.2 ml/min). Immediately after, the Cispt+H2 group also received gaseous H2 (2% in air, 60 min). The H2 group (n = 5) received only H2 and the Control group (n = 7) received neither cisplatin nor H2. Ototoxicity was assessed by measuring frequency specific ABR thresholds before and 96 h after treatment, loss of inner (IHCs) and outer (OHCs) hair cells, and by performing densitometry-based immunohistochemistry analysis of cochlear synaptophysin, organic transporter 2 (OCT2), and copper transporter 1 (CTR1) at 12 and 7 mm from the round window. By utilizing metabolomics analysis of perilymph the change of metabolites in the perilymph was assessed.

    Results: Cisplatin induced electrophysiological threshold shifts, hair cell loss, and reduced synaptophysin immunoreactivity in the synapse area around the IHCs and OHCs. H2 inhalation mitigated all these effects. Cisplatin also reduced the OCT2 intensity in the inner and outer pillar cells and in the stria vascularis as well as the CTR1 intensity in the synapse area around the IHCs, the Deiters' cells, and the stria vascularis. H2 prevented the majority of these effects.

    Conclusion: H2 inhalation can reduce cisplatin-induced ototoxicity on functional, cellular, and subcellular levels. It is proposed that synaptopathy may serve as a marker for cisplatin ototoxicity. The effect of H2 on the antineoplastic activity of cisplatin needs to be further explored.

  • 54.
    Grudén, Stefan
    et al.
    LIDDS AB, Uppsala, Sweden.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Rasanen, Veera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, Uppsala, Sweden.
    Axén, Niklas
    LIDDS AB, Uppsala, Sweden.
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel2017In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 114, p. 186-193Article in journal (Refereed)
    Abstract [en]

    Background

    Docetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Although docetaxel is an effective cytostatic agent, its effectiveness in clinical practice is associated with a variety of acute and long term side-effects. To overcome systemic side-effects, a slow release formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed.

    Methods

    Two formulations with the calcium sulfate NanoZolid technology were generated with a twofold difference in docetaxel drug load. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two intra-tumoral injection formulations were tested in female mice (n = 60) inoculated with subcutaneous Lewis lung carcinoma cells. The two formulations were compared to systemic intraperitoneal injection of docetaxel and a placebo formulation without docetaxel. Tumor volumes were measured and systemic side-effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations.

    Results

    Both docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts.

    Conclusions

    The results suggest that intra-tumoral slow release calcium sulfate based formulations with docetaxel can be an alternative strategy as an efficient local antitumoral treatment with reduced systemic toxicity.

  • 55. Guddat, S.
    et al.
    Fusshoeller, G.
    Beuck, S.
    Thomas, A.
    Geyer, H.
    Rydevik, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    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.
    Lagojda, A.
    Schaenzer, W.
    Thevis, M.
    Synthesis, characterization, and detection of new oxandrolone metabolites as long-term markers in sports drug testing2013In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 405, no 25, p. 8285-8294Article in journal (Refereed)
    Abstract [en]

    The discovery and implementation of the long-term metabolite of metandienone, namely 17 beta-hydroxymethyl-17 alpha-methyl-18-norandrost-1,4,13-trien-3-one, to doping control resulted in hundreds of positive metandienone findings worldwide and impressively demonstrated that prolonged detection periods significantly increase the effectiveness of sports drug testing. For oxandrolone and other 17-methyl steroids, analogs of this metabolite have already been described, but comprehensive characterization and pharmacokinetic data are still missing. In this report, the synthesis of the two epimeric oxandrolone metabolites-17 beta-hydroxymethyl-17 alpha-methyl-18-nor-2-oxa-5 alpha-androsta-13-en-3-one and 17 alpha-hydroxymethyl-17 beta-methyl-18-nor-2-oxa-5 alpha-androsta-13-en-3-one-using a fungus (Cunninghamella elegans) based protocol is presented. The reference material was fully characterized by liquid chromatography nuclear magnetic resonance spectroscopy and high resolution/high accuracy mass spectrometry. To ensure a specific and sensitive detection in athlete's urine, different analytical approaches were followed, such as liquid chromatography-tandem mass spectrometry (QqQ and Q-Orbitrap) and gas chromatography-tandem mass spectrometry, in order to detect and identify the new target analytes. The applied methods have demonstrated good specificity and no significant matrix interferences. Linearity (R (2) > 0.99) was tested, and precise results were obtained for the detection of the analytes (coefficient of variation < 20 %). Limits of detection (S/N) for confirmatory and screening analysis were estimated at 1 and 2 ng/mL of urine, respectively. The assay was applied to oxandrolone post-administration samples to obtain data on the excretion of the different oxandrolone metabolites. The studied specimens demonstrated significantly longer detection periods (up to 18 days) for the new oxandrolone metabolites compared to commonly targeted metabolites such as epioxandrolone or 18-nor-oxandrolone, presenting a promising approach to improve the fight against doping.

  • 56.
    Gyllenhaal, Olle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Evaluation Conditions for SFC of Metoprolol and Related Amino Alcohols on Hypercarb (Porous Graphitic Carbon) with Respect to Structure–Selectivity Relations2010In: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 71, no 1-2, p. 7-13Article in journal (Refereed)
    Abstract [en]

    Mobile phase chromatographic conditions for the selective separation of metoprolol from related amino alcohols have been evaluated using Hypercarb as support and carbon dioxide with addition of methanol as mobile phase. The objective for the presented study was to show the unique ability of the porous graphitized carbon surface to separate closely structurally related substances. Experimental results, using Hypercarb and “chromatographic normal phase conditions” (SFC), are presented with focus on how to control retention and to improve peak performance. A high concentration of basic aliphatic amine additive was required in order to elute the amine analytes as symmetrical peaks. N,N-Dimethyloctylamine was preferred over triethylamine since the retention was markedly shorter though the selectivity and resolution were virtually the same. The selectivity can be optimized by altering the temperature of the column. A high selectivity was demonstrated between metoprolol and two homologues with one and two extra methylene groups inserted between the secondary nitrogen atom and the carbon atom with a hydroxyl group attached. The mobile phase flow rate effect the column efficiency only to a minor extent as the steepness of the van Deemter curve for metoprolol was virtually flat in the range studied: 0.5–3.0 mL min−1.

  • 57.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Enantiomeric Separations using Chiral Counter-Ions2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the use of chiral counter-ions for the enantiomeric separation of amines in non-aqueous capillary electrophoresis. The investigations have been concentrated on studies of the influence, of the chiral counter-ion, the solvent, the electrolyte and the analyte, on the enantioselective separation.

    Modified divalent dipeptides have been introduced in capillary electrophoresis for the separation of amino alcohols and chiral resolution of amines. Association constants for the ion-pair between dipeptide and amino alcohol could be utilized for development of separation systems with higher amino alcohol selectivity. Chiral discrimination (ion-pair formation) between the dipeptides and amines are preferably generated in non-aqueous background electrolytes (BGEs). The amount of triethylamine in the BGE determined the dipeptide charge and a divalent dipeptide promoted higher enantioselectivity than a monovalent dipeptide. An N-terminal-end blocking group and glutamic acid at the C-terminal-end of the dipeptide was important for chiral separation of the amines.

    Chemometric and univariate methods have been employed for evaluation of suitable solvent compositions in the BGE. An experimental design including a single solvent as well as binary, ternary and quaternary mixtures of polar organic solvents, showed that optimal enantioresolution was obtained with an ethanol:methanol 80:20 mixture in the BGE.  Furthermore, water was found to have an adverse influence on enantioselectivity and no enantioresolution was obtained with BGEs containing more than 30 % water.

    An alkali metal hydroxide added to the BGE affected the chiral separation by competing ion-pair formation with the selector. The electroosmosis was reduced in order of decreasing alkali metal ion solvated radius and became anodic using K, Rb or Cs in ethanolic BGEs.

    The correlation between the amino alcohol structure and the enantioselectivity was investigated using chemometrics. The obtained models showed that enantioselectivity for the amino alcohols was promoted by e.g. degree of substitution and substituent size on the nitrogen.

    List of papers
    1.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    2. Separation of amino alcohols using divalent dipeptides as counter ions in aqueous CE
    Open this publication in new window or tab >>Separation of amino alcohols using divalent dipeptides as counter ions in aqueous CE
    2010 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 31, no 10, p. 1706-1712Article in journal (Refereed) Published
    Abstract [en]

    Divalent dipeptides have been introduced as counter ions in aqueous CZE. The dipeptides form ion pairs with amino alcohols in the BGE and facilitate the separation of amino alcohols. High concentrations of dipeptide caused reversed effective mobility for the analytes. The net charge of the dipeptide can be controlled using a buffer or a strong base, and regulates the interaction between the dipeptide and the amino alcohol. A stronger interaction and higher selectivity of amino alcohols was observed when the dipeptides were used as divalent counter ions, than in monovalent or uncharged form. Association constants for ion pairs between divalent dipeptides and amino alcohols can be used to enhance selectivity for amino alcohols in CZE. No chiral separation of amino alcohols was observed when using the dipeptides as ion-pairing chiral selectors in aqueous BGE, but addition of methanol to the BGE promoted enantioselectivity.

    Keywords
    Association constants, CE, divalent counter ion, Ion-pair formation, reversed mobility
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-125470 (URN)10.1002/elps.200900702 (DOI)000278650500015 ()20414882 (PubMedID)
    Available from: 2010-05-19 Created: 2010-05-19 Last updated: 2018-01-12Bibliographically approved
    3. Enantiomeric separation of amines using divalent dipeptides as chiral counter-ions in non-aqueous CE
    Open this publication in new window or tab >>Enantiomeric separation of amines using divalent dipeptides as chiral counter-ions in non-aqueous CE
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Capillary electrophoresis, nonaqueous solvents, divalent chiral counter ion, ion-pairing
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-130047 (URN)
    Available from: 2010-08-30 Created: 2010-08-30 Last updated: 2018-01-12
    4. Multivariate data analysis of a chiral separation system using N-derivatized dipeptides as chiral counter-ions on porous graphitic carbon stationary phase
    Open this publication in new window or tab >>Multivariate data analysis of a chiral separation system using N-derivatized dipeptides as chiral counter-ions on porous graphitic carbon stationary phase
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Chiral counter ion, selectivity, molecular descriptor, topological index, PCA, PLS, OPLS
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-130048 (URN)
    Available from: 2010-08-30 Created: 2010-08-30 Last updated: 2018-01-12
  • 58.
    Haglöf, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Multivariate analysis of enantiomeric separation of amino alcohols using N-derivatized dipeptides as chiral selectors in HPLC2010Conference paper (Other academic)
  • 59.
    Haglöf, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Multivariate data analysis of a chiral separation system using N-derivatized dipeptides as chiral counter-ions on porous graphitic carbon stationary phaseManuscript (preprint) (Other academic)
  • 60.
    Haglöf, Jakob
    et al.
    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.
    Capillary electrophoretic studies of ion pairing in aqueous solution using N-derivatized dipeptides2008Conference paper (Other academic)
  • 61.
    Haglöf, Jakob
    et al.
    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.
    Enantiomeric separation of amines using divalent dipeptides as chiral counter-ions in non-aqueous CEManuscript (preprint) (Other academic)
  • 62.
    Haglöf, Jakob
    et al.
    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.
    Enantiomeric separation of amines using divalent N-derivatized dipeptides as chiral selectors in non-aqueous capillary electrophoresis2008Conference paper (Other academic)
  • 63.
    Haglöf, Jakob
    et al.
    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.
    Separation of amino alcohols using divalent dipeptides as counter ions in aqueous CE2010In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 31, no 10, p. 1706-1712Article in journal (Refereed)
    Abstract [en]

    Divalent dipeptides have been introduced as counter ions in aqueous CZE. The dipeptides form ion pairs with amino alcohols in the BGE and facilitate the separation of amino alcohols. High concentrations of dipeptide caused reversed effective mobility for the analytes. The net charge of the dipeptide can be controlled using a buffer or a strong base, and regulates the interaction between the dipeptide and the amino alcohol. A stronger interaction and higher selectivity of amino alcohols was observed when the dipeptides were used as divalent counter ions, than in monovalent or uncharged form. Association constants for ion pairs between divalent dipeptides and amino alcohols can be used to enhance selectivity for amino alcohols in CZE. No chiral separation of amino alcohols was observed when using the dipeptides as ion-pairing chiral selectors in aqueous BGE, but addition of methanol to the BGE promoted enantioselectivity.

  • 64.
    Hansson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Design of an LC-MS/MS method for measuring concentrations of Cyclosporine A and Tacrolimus from dried blood spots2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Patients that have undergone organ transplantation are life-long treated with immunosuppressant drugs and these have to be monitored regularly to get the desired effect of suppressing the immune system. To monitor the drug concentration normally a venous blood sample is collected at a clinic but the use of dried blood spots (DBS) as a matrix for drug monitoring for immunosuppressant drugs will make home sampling possible for this patient group. The aim of this study was to develop and validate a bioanalytical method for quantifying cyclosporine A and tacrolimus in dried blood spots. The method consist of punching out a 5 mm disc from a blood spot , followed by extracting the spot in a 96-well hydrophobic filter plate with 150 µL extraction solution containing internal standard (ascomycin and cyclosporine A d12) in a methanol water solution (80:20v/v%). The extract is then centrifuged through the filter plate down in a 96-deep well plate and injected on the LC-MS/MS, with an analysis time of 2.5min. The method will be validated in accordance with the guidelines set by the European Medicines Agency with additions specific to DBS. The method is not fully validated but will be in due time. The validated parameters show a robust and fast analysing method that has the prospects of being used for analysing DBS samples for patients and in the future can possibly be used by patients in home environment.

  • 65.
    Hansson, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knych, Heather
    Stanley, Scott
    Thevis, Mario
    Bondesson, Ulf
    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.
    Characterization of equine urinary metabolites of selective androgen receptor modulators (SARMs) S1, S4 and S22 for doping control purposes2015In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 7, no 8, p. 673-683Article in journal (Refereed)
    Abstract [en]

    Selective androgen receptor modulators, SARMs, constitute a class of compounds with anabolic properties but with few androgenic side-effects. This makes them possible substances of abuse and the World Anti-Doping Agency (WADA) has banned the entire class of substances. There have been several cases of illicit use of aryl propionamide SARMs in human sports and in 2013, 13 cases were reported. These substances have been found to be extensively metabolized in humans, making detection of metabolites necessary for doping control. SARMs are also of great interest to equine doping control, but the in vivo metabolite pattern and thus possible analytical targets have not been previously studied in this species. In this study, the urinary metabolites of the SARMs S1, S4, and S22 in horses were studied after intravenous injection, using ultra high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QToF-MS). Eight different metabolites were found for SARM S1, nine for SARM S4, and seven for SARM S22. The equine urinary metabolite profiles differed significantly from those of humans. The parent compounds were only detected for SARMs S4 and S22 and only at the first sampling time point at 3h post administration, making them unsuitable as target compounds. For all three SARMs tested, the metabolite yielding the highest response had undergone amide hydrolysis, hydroxylation and sulfonation. The resulting phase II metabolites (4-nitro-3-trifluoro-methyl-phenylamine sulfate for SARMs S1 and S4 and 4-cyano-3-trifluoro-methyl-phenylamine sulfate for SARM S22) are proposed as analytical targets for use in equine doping control.

  • 66.
    Hansson, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knych, Heather
    Univ Calif Davis, Sch Vet Med, KL Maddy Equine Analyt Chem Lab, Davis, CA 95616 USA.;Univ Calif Davis, Sch Vet Med, Dept Vet Mol Biosci, Davis, CA 95616 USA..
    Stanley, Scott
    Univ Calif Davis, Sch Vet Med, KL Maddy Equine Analyt Chem Lab, Davis, CA 95616 USA..
    Thevis, Mario
    German Sport Univ Cologne, Inst Biochem, Cologne, Germany.;German Sport Univ Cologne, Ctr Prevent Doping Res, Cologne, Germany..
    Bondesson, Ulf
    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, SE-75651 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, SE-75651 Uppsala, Sweden..
    Investigation of the selective androgen receptor modulators S1, S4 and S22 and their metabolites in equine plasma using high-resolution mass spectrometry2016In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 30, no 7, p. 833-842Article in journal (Refereed)
    Abstract [en]

    RationaleSelective androgen receptor modulators (SARMs) are prohibited in sports due to their performance enhancing ability. It is important to investigate the metabolism to determine appropriate targets for doping control. This is the first study where the equine metabolites of SARMs S1, S4 (Andarine) and S22 (Ostarine) have been studied in plasma. MethodsEach SARM was administered to three horses as an intravenous bolus dose and plasma samples were collected. The samples were pretreated with protein precipitation using cold acetonitrile before separation by liquid chromatography. The mass spectrometric analysis was performed using negative electrospray, quadrupole time-of-flight mass spectrometry operated in MSE mode and triple-quadrupole mass spectrometry operated in selected reaction monitoring mode. For the quantification of SARM S1, a deuterated analogue was used as internal standard. ResultsThe numbers of observed metabolites were eight, nine and four for the SARMs S1, S4 and S22, respectively. The major metabolite was formed by the same metabolic reactions for all three SARMs, namely amide hydrolysis, hydroxylation and sulfonation. The values of the determined maximum plasma concentrations were in the range of 97-170 ng/mL for SARM S1, 95-115 ng/mL for SARM S4 and 92-147 ng/mL for SARM S22 and the compounds could be detected for 96 h, 12 h and 18 h, respectively. ConclusionsThe maximum plasma concentration of SARMs S1, S4 and S22 was measured in the first sample (5 min) after administration and they were eliminated fast from plasma. The proposed targets to be used in equine doping control are the parent compounds for all three SARMs, but with the metabolite yielding the highest response as a complementary target. 

  • 67.
    Hansson, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knych, Heather
    Stanley, Scott
    Thevis, Mario
    Bondesson, Ulf
    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.
    Quantification of SARMs S1, S4 and S22 and detection of their metabolites in equine plasma using UHPLC-Q-TOF2015Conference paper (Other academic)
  • 68.
    Hansson, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knych, Heather
    Stanley, Scott
    Thevis, Mario
    Bondesson, Ulf
    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.
    Quantification of SARMs S1, S4 and S22 and detection of their metabolites in equine plasma usning UHPLC-Q-TOF2015Conference paper (Other academic)
  • 69.
    Hansson, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Thevis, Mario
    German Sport Univ Cologne, Inst Biochem, Cologne, Germany.;German Sport Univ Cologne, Ctr Prevent Doping Res, Cologne, Germany..
    Cox, Holly
    Sports Med Res & Testing Lab, Salt Lake City, UT USA..
    Miller, Geoff
    Sports Med Res & Testing Lab, Salt Lake City, UT USA..
    Eichner, Daniel
    Sports Med Res & Testing Lab, Salt Lake City, UT USA..
    Bondesson, Ulf
    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, SE-75189 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, SE-75189 Uppsala, Sweden..
    Investigation of the metabolites of the HIF stabilizer FG-4592 (roxadustat) in five different in vitro models and in a human doping control sample using high resolution mass spectrometry2017In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 134, p. 228-236Article in journal (Refereed)
    Abstract [en]

    FG-4592 is a hypoxia-inducible factor (HIF) stabilizer, which can increase the number of red blood cells in the body. It has not been approved by regulatory authorities, but is available for purchase on the Internet. Due to its ability to improve the oxygen transportation mechanism in the body, FG-4592 is of interest for doping control laboratories, but prior to this study, little information about its metabolism was available. In this study, the metabolism of FG-4592 was investigated in a human doping control sample and in five in vitro models: human hepatocytes and liver microsomes, equine liver microsomes and S9 fraction and the fungus Cunninghamella elegans. By using liquid chromatography coupled to a Q-TOF mass spectrometer operated in MSE and MSMS modes, twelve different metabolites were observed for FG-4592. One monohydroxylated metabolite was detected in both the human and equine liver microsome incubations. For the fungus Cunninghamella elegans eleven different metabolites were observed of which the identical monohydroxylated metabolite had the highest response. This rich metabolic profile and the higher levels of metabolites produced by Cunninghamella elegans demonstrates its usefulness as a metabolite producing medium. In the doping control urine sample, one metabolite, which was the result of a direct glucuronidation, was observed. No metabolites were detected in neither the human hepatocyte nor in the equine liver S9 fraction incubates.

  • 70.
    Hansson, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Thevis, Mario
    Lagodja, Andreas
    Thomas, Andreas
    Dib, Josef
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Wigger, Tina
    Karst, Uwe
    Schänzer, Wilhelm
    Characterization of a Selective Androgen Receptor Modulator Drug Candidate and Identification of In Vitro Generated Metabolites for Sports Drug Testing2015Conference paper (Other academic)
  • 71.
    Harang, Valérie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Aspects of Optimisation of Separation of Drugs by Chemometrics2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Statistical experimental designs have been used for method development and optimisation of separation. Two reversed phase HPLC methods were optimised. Parameters such as the pH, the amount of tetrabutylammonium (TBA; co-ion) and the gradient slope (acetonitrile) were investigated and optimised for separation of erythromycin A and eight related compounds. In the second method, a statistical experimental design was used, where the amounts of acetonitrile and octane sulphonate (OSA; counter ion) and the buffer concentration were studied, and generation of an α-plot with chromatogram simulations optimised the separation of six analytes.

    The partial filling technique was used in capillary electrophoresis to introduce the chiral selector Cel7A. The effect of the pH, the ionic strength and the amount of acetonitrile on the separation and the peak shape of R- and S-propranolol were investigated.

    Microemulsion electrokinetic chromatography (MEEKC) is a technique similar to micellar electrokinetic chromatography (MEKC), except that the microemulsion has a core of tiny droplets of oil inside the micelles. A large number of factors can be varied when using this technique. A screening design using the amounts of sodium dodecyl sulphate (SDS), Brij 35, 1-butanol and 2-propanol, the buffer concentration and the temperature as factors revealed that the amounts of SDS and 2-propanol were the most important factors for migration time and selectivity manipulation of eight different compounds varying in charge and hydrophobicity. SDS and 2-propanol in the MEEKC method were further investigated in a three-level full factorial design analysing 29 different compounds sorted into five different groups. Different optimisation strategies were evaluated such as generating response surface plots of the selectivity/resolution of the most critical pair of peaks, employing chromatographic functions, simplex optimisation in MODDE and 3D resolution maps in DryLab™.

    Molecular descriptors were fitted in a PLS model to retention data from the three-level full factorial design of the MEEKC system. Two different test sets were used to study the predictive ability of the training set. It was concluded that 86 – 89% of the retention data could be predicted correctly for new molecules (80 – 120% of the experimental values) with different settings of SDS and 2-propanol.

    Statistical experimental designs and chemometrics are valuable tools for the development and optimisation of analytical methods. The same chemometric strategies can be employed for all types of separation techniques.

    List of papers
    1. Optimization of an HPLC Method for the Separation of Erythromycin and Related Compounds using Factorial Design
    Open this publication in new window or tab >>Optimization of an HPLC Method for the Separation of Erythromycin and Related Compounds using Factorial Design
    1999 In: Chromatographia, ISSN 0009-5893-99-11-525-07, Vol. 50, no 9/10, p. 525-531Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90998 (URN)
    Available from: 2003-11-06 Created: 2003-11-06Bibliographically approved
    2. Liquid Chromatography Method Development and Optimization by Statistical Experimental Design and Chromatogram Simulations
    Open this publication in new window or tab >>Liquid Chromatography Method Development and Optimization by Statistical Experimental Design and Chromatogram Simulations
    2001 In: Chromatographia, ISSN 0009-5893-00-02-703-07, Vol. 54, no 11/12, p. 703-709Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90999 (URN)
    Available from: 2003-11-06 Created: 2003-11-06Bibliographically approved
    3. A statistical experimental design to study factors affecting enantioseparation of propranolol by capillary electrophoresis with cellobiohydrolase (Cel7A) as chiral selector.
    Open this publication in new window or tab >>A statistical experimental design to study factors affecting enantioseparation of propranolol by capillary electrophoresis with cellobiohydrolase (Cel7A) as chiral selector.
    Show others...
    2002 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 23, no 14, p. 2306-2319Article in journal (Refereed) Published
    Abstract [en]

    The capillary electrophoretic enantioseparation of rac-propranolol using cellobiohydrolase Tr Cel7A as selector was optimized by an unbiased statistical experimental design. A set of pre-experiments was performed in order to identify critical experimental factors. In the definitive chemometric design pH, ranging from 5 to 7, ionic strength ranging between 0.01 and 0.02 and organic solvent additive in concentration from 1 to 19% v/v were studied. The response surface plot revealed a separation optimum in the pH interval studied. When all parameters were taken into account, a background electrolyte consisting of 0.016 M bistris-acetate buffer with pH 6.5 and 17% v/v acetonitrile gave the optimum separation. The significance of the statistical design was confirmed by the generally good agreement obtained between predicted response and actual experimental data.

    Keywords
    Capillary electrophoresis, chiral separation, CBHI, propranolol, statistical experimental design
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91000 (URN)000177337000021 ()12210237 (PubMedID)
    Available from: 2003-11-06 Created: 2003-11-06 Last updated: 2017-12-14Bibliographically approved
    4. Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: I. Impact of parameters on separation performance evaluated by multiple linear regression models
    Open this publication in new window or tab >>Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: I. Impact of parameters on separation performance evaluated by multiple linear regression models
    Show others...
    2004 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 25, no 1, p. 80-93Article in journal (Refereed) Published
    Abstract [en]

    The separation of anionic, cationic and neutral drugs in microemulsion electrokinetic chromatography (MEEKC) was studied with a statistical experimental design. The concentration of sodium dodecyl sulfate (SDS, surfactant), 1-butanol (co-surfactant) and borate buffer and the factors Brij 35 (surfactant), 2-propanol (organic solvent) and cassette temperature were varied simultaneously, while the parameters pH (9.2), the concentration of octane (oil, 0.8% w/w), the voltage (10 kV) and the dimension of the fused-silica capillary, were kept constant. Eight different model substances were chosen with different hydrophobicities. Two of the analytes were positively charged, two were negatively charged, and the remaining four were neutral or close to neutral at the pH explored. The importance of each parameter on the separation window, the plate height and the retention factor for each of the analytes was studied by means of multiple linear regression (MLR) models. A new response was evaluated for anions, the quotient between the effective mobility in the microemulsion and the effective mobility in the corresponding buffer. Factors affecting selectivity changes were also explored, and it was found that SDS and 2-propanol had the largest effect on selectivity.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91001 (URN)10.1002/elps.200305671 (DOI)14730572 (PubMedID)
    Available from: 2003-11-06 Created: 2003-11-06 Last updated: 2017-12-14Bibliographically approved
    5. Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: II. Strategies for optimisation of separation
    Open this publication in new window or tab >>Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: II. Strategies for optimisation of separation
    2004 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 25, no 12, p. 1792-1809Article in journal (Refereed) Published
    Abstract [en]

    The separation of anionic, cationic, and neutral drugs in microemulsion electrokinetic chromatography (MEEKC) was studied. The concentration of sodium dodecyl sulfate (SDS; surfactant) and 2-propanol (organic solvent) was varied in a three-level full factorial design. 29 different model substances were chosen with different hydrophobicities and charges (neutral, positive, and negative). The models were calculated by means of multiple linear regression (MLR). The compounds were divided into five different subgroups, and different strategies for optimization of the separation within each group were investigated. The optimization was done by maximizing the selectivity using response surface plots in MODDE, by calculation of different chromatographic functions, and by using the software DryLab. For all the different groups, MODDE, almost all chromatographic functions and DryLab gave approximately the same settings of the factors for optimum separation. Attempts were made to fit descriptors of the compounds to the retention data from the three-level full factorial design by means of partial least squares projection to latent structures (PLS). Between 86 and 89% of all predictions of migration times were acceptable (80-120% of the observed value).

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91002 (URN)10.1002/elps.200305812 (DOI)15213977 (PubMedID)
    Available from: 2003-11-06 Created: 2003-11-06 Last updated: 2017-12-14Bibliographically approved
  • 72.
    Harang, Valérie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Eriksson, Jessica
    Sänger-van de Griend, Cari
    Jacobsson, Sven P.
    Westerlund, Douglas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: I. Impact of parameters on separation performance evaluated by multiple linear regression models2004In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 25, no 1, p. 80-93Article in journal (Refereed)
    Abstract [en]

    The separation of anionic, cationic and neutral drugs in microemulsion electrokinetic chromatography (MEEKC) was studied with a statistical experimental design. The concentration of sodium dodecyl sulfate (SDS, surfactant), 1-butanol (co-surfactant) and borate buffer and the factors Brij 35 (surfactant), 2-propanol (organic solvent) and cassette temperature were varied simultaneously, while the parameters pH (9.2), the concentration of octane (oil, 0.8% w/w), the voltage (10 kV) and the dimension of the fused-silica capillary, were kept constant. Eight different model substances were chosen with different hydrophobicities. Two of the analytes were positively charged, two were negatively charged, and the remaining four were neutral or close to neutral at the pH explored. The importance of each parameter on the separation window, the plate height and the retention factor for each of the analytes was studied by means of multiple linear regression (MLR) models. A new response was evaluated for anions, the quotient between the effective mobility in the microemulsion and the effective mobility in the corresponding buffer. Factors affecting selectivity changes were also explored, and it was found that SDS and 2-propanol had the largest effect on selectivity.

  • 73.
    Harang, Valérie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Jacobsson, Sven P.
    Westerlund, Douglas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: II. Strategies for optimisation of separation2004In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 25, no 12, p. 1792-1809Article in journal (Refereed)
    Abstract [en]

    The separation of anionic, cationic, and neutral drugs in microemulsion electrokinetic chromatography (MEEKC) was studied. The concentration of sodium dodecyl sulfate (SDS; surfactant) and 2-propanol (organic solvent) was varied in a three-level full factorial design. 29 different model substances were chosen with different hydrophobicities and charges (neutral, positive, and negative). The models were calculated by means of multiple linear regression (MLR). The compounds were divided into five different subgroups, and different strategies for optimization of the separation within each group were investigated. The optimization was done by maximizing the selectivity using response surface plots in MODDE, by calculation of different chromatographic functions, and by using the software DryLab. For all the different groups, MODDE, almost all chromatographic functions and DryLab gave approximately the same settings of the factors for optimum separation. Attempts were made to fit descriptors of the compounds to the retention data from the three-level full factorial design by means of partial least squares projection to latent structures (PLS). Between 86 and 89% of all predictions of migration times were acceptable (80-120% of the observed value).

  • 74.
    Harang, Valérie
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Karlsson, Anders
    Josefson, Mats
    Liquid Chromatography Method Development and Optimization by Statistical Experimental Design and Chromatogram Simulations2001In: Chromatographia, ISSN 0009-5893-00-02-703-07, Vol. 54, no 11/12, p. 703-709Article in journal (Refereed)
  • 75. Harang, Valérie
    et al.
    Tysk, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Westerlund, Douglas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Isaksson, Roland
    Johansson, Gunnar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    A statistical experimental design to study factors affecting enantioseparation of propranolol by capillary electrophoresis with cellobiohydrolase (Cel7A) as chiral selector.2002In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 23, no 14, p. 2306-2319Article in journal (Refereed)
    Abstract [en]

    The capillary electrophoretic enantioseparation of rac-propranolol using cellobiohydrolase Tr Cel7A as selector was optimized by an unbiased statistical experimental design. A set of pre-experiments was performed in order to identify critical experimental factors. In the definitive chemometric design pH, ranging from 5 to 7, ionic strength ranging between 0.01 and 0.02 and organic solvent additive in concentration from 1 to 19% v/v were studied. The response surface plot revealed a separation optimum in the pH interval studied. When all parameters were taken into account, a background electrolyte consisting of 0.016 M bistris-acetate buffer with pH 6.5 and 17% v/v acetonitrile gave the optimum separation. The significance of the statistical design was confirmed by the generally good agreement obtained between predicted response and actual experimental data.

  • 76.
    Harang, Valérie
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Westerlund, Douglas
    Optimization of an HPLC Method for the Separation of Erythromycin and Related Compounds using Factorial Design1999In: Chromatographia, ISSN 0009-5893-99-11-525-07, Vol. 50, no 9/10, p. 525-531Article in journal (Refereed)
  • 77.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Preparation of Drug Metabolites2009Conference paper (Other academic)
  • 78.
    Hedeland, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hansson, Annelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Rydevik, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Krug, Oliver
    Thevis, Mario
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knych, Heather
    Stanley, Scott
    In vivo metabolism of selective androgen receptor modulators (SARMs) in the horse2014Conference paper (Other academic)
  • 79.
    Hedeland, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hansson, Annelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Rydevik, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Krug, Oliver
    Thevis, Mario
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knych, Heather
    Stanley, Scott
    In vivo metabolism of Selective Androgen Receptor Modulators (SARMs) in the horse2014Conference paper (Other academic)
  • 80.
    Hedeland, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Moura, Hercules
    Båverud, Viveca
    Woolfitt, Adrian R
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Barr, John R.
    Confirmation of botulism in birds and cattle by the mouse bioassay and Endopep-MS2011In: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 60, no 9, p. 1299-1305Article in journal (Refereed)
    Abstract [en]

    There have been several outbreaks of botulism among poultry and wild birds in Sweden in recent years. The National Veterinary Institute of Sweden (SVA) has identified botulinum neurotoxin (BoNT)/C1 or the mosaic BoNT/C1D using the mouse bioassay. This is believed to be the first report on the application of the Endopep mass spectrometry (Endopep-MS) method to selected clinical animal (serum and liver) samples and a feed sample that had previously given positive test results with the mouse bioassay. In the mouse bioassay eight of the eleven samples were found to be neutralized by both BoNT/C1 and /D antitoxins; the other three were neutralized only by BoNT/C1 antitoxin, but the mice showed a prolonged survival time when the samples had been treated with /D antitoxin. The Endopep-MS analysis, on the other hand, demonstrated only BoNT/C1 activity for all eleven samples. This suggests that at least eight of the samples were of the chimeric toxin type BoNT/C1D, where the enzymically active site is identical to that of BoNT/C1, while other parts of the protein contain sequences of BoNT/D. This is the first step of a cross-validation between the established mouse bioassay and the Endopep-MS of serotypes BoNT/C1 and /C1D. Endopep-MS is concluded to have potential as an attractive alternative to the mouse bioassay.

  • 81.
    Hedeland, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Rydevik, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Krug, O
    Thevis, M
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Mass spectrometric study of the metabolism of Selective Androgen Receptor Modulators (SARMs) in the fungus Cunninghamella elegans2012Conference paper (Other academic)
  • 82.
    Hedeland, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Rydevik, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Krug, O
    Thevis, M
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Mass spectrometric study of the metabolism of Selective Androgen Receptor Modulators (SARMs) in the fungus Cunninghamella elegans2012Conference paper (Other academic)
  • 83.
    Hedeland, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Rydevik, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Krug, O
    Thevis, M
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Mass spectrometric study of the metabolism of Selective Androgen Receptor Modulators (SARMs) in the fungus Cunninghamella elegans2012Conference paper (Other academic)
  • 84.
    Hedeland, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Tevell Åberg, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    The relevance of using a fungus as a model of equine metabolism2010Conference paper (Other academic)
  • 85.
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Chiral Separation of Amines by Non-Aqueous Capillary Electrophoresis using Low Molecular Weight Selectors2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Three chiral selectors (diketogulonic acid, benzoxycarbonylglycylproline and ketopinic acid) have been introduced for enantioseparation of pharmacologically active amines in non-aqueous capillary electrophoresis. The use of organic solvents, instead of aqueous buffers in the background electrolyte facilitated ion-pair formation between the analytes and the chiral selectors. The enantioresolution was strongly affected by the choice of selector and organic solvent but also depended on the other electrolytes. The most important parameter for the enantioresolution, apart from the choice of chiral selector, was the direction and magnitude of the electro-osmosis. Thus, covalently coated capillaries were used to suppress and to reverse this flow. Furthermore, the alkali metal hydroxide added to the background electrolyte had a great influence on the electro-osmosis. Exchanging LiOH for NaOH, was found to decrease the electro-osmotic flow. Interestingly, the flow was altered from cathodic to anodic, with KOH, RbOH or CsOH added to the ethanolic BGE. The occurrence of a reversed electro-osmosis had a great positive effect on the enantioresolution. An appropriate choice of solvent and electrolytes promoted also fast chiral separations, e.g., the enantiomers of isoprenaline were resolved within one minute.

    The capillary electrophoresis systems developed within this work were applied for enantiomeric purity determinations of different pharmaceutical forms of drug products. A detection limit of 0.033 % was achieved for 1S,2R-ephedrine, the enantiomeric impurity in Efedrin®, when diketogulonic acid was used as the selector.

    By using the pre-concentration technique, transient isotachophoresis, the peak efficiency was enhanced for the enantiomers of timolol. This facilitated the introduction of a higher concentration of the sample into the capillary electrophoretic system containing ketopinic acid as the selector, and lowered the detection limit from 2.5 % to 0.2 % for the enantiomeric impurity R-timolol compared with injection without transient isotachophoresis.

    The volatility of the non-aqueous media in capillary electrophoresis facilitated the hyphenation to mass spectrometry. The partial filling technique ensured that the selector did not contaminate the mass spectrometer, and the separated enantiomers of e.g., pronethalol were detected in the selector-free zone.

    List of papers
    1. Non-aquoeus capillary electrophoretic separation of enantiomeric amines with (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid as chiral counter ion
    Open this publication in new window or tab >>Non-aquoeus capillary electrophoretic separation of enantiomeric amines with (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid as chiral counter ion
    2001 (English)In: Journal of Chromatography A, ISSN 0021-9673, Vol. 922, no 1-2, p. 303-311Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Elsevier, 2001
    Keywords
    Non-aqueous capillary electrophoresis; Enantiomer separation; Background electrolyte composition; Amines; Diisopropylideneketogulonic acid; Labetalol
    National Category
    Analytical Chemistry Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-94277 (URN)10.1016/S0021-9673(01)00925-6 (DOI)
    Available from: 2006-04-12 Created: 2006-04-12 Last updated: 2018-01-13
    2. Development of a chiral non-aqueous capillary electrophoretic system using the partial filling technique with UV and mass spectrometric detection
    Open this publication in new window or tab >>Development of a chiral non-aqueous capillary electrophoretic system using the partial filling technique with UV and mass spectrometric detection
    Show others...
    In: Journal of Chromatography A, ISSN 0021-9673Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94278 (URN)
    Available from: 2006-04-12 Created: 2006-04-12Bibliographically approved
    3. Chiral separation of amined with N-benzoxycarbonylglycyl-L-proline as selector in non-aqueous capillary electrophoresis using methanol and 1,2-dechloroethane in the background electrolyte
    Open this publication in new window or tab >>Chiral separation of amined with N-benzoxycarbonylglycyl-L-proline as selector in non-aqueous capillary electrophoresis using methanol and 1,2-dechloroethane in the background electrolyte
    In: Journal of Chromatography A, ISSN 0021-9673Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94279 (URN)
    Available from: 2006-04-12 Created: 2006-04-12Bibliographically approved
    4. Effect of alkali metal hydroxides on the enantioseparation of amines using di-O-isopropylidene-keto-L-gulonic acid as the selector in NACE
    Open this publication in new window or tab >>Effect of alkali metal hydroxides on the enantioseparation of amines using di-O-isopropylidene-keto-L-gulonic acid as the selector in NACE
    2006 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 27, no 22, p. 4469-4479Article in journal (Refereed) Published
    Abstract [en]

    The present work demonstrates the importance of the ionic composition in the BGE for enantioseparation. (-)-2,3:4,6-di-O-Isopropylidene-2-keto-L-gulonic acid ((-)-DIKGA) has been used as the chiral selector in methanolic and ethanolic BGEs. The influence of added alkali metal hydroxides on the EOF and the chiral separation of amines; (atenolol, isoprenaline, pindolol and propranolol) have been studied. The ion-pair formation constants in ethanol were determined by precision conductometry for the enantiomers of pindolol with (-)-DIKGA, for Li+, Na+ and Cs+ with (-)-DIKGA, and also for the corresponding alkali metal hydroxides. The effective mobilities and the enantiomeric mobility differences were affected by the type of alkali metal hydroxide (LiOH, NaOH, KOH, RbOH or CsOH) added to the BGE. The effective mobility and mobility difference were increased with decrease in solvated radius of the alkali metal cation. These differences could partly be correlated to the ion-pair formation constants of the alkali metal cations with the chiral selector, affecting the equilibrium concentration of the free selector. The electroosmosis was also affected by the alkali metal hydroxide added to the BGE. The cathodic electroosmosis decreased with decreasing solvated radius of the alkali metal cation added to the BGE. Interestingly, the cathodic EOF was even reversed, i.e. became anodic in the ethanolic BGEs containing KOH, RbOH or CsOH and the methanolic ones with RbOH and CsOH.

    Keywords
    Alkali metal cation, Chiral separation, Electroosmosis, NACE, Precision conductometry
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-94280 (URN)10.1002/elps.200600297 (DOI)000242695900010 ()17066385 (PubMedID)
    Available from: 2006-04-12 Created: 2006-04-12 Last updated: 2018-01-13
    5. Determination of the enantiomeric impurity in 1R,2S-ephedrine and S-timolol by chiral ion-pair non-aqueous capillary electrophoresis
    Open this publication in new window or tab >>Determination of the enantiomeric impurity in 1R,2S-ephedrine and S-timolol by chiral ion-pair non-aqueous capillary electrophoresis
    2007 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1141, p. 287-294Article in journal (Refereed) Published
    Abstract [en]

    1S,4R-(+)-ketopinic acid [(+)-KPA] has been introduced as a chiral selector for the separation of pharmacologically active amines by non-aqueouscapillary electrophoresis (NACE). (+)-KPA gave enantioresolution for most of the compounds previously separated by 2R,3S,4R,5S-(−)-2,3:4,6-di-O-isopropylidene-2-keto-l-gulonic acid [(−)-DIKGA], but with a reversed migration order. A complete enantioresolution (Rs = 4.2) was obtainedfor timolol, a compound that could not be resolved using (−)-DIKGA as the selector. Thus, (+)-KPA was evaluated for the enantiomeric puritydetermination of S-timolol. A method based on pre-concentration by transient isotachophoresis (tITP) provided a limit of detection (LOD) of0.2% R-timolol in S-timolol samples. Because of the lack of enantioresolution of ephedrine when (+)-KPA was used as the selector, a methodwith (−)-DIKGA has been developed and validated for determination of the enantiomeric purity of the 1R,2S enantiomer. The method gave goodprecision and accuracy with an LOD (S/N = 3) of 0.033% for the enantiomeric impurity 1S,2R-ephedrine.

    Place, publisher, year, edition, pages
    Elsevier, 2007
    Keywords
    Diisoproylideneketogulonic acid; Enantiomeric purity; Ephedrine; Ketopinic acid; Timolol; Non-aqueous capillary electrophoresis
    National Category
    Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-94281 (URN)10.1016/j.chroma.2006.12.013 (DOI)
    Available from: 2006-04-12 Created: 2006-04-12 Last updated: 2017-12-14
  • 86.
    Hedeland, Ylva
    et al.
    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.
    Beronius, Per
    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.
    Effect of alkali metal hydroxides on the enantioseparation of amines using di-O-isopropylidene-keto-L-gulonic acid as the selector in NACE2006In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 27, no 22, p. 4469-4479Article in journal (Refereed)
    Abstract [en]

    The present work demonstrates the importance of the ionic composition in the BGE for enantioseparation. (-)-2,3:4,6-di-O-Isopropylidene-2-keto-L-gulonic acid ((-)-DIKGA) has been used as the chiral selector in methanolic and ethanolic BGEs. The influence of added alkali metal hydroxides on the EOF and the chiral separation of amines; (atenolol, isoprenaline, pindolol and propranolol) have been studied. The ion-pair formation constants in ethanol were determined by precision conductometry for the enantiomers of pindolol with (-)-DIKGA, for Li+, Na+ and Cs+ with (-)-DIKGA, and also for the corresponding alkali metal hydroxides. The effective mobilities and the enantiomeric mobility differences were affected by the type of alkali metal hydroxide (LiOH, NaOH, KOH, RbOH or CsOH) added to the BGE. The effective mobility and mobility difference were increased with decrease in solvated radius of the alkali metal cation. These differences could partly be correlated to the ion-pair formation constants of the alkali metal cations with the chiral selector, affecting the equilibrium concentration of the free selector. The electroosmosis was also affected by the alkali metal hydroxide added to the BGE. The cathodic electroosmosis decreased with decreasing solvated radius of the alkali metal cation added to the BGE. Interestingly, the cathodic EOF was even reversed, i.e. became anodic in the ethanolic BGEs containing KOH, RbOH or CsOH and the methanolic ones with RbOH and CsOH.

  • 87.
    Hedeland, Ylva
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Bondesson, Ulf
    Pettersson, Curt
    Chiral separation of amined with N-benzoxycarbonylglycyl-L-proline as selector in non-aqueous capillary electrophoresis using methanol and 1,2-dechloroethane in the background electrolyteIn: Journal of Chromatography A, ISSN 0021-9673Article in journal (Refereed)
  • 88.
    Hedeland, Ylva
    et al.
    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.
    Bondesson, Ulf
    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.
    Chiral separation of amines with N-benzoxycarbonylglycyl-L-proline as selector in non-aqueous capillary electrophoresis using methanol and 1,2-dichloroethane in the background electrolyte2003In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 984, no 2, p. 261-271Article in journal (Refereed)
    Abstract [en]

    N-Benzoxycarbonylglycyl-L-proline (L-ZGP) has been introduced as a chiral selector for enantioseparation of amines in non-aqueous capillary electrophoresis. Methanol mixed with different proportions of dichloromethane, 1,2-dichloroethane or 2-propanol containing L-ZGP and ammonium acetate was used as the background electrolyte. Enantioseparation of different types of pharmacologically active amines was performed, e.g. the local anaesthetic bupivacaine and the beta-adrenoceptor blocking agent pindolol. Addition of the solvents (dichloromethane, 1,2-dichloroethane or 2-propanol) gave an improved chiral separation partly due to a distinct decrease in the electroosmotic flow. The use of 1,2-dichloroethane in the background electrolyte gave higher precision in migration time (RSD 2.2%) compared to the systems containing dichloromethane. An enantiomeric separation of mepivacaine was performed within 72 s by use of short-end injection with an effective capillary length of 8.5 cm.

  • 89.
    Hedeland, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lehtinen, Jenni
    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.
    Ketopinic acid and diisoproylideneketogulonic acid as chiral ion-pair selectors in capillary electrophoresis: Enantiomeric impurity analysis of S-timolol and 1R,2S-ephedrine2007In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1141, no 2, p. 287-294Article in journal (Refereed)
    Abstract [en]

    1S,4R-(+)-ketopinic acid [(+)-KPA] has been introduced as a chiral selector for the separation of pharmacologically active amines by non-aqueous capillary electrophoresis (NACE). (+)-KPA gave enantioresolution for most of the compounds previously separated by 2R,3S,4R,5S-(−)-2,3:4,6-di-O-isopropylidene-2-keto-l-gulonic acid [(−)-DIKGA], but with a reversed migration order. A complete enantioresolution (Rs = 4.2) was obtained for timolol, a compound that could not be resolved using (−)-DIKGA as the selector. Thus, (+)-KPA was evaluated for the enantiomeric purity determination of S-timolol. A method based on pre-concentration by transient isotachophoresis (tITP) provided a limit of detection (LOD) of 0.2% R-timolol in S-timolol samples. Because of the lack of enantioresolution of ephedrine when (+)-KPA was used as the selector, a method with (−)-DIKGA has been developed and validated for determination of the enantiomeric purity of the 1R,2S enantiomer. The method gave good precision and accuracy with an LOD (S/N = 3) of 0.033% for the enantiomeric impurity 1S,2R-ephedrine.

  • 90.
    Hedeland, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lethinen, Jenni
    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.
    Determination of the enantiomeric impurity in 1R,2S-ephedrine and S-timolol by chiral ion-pair non-aqueous capillary electrophoresis2007In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1141, p. 287-294Article in journal (Refereed)
    Abstract [en]

    1S,4R-(+)-ketopinic acid [(+)-KPA] has been introduced as a chiral selector for the separation of pharmacologically active amines by non-aqueouscapillary electrophoresis (NACE). (+)-KPA gave enantioresolution for most of the compounds previously separated by 2R,3S,4R,5S-(−)-2,3:4,6-di-O-isopropylidene-2-keto-l-gulonic acid [(−)-DIKGA], but with a reversed migration order. A complete enantioresolution (Rs = 4.2) was obtainedfor timolol, a compound that could not be resolved using (−)-DIKGA as the selector. Thus, (+)-KPA was evaluated for the enantiomeric puritydetermination of S-timolol. A method based on pre-concentration by transient isotachophoresis (tITP) provided a limit of detection (LOD) of0.2% R-timolol in S-timolol samples. Because of the lack of enantioresolution of ephedrine when (+)-KPA was used as the selector, a methodwith (−)-DIKGA has been developed and validated for determination of the enantiomeric purity of the 1R,2S enantiomer. The method gave goodprecision and accuracy with an LOD (S/N = 3) of 0.033% for the enantiomeric impurity 1S,2R-ephedrine.

  • 91.
    Hedeland, Ylva
    et al.
    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.
    Chiral Separations in Nonaqueous Media2010In: Chiral Separations by Capillary Electrophoresis / [ed] Ann van Eeckhaut, Yvette Michotte, Boca Raton: CRC Press, 2010, 1.uppl., p. 271-312Chapter in book (Other academic)
  • 92.
    Hedeland, Ylva
    et al.
    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.
    HPLC In Chiral Pharmaceutical Analysis2011In: Handbook of HPLC / [ed] Danilo Corradini, Boca Raton: CRC Press, 2011, 2nd ed., p. 507-534Chapter in book (Other academic)
  • 93.
    Heiene, Reidun
    et al.
    University of Utrecht.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Neusüß, Christian
    Aalen University.
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Carbamylated hemoglobin project AKI vs CKD- or the magnitude of the chronic component2016Conference paper (Refereed)
  • 94.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Ylva
    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.
    Chiral separation by non-aqueous capillary electrophoresis using the partial filling technique2011Conference paper (Other academic)
  • 95.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Ylva
    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.
    Electroosmotic markers2012Conference paper (Refereed)
  • 96.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Ylva
    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.
    Electroosmotic markers2012Conference paper (Refereed)
  • 97.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Ylva
    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.
    Evaluation of electro-osmotic markers in aqueous and non-aqueous capillary electrophoresis2013Conference paper (Refereed)
  • 98.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Ylva
    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.
    Evaluation of electroosmotic markers in aqueous and nonaqueous capillary electrophoresis2013In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 34, no 24, p. 3252-3259Article in journal (Refereed)
    Abstract [en]

    The most common method to determine the EOF in CE is to measure the migration time for a neutral marker. In this study, 12 compounds (three novel and some previously used) were investigated as EOF markers in aqueous and nonaqueous BGEs. In the aqueous buffer systems (ammonium acetate, sodium phosphate, and sodium borate) the evaluation included a wide pH range (2-12). Two BGEs contained chiral selectors (sulphated-β-CD, (-)-diketogulonic acid) and one that contained a micellar agent (SDS) were included in the study. The majority of the evaluated compounds were found to migrate with the EOF in the water-based BGEs and are thus useful as EOF markers. However, in the SDS-based BGE only four of the compounds (acetone, acrylamide, DMSO, and ethanol) were found to be applicable. In the nonaqueous BGEs 11 markers (acetone, acetophenone, acrylamide, anthracene, benzene, 4-(4-methoxybenzylamino)-7-nitro-2,1,3-benzoxadiazole, benzyl alcohol, 2,5-diphenyloxazole, ethanol, flavone, and mesityl oxide) seemed to be functional as EOF markers. Even though several of the evaluated compounds can be used as EOF markers in the investigated BGEs, the authors would recommend the use of acrylamide as a general marker for UV detection. Furthermore, the four fluorescent markers (of which three were novel) gave RSD values equal to the other markers and can be used for the determination of the EOF in CE or microchip CE with fluorescence detection.

  • 99.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Heiene, Reidun
    Norwegian School of Veterinary Science.
    Croubles, Siska
    Ghent University.
    De Baere, Siegrid
    Ghent University.
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Development of a capillary electrophoretic method for determination of plasma clearance of iohexol in dogs and cats2013Conference paper (Refereed)
  • 100.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Heiene, Reidun
    De Baere, Siegrid
    Croubels, Siska
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Development of a capillary electrophoretic method for determination of plasma clearance of iohexol in dogs and cats2015In: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 29, no 4, p. 504-513Article in journal (Refereed)
    Abstract [en]

    Renal function can be monitored by estimation of the glomerular filtration rate (GFR), for example, through measurement of the plasma clearance of a marker that is freely filtrated through the kidney without reabsorption. It has been proposed that iohexol is the most accurate marker for GFR determination in cats and dogs. However, there is a need for a validated capillary electrophoretic method that covers the concentration range for a full curve clearance estimate of iohexol. In the final method, the plasma samples were protein precipitated and the supernatant was analyzed in a background electrolyte containing borate buffer (0.06 m, pH 10.0). The method developed was proved to be linear (concentration range 18- 2900 mg/L) and had a good precision (e.g. 2.3-2.9% at 88 mg/L) and accuracy (e.g. 101-105% at 88 mg/L). Finally, the method was compared with a previously published and validated HPLC-UV method by parallel analysis of clinical plasma samples from dogs and cats administered Omnipaque®. This comparison showed excellent agreement between the two methods and no proportional or systematic error was observed. The proposed method is simple and has a low cost per sample, which makes it applicable for routine analysis.

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