uu.seUppsala universitets publikasjoner
Endre søk
Begrens søket
1 - 14 of 14
RefereraExporteraLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Treff pr side
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Forfatter A-Ø
  • Forfatter Ø-A
  • Tittel A-Ø
  • Tittel Ø-A
  • Type publikasjon A-Ø
  • Type publikasjon Ø-A
  • Eldste først
  • Nyeste først
  • Skapad (Eldste først)
  • Skapad (Nyeste først)
  • Senast uppdaterad (Eldste først)
  • Senast uppdaterad (Nyeste først)
  • Disputationsdatum (tidligste først)
  • Disputationsdatum (siste først)
  • Standard (Relevans)
  • Forfatter A-Ø
  • Forfatter Ø-A
  • Tittel A-Ø
  • Tittel Ø-A
  • Type publikasjon A-Ø
  • Type publikasjon Ø-A
  • Eldste først
  • Nyeste først
  • Skapad (Eldste først)
  • Skapad (Nyeste først)
  • Senast uppdaterad (Eldste først)
  • Senast uppdaterad (Nyeste først)
  • Disputationsdatum (tidligste først)
  • Disputationsdatum (siste først)
Merk
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 1.
    Elmsjö, Albert
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Haglöf, Jakob
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Engskog, Mikael K R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Erngren, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Arvidsson, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Method selectivity evaluation using the co-feature ratio in LC/MS metabolomics: Comparison of HILIC stationary phase performance for the analysis of plasma, urine and cell extracts.2018Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1568, s. 49-56Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Evaluation of the chromatographic separation in metabolomics studies has primarily been done using preselected sets of standards or by counting the number of detected features. An alternative approach is to calculate each feature's co-feature ratio, which is a combined selectivity measurement for the separation (i.e. extent of co-elution) and the MS-signal (i.e. adduct formation and in-source fragmentation). The aim of this study was to demonstrate how the selectivity of different HILIC stationary phases can be evaluated using the co-feature ratio approach. The study was based on three sample types; plasma, urine and cell extracts. Samples were analyzed on an UHPLC-ESI-Q-ToF system using an amide, a bare silica and a sulfobetaine stationary phase. For each feature, a co-feature ratio was calculated and used for multivariate analysis of the selectivity differences between the three stationary phases. Unsupervised PCA models indicated that the co-feature ratios were highly dependent on type of stationary phase. For several metabolites a 15-30 fold difference in the co-feature ratio were observed between the stationary phases. Observed selectivity differences related primarily to the retention patterns of unwanted matrix components such as inorganic salts (detected as salt clusters), glycerophospholipids, and polyethylene glycols. These matrix components affected the signal intensity of co-eluting metabolites by interfering with the ionization efficiency and/or their adduct formation. Furthermore, the retention pattern of these matrix components had huge influence on the number of detected features. The co-feature ratio approach has successfully been applied for evaluation of the selectivity performance of three HILIC stationary phases. The co-feature ratio could therefore be used in metabolomics for developing selective methods fit for their purpose, thereby avoiding generic analytical approaches, which are often biased, as type and amount of interfering matrix components are metabolome dependent.

  • 2.
    Garg, Neeraj
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Kemisk biologi för biomarkörer. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hansson, Annelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Nat Vet Inst SVA, Dept Chem Environm & Feed Hyg, SE-75189 Uppsala, Sweden..
    Knych, Heather K.
    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 D.
    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..
    Thevis, Mario
    German Sport Univ Cologne, Inst Biochem, D-50933 Cologne, Germany.;German Sport Univ Cologne, Ctr Prevent Doping Res, D-50933 Cologne, Germany..
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Nat Vet Inst SVA, Dept Chem Environm & Feed Hyg, SE-75189 Uppsala, Sweden..
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Nat Vet Inst SVA, Dept Chem Environm & Feed Hyg, SE-75189 Uppsala, Sweden..
    Globisch, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Kemisk biologi för biomarkörer. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Structural elucidation of major selective androgen receptor modulator (SARM) metabolites for doping control2018Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 16, nr 5, s. 698-702Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Selective androgen receptor modulators (SARMs) are a class of androgen receptor drugs, which have a high potential to be performance enhancers in human and animal sports. Arylpropionamides are one of the major SARM classes and get rapidly metabolized significantly complicating simple detection of misconduct in blood or urine sample analysis. Specific drug-derived metabolites are required as references due to a short half-life of the parent compound but are generally lacking. The difficulty in metabolism studies is the determination of the correct regio and stereoselectivity during metabolic conversion processes. In this study, we have elucidated and verified the chemical structure of two major equine arylpropionamide-based SARM metabolites using a combination of chemical synthesis and liquid chromatography- mass spectrometry (LC-MS) analysis. These synthesized SARM-derived metabolites can readily be utilized as reference standards for routine mass spectrometry-based doping control analysis of at least three commonly used performance-enhancing drugs to unambigously identify misconduct.

  • 3.
    Haglind, Alfred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Determination of the Environmental Fate of Drug Substances and the Matrix Effects of Complex Samples in SFC/ESI-MS2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Awareness of the potential problems caused by drug compounds in the environment has increased over the last decade, both among researchers and with the public. This thesis describes the development of analytical methods and their application to wetlands constructed for purification of wastewater from e.g. drug compounds. Different wetlands were investigated using microcosm-models, to determine their biodegradation. An enantioselective and sensitive SFC/ESI-QqQ method was developed and validated for the enantiomeric separation of atenolol, metoprolol, propranolol and metoprolol acid. It was applied measuring the enantiomeric fraction of the compounds in three different microcosm-models. The same microcosms were also used to investigate the transformation products formed in these wetlands. In this work, LC/ESI-QToF was used to identify the transformation products using standard references, the original compounds or analogs, comparing their accurate mass and product ions. One not previously observed major transformation product identified from propranolol were 1-naphthol. Several minor transformation products were also identified, showing how diverse the formation might be in wetlands.

    A second part compares the matrix effect of ESI/MS using SFC and reversed phase LC, utilizing general screening methods for drug compounds in plasma, horse urine and influent/effluent wastewater. These matrices are known to suffer from matrix effects when using the ESI-source, and if SFC would suffer less than LC it could be a great benefit. The matrix profiles showed that this is likely not the case: although SFC was affected by different interferences then LC. One example is the formation of clusters causing major ion suppression. This unique SFC-phenomenon was investigated further, showing that metal ions were separated and eluted at different retention times, forming clusters in the ion source between metal ions and the organic modifier and/or make-up solvent.

    In conclusion, the first part of this thesis describes analytical methods for determination of drug compounds in the environment, using LC and SFC, connected to both high and low resolving MS. The second part focuses on fundamental analytical chemistry, comparing the matrix effects of SFC/ESI-MS with LC/ESI-MS, and investigates the cluster phenomena observed for samples containing alkali ions and an organic modifier in the mobile phase in SFC/ESI-MS.

    Delarbeid
    1. Rapid chiral separation of atenolol, metoprolol, propranolol and the zwitterionic metoprolol acid using supercritical fluid chromatography-tandem mass spectrometry - Application to wetland microcosms
    Åpne denne publikasjonen i ny fane eller vindu >>Rapid chiral separation of atenolol, metoprolol, propranolol and the zwitterionic metoprolol acid using supercritical fluid chromatography-tandem mass spectrometry - Application to wetland microcosms
    Vise andre…
    2015 (engelsk)Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1409, s. 251-258Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A method for enantiomeric separation of the three beta-blocking agents atenolol, metoprolol, propranolol and the zwitterionic metoprolol acid, a major metabolite of both metoprolol and in environmental matrices also atenolol, has been developed. By use of supercritical fluid chromatography and the polysaccharide-based Chiralpak (R) IB-3, all four compounds were simultaneously enantiomerically separated (R-s >1.5) within 8 min. Detection was performed using tandem mass spectrometry, and to avoid isobaric interference between the co-eluting metoprolol and metoprolol acid, the achiral column Acquity (R) UPC2 BEH 2-EP was attached ahead of to the chiral column. Carbon dioxide with 18% methanol containing 0.5% (v/v) of the additives trifluoroacetic acid and ammonia in a 2:1 molar ratio were used as mobile phase. A post column make-up flow (0.3 mL/min) of methanol containing 0.1% (v/v) formic acid was used to enhance the positive electrospray ionization. Detection was carried out using a triple quadrupole mass spectrometer operating in the selected reaction monitoring mode, using one transition per analyte and internal standard. The method was successfully applied for monitoring the enantiomeric fraction change over time in a laboratory scale wetland degradation study. It showed good precision, recovery, sensitivity and low effect of the sample matrix.

    Emneord
    Enantiomeric separation, SFC-MS, Metoprolol acid, Wetland microcosm, Chiralpak IB-3, UPC2
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-262417 (URN)10.1016/j.chroma.2015.07.075 (DOI)000359882600029 ()26228849 (PubMedID)
    Tilgjengelig fra: 2015-09-18 Laget: 2015-09-15 Sist oppdatert: 2018-03-15bibliografisk kontrollert
    2. Identification of transformation products from -blocking agents formed in wetland microcosms using LC-Q-ToF
    Åpne denne publikasjonen i ny fane eller vindu >>Identification of transformation products from -blocking agents formed in wetland microcosms using LC-Q-ToF
    Vise andre…
    2016 (engelsk)Inngår i: Journal of Mass Spectrometry, ISSN 1076-5174, E-ISSN 1096-9888, Vol. 51, nr 3, s. 207-218Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Identification of degradation products from trace organic compounds, which may retain the biological activity of the parent compound, is an important step in understanding the long-term effects of these compounds on the environment. Constructed wetlands have been successfully utilized to remove contaminants from wastewater effluent, including pharmacologically active compounds. However, relatively little is known about the transformation products formed during wetland treatment. In this study, three different wetland microcosm treatments were used to determine the biotransformation products of the -adrenoreceptor antagonists atenolol, metoprolol and propranolol. LC/ESI-Q-ToF run in the MSE and MS/MS modes was used to identify and characterize the degradation products through the accurate masses of precursor and product ions. The results were compared with those of a reference standard when available. Several compounds not previously described as biotransformation products produced in wetlands were identified, including propranolol-O-sulfate, 1-naphthol and the human metabolite N-deaminated metoprolol. Transformation pathways were significantly affected by microcosm conditions and differed between compounds, despite the compounds' structural similarities. Altogether, a diverse range of transformation products in wetland microcosms were identified and elucidated using high resolving MS. This work shows that transformation products are not always easily predicted, nor formed via the same pathways even for structurally similar compounds.

    Emneord
    HRMS, wetland microcosms, transformation products, identification, LC-QToF, metoprolol, atenolol, propranolol
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-283784 (URN)10.1002/jms.3737 (DOI)000372280300003 ()26956388 (PubMedID)
    Tilgjengelig fra: 2016-04-14 Laget: 2016-04-14 Sist oppdatert: 2018-03-15bibliografisk kontrollert
    3. The differences in matrix effect between supercritical fluid chromatography and reversed phase liquid chromatography coupled to ESI/MS
    Åpne denne publikasjonen i ny fane eller vindu >>The differences in matrix effect between supercritical fluid chromatography and reversed phase liquid chromatography coupled to ESI/MS
    2018 (engelsk)Inngår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 1000, s. 163-171Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    For many sample matrices, matrix effects are a troublesome phenomenon using the electrospray ionization source. The increasing use of supercritical fluid chromatography with CO2 in combination with the electrospray ionization source for MS detection is therefore raising questions: is the matrix effect behaving differently using SFC in comparison with reversed phase LC? This was investigated using urine, plasma, influent-and effluent-wastewater as sample matrices. The matrix effect was evaluated using the post-extraction addition method and through post-column infusions. Matrix effect profiles generated from the post-column infusions in combination with time of flight-MS detection provided the most valuable information for the study. The combination of both qualitative and semi-quantitative information with the ability to use HRMS-data for identifying interfering compounds from the same experiment was very useful, and has to the authors' knowledge not been used this way before. The results showed that both LC and SFC are affected by matrix effects, however differently depending on sample matrix. Generally, both suppressions and enhancements were seen, with a higher amount of enhancements for LC, where 65% of all compounds and all sample matrices were enhanced, compared to only 7% for SFC. Several interferences were tentatively identified, with phospholipids, creatinine, and metal ion clusters as examples of important interferences, with different impact depending on chromatographic technique. SFC needs a different strategy for limiting matrix interferences, owing to its almost reverse retention order compared to RPLC.

    sted, utgiver, år, opplag, sider
    ELSEVIER SCIENCE BV, 2018
    Emneord
    Matrix effects, Supercritical fluid chromatography, Electrospray ionization, Liquid chromatography, Ion enhancement, Ion suppression
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-338947 (URN)10.1016/j.aca.2017.10.014 (DOI)000418832900015 ()29289305 (PubMedID)
    Tilgjengelig fra: 2018-01-25 Laget: 2018-01-25 Sist oppdatert: 2018-03-15bibliografisk kontrollert
    4. Major signal suppression from metal ion clusters in SFC/ESI-MS: Cause and Effects
    Åpne denne publikasjonen i ny fane eller vindu >>Major signal suppression from metal ion clusters in SFC/ESI-MS: Cause and Effects
    2018 (engelsk)Inngår i: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1084, s. 96-105Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The widening application area of SFC-MS with polar analytes and water-containing samples facilitates the use of quick and simple sample preparation techniques such as “dilute and shoot” and protein precipitation. This has also introduced new polar interfering components such as alkali metal ions naturally abundant in e.g. blood plasma and urine, which have shown to be retained using screening conditions in SFC/ESI-TOF-MS and causing areas of major ion suppression. Analytes co-eluting with these clusters will have a decreased signal intensity, which might have a major effect on both quantification and identification. When investigating the composition of the alkali metal clusters using accurate mass and isotopic pattern, it could be concluded that they were previously not described in the literature. Using NaCl and KCl standards and different chromatographic conditions, varying e.g. column and modifier, the clusters proved to be formed from the alkali metal ions in combination with the alcohol modifier and make-up solvent. Their compositions were [(XOCH3)n+X]+, [(XOH)n+X]+, [(X2CO3)n+X]+ and [(XOOCOCH3)n+X]+ for X= Na+ or K+ in ESI+. In ESI-, the clusters depended more on modifier, with [(XCl)n+Cl]- and [(XOCH3)n+OCH3]- mainly formed in pure methanol and [(XOOCH)n+OOCH]- when 20 mM NH4Fa was added.

    To prevent the formation of the clusters by avoiding methanol as modifier might be difficult, as this is a widely used modifier providing good solubility when analyzing polar compounds in SFC. A sample preparation with e.g. LLE would remove the alkali ions, however also introducing a time consuming and discriminating step into the method. Since the alkali metal ions were retained and affected by chromatographic adjustments as e.g. mobile phase modifications, a way to avoid them could therefore be chromatographic tuning, when analyzing samples containing them.

    Emneord
    SFC-MS, matrix effect, alkali metal, ion cluster, Supercritical fluid chromatography, ESI
    HSV kategori
    Forskningsprogram
    Analytisk farmaceutisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-345978 (URN)10.1016/j.jchromb.2018.03.024 (DOI)000430524400012 ()29579734 (PubMedID)
    Tilgjengelig fra: 2018-03-13 Laget: 2018-03-13 Sist oppdatert: 2018-06-26bibliografisk kontrollert
  • 4.
    Hansson, Annelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Structural Determination of Drug Metabolites from Doping Classed Compounds Using Mass Spectrometry2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Doping control in equine sports is important for a fair competition, but also to ensure the integrity of the betting system, as well as for animal welfare reasons. To detect the use of illicit compounds, screening for the parent compound is common. However, by using a metabolite as the analytical target instead, the detection time can be prolonged. For some compounds, the use of a metabolite is a necessity since the parent drug may not be detected at all.

    The metabolites of the selective androgen receptor modulators (SARM) S1, S4 and S22 were investigated in horse urine and plasma. The unchanged parent compounds had the longest detection time in plasma, but were not detected at all in urine. Instead, the longest detection time was measured for the metabolites 2-amino-5-nitro-4-(trifluoromethyl)phenyl hydrogen sulfate (SARMs S1 and S4) and 2-amino-5-cyano-4-(trifluoromethyl)phenyl hydrogen sulfate (SARM S22). These metabolites were thus suggested as analytical targets for doping control in urine while the parent compounds were suggested for plasma samples. 2-amino-5-nitro-4-(trifluoromethyl)phenyl hydrogen sulfate could also be produced in large quantities by the fungus Cunninghamella elegans to potentially be used as reference compound.

    The horse metabolites of the SARM LGD-4033 were also studied in urine and plasma. The formate adduct of LGD-4033 had the longest detection time in plasma and in urine after hydrolysis with β-glucuronidase. In non-hydrolyzed urine, the glucuronidated LGD-4033 was detected instead.

    Different in vitro models were used to predict in vivo metabolites of roxadustat, a hypoxia-inducible factor stabilizer. Cunninghamella elegans was successful in producing more metabolites compared to human and equine liver microsomes and human hepatocytes.

    The metabolite detection and identification in all experiments were accomplished using a UHPLC-Q-TOF MS instrument, where the high-resolution MS data was vital in determining which metabolites were formed.

    The thesis shows the benefits of investigating the metabolites of doping substances to allow for a successful doping control method in horse urine and plasma by prolonging the detection time. It also highlights the usefulness of Cunninghamella elegans as an alternative to the more commonly used in vitro models for both predicting and producing metabolites.

    Delarbeid
    1. Characterization of equine urinary metabolites of selective androgen receptor modulators (SARMs) S1, S4 and S22 for doping control purposes
    Åpne denne publikasjonen i ny fane eller vindu >>Characterization of equine urinary metabolites of selective androgen receptor modulators (SARMs) S1, S4 and S22 for doping control purposes
    Vise andre…
    2015 (engelsk)Inngår i: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 7, nr 8, s. 673-683Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    Emneord
    selective androgen receptor modulators, SARM, metabolite, equine, horse
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-261969 (URN)10.1002/dta.1768 (DOI)000359603700003 ()25560998 (PubMedID)
    Tilgjengelig fra: 2015-09-08 Laget: 2015-09-07 Sist oppdatert: 2018-03-14bibliografisk kontrollert
    2. Investigation of the selective androgen receptor modulators S1, S4 and S22 and their metabolites in equine plasma using high-resolution mass spectrometry
    Åpne denne publikasjonen i ny fane eller vindu >>Investigation of the selective androgen receptor modulators S1, S4 and S22 and their metabolites in equine plasma using high-resolution mass spectrometry
    Vise andre…
    2016 (engelsk)Inngår i: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 30, nr 7, s. 833-842Artikkel i tidsskrift (Fagfellevurdert) Published
    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. 

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-286622 (URN)10.1002/rcm.7512 (DOI)000372508100006 ()26969924 (PubMedID)
    Tilgjengelig fra: 2016-04-28 Laget: 2016-04-21 Sist oppdatert: 2018-03-14bibliografisk kontrollert
    3. Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.
    Åpne denne publikasjonen i ny fane eller vindu >>Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.
    Vise andre…
    2018 (engelsk)Inngår i: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1074-1075, s. 91-98Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    LGD-4033 has been found in human doping control samples and has the potential for illicit use in racehorses as well. It belongs to the pharmacological class of selective androgen receptor modulators (SARMs) and can stimulate muscle growth, much like anabolic steroids. However, SARMs have shown superior side effect profiles compared to anabolic steroids, which arguably makes them attractive for use by individuals seeking an unfair advantage over their competitors. The purpose of this study was to investigate the metabolites formed from LGD-4033 in the horse in order to find suitable analytical targets for doping controls. LGD-4033 was administered to three horses after which plasma and urine samples were collected and analyzed for metabolites using ultra high performance liquid chromatography coupled to a high resolution mass spectrometer. In horse urine, eight metabolites, both phase I and phase II, were observed most of which had not been described in other metabolic systems. Six of these were also detected in plasma. The parent compound was detected in plasma, but not in non-hydrolyzed urine. The longest detection times were observed for unchanged LGD-4033 in plasma and in urine hydrolyzed with β-glucuronidase and is thus suggested as the analytical target for doping control in the horse. The metabolite profile determined in the horse samples was also compared to those of human urine and fungal incubate from Cunninghamella elegans. The main human metabolite, dihydroxylated LGD-4033, was detected in the horse samples and was also produced by the fungus. However, it was a not a major metabolite for horse and fungus, which highlights the importance of performing metabolism studies in the species of interest.

    Emneord
    Doping, LGD-4033, Horse, Mass Spectrometry, Metabolite, SARM, Selective Androgen Receptor Modulator
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-344303 (URN)10.1016/j.jchromb.2017.12.010 (DOI)000425204900013 ()29334634 (PubMedID)
    Tilgjengelig fra: 2018-03-06 Laget: 2018-03-06 Sist oppdatert: 2018-05-07bibliografisk kontrollert
    4. 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 spectrometry
    Åpne denne publikasjonen i ny fane eller vindu >>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 spectrometry
    Vise andre…
    2017 (engelsk)Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 134, s. 228-236Artikkel i tidsskrift (Fagfellevurdert) Published
    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.

    Emneord
    FG-4592, Drug metabolism, High resolution mass spectrometry
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-317588 (URN)10.1016/j.jpba.2016.11.041 (DOI)000392909900029 ()27918992 (PubMedID)
    Tilgjengelig fra: 2017-03-24 Laget: 2017-03-24 Sist oppdatert: 2018-03-14bibliografisk kontrollert
  • 5.
    Hansson, Annelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Knych, Heather
    Stanley, Scott
    Berndtson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, SE-75651 Uppsala, Sweden.
    Jackson, Liora
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, SE-75651 Uppsala, Sweden.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, SE-75651 Uppsala, Sweden.
    Thevis, Mario
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, SE-75651 Uppsala, Sweden.
    Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.2018Inngår i: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1074-1075, s. 91-98Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    LGD-4033 has been found in human doping control samples and has the potential for illicit use in racehorses as well. It belongs to the pharmacological class of selective androgen receptor modulators (SARMs) and can stimulate muscle growth, much like anabolic steroids. However, SARMs have shown superior side effect profiles compared to anabolic steroids, which arguably makes them attractive for use by individuals seeking an unfair advantage over their competitors. The purpose of this study was to investigate the metabolites formed from LGD-4033 in the horse in order to find suitable analytical targets for doping controls. LGD-4033 was administered to three horses after which plasma and urine samples were collected and analyzed for metabolites using ultra high performance liquid chromatography coupled to a high resolution mass spectrometer. In horse urine, eight metabolites, both phase I and phase II, were observed most of which had not been described in other metabolic systems. Six of these were also detected in plasma. The parent compound was detected in plasma, but not in non-hydrolyzed urine. The longest detection times were observed for unchanged LGD-4033 in plasma and in urine hydrolyzed with β-glucuronidase and is thus suggested as the analytical target for doping control in the horse. The metabolite profile determined in the horse samples was also compared to those of human urine and fungal incubate from Cunninghamella elegans. The main human metabolite, dihydroxylated LGD-4033, was detected in the horse samples and was also produced by the fungus. However, it was a not a major metabolite for horse and fungus, which highlights the importance of performing metabolism studies in the species of interest.

  • 6.
    Henrohn, Dan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Björkstrand, Kristoffer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Lundberg, Jon O
    Granstam, Sven-Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Baron, Tomasz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingimarsdóttir, Inga J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hedenström, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Malinovschi, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Wernroth, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Jansson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Wikström, Gerhard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Effects of Oral Supplementation With Nitrate-Rich Beetroot Juice in Patients With Pulmonary Arterial Hypertension-Results From BEET-PAH, an Exploratory Randomized, Double-Blind, Placebo-Controlled, Crossover Study.2018Inngår i: Journal of Cardiac Failure, ISSN 1071-9164, E-ISSN 1532-8414, Vol. 24, nr 10, s. 640-653Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The nitrate-nitrite-nitric oxide (NO) pathway may represent a potential therapeutic target in patients with pulmonary arterial hypertension (PAH). We explored the effects of dietary nitrate supplementation, with the use of nitrate-rich beetroot juice (BRJ), in patients with PAH.

    METHODS AND RESULTS: We prospectively studied 15 patients with PAH in an exploratory randomized, double-blind, placebo-controlled, crossover trial. The patients received nitrate-rich beetroot juice (∼16 mmol nitrate per day) and placebo in 2 treatment periods of 7 days each. The assessments included; exhaled NO and NO flow-independent parameters (alveolar NO and bronchial NO flux), plasma and salivary nitrate and nitrite, biomarkers and metabolites of the NO-system, N-terminal pro-B-type natriuretic peptide, echocardiography, ergospirometry, diffusing capacity of the lung for carbon monoxide, and the 6-minute walk test. Compared with placebo ingestion of BRJ resulted in increases in; fractional exhaled NO at all flow-rates, alveolar NO concentrations and bronchial NO flux, and plasma and salivary levels of nitrate and nitrite. Plasma ornithine levels decreased and indices of relative arginine availability increased after BRJ compared to placebo. A decrease in breathing frequency was observed during ergospirometry after BRJ. A tendency for an improvement in right ventricular function was observed after ingestion of BRJ. In addition a tendency for an increase in the peak power output to peak oxygen consumption ratio (W peak/VO2 peak) was observed, which became significant in patients reaching an increase of plasma nitrite >30% (responders).

    CONCLUSIONS: BRJ administered for 1 week increases pulmonary NO production and the relative arginine bioavailability in patients with PAH, compared with placebo. An increase in the W peak/VO2 peak ratio was observed after BRJ ingestion in plasma nitrite responders. These findings indicate that supplementation with inorganic nitrate increase NO synthase-independent NO production from the nitrate-nitrite-NO pathway.

  • 7.
    Lundgren, Jakob
    et al.
    Lund Univ, Dept Clin Sci Lund, Cardiol, Lund, Sweden; Skåne Univ Hosp, Sect Heart Failure & Valvular Dis, Hemodynam Lab, Heart & Lung Clin, Lund, Sweden.
    Sandqvist, Anna
    Umeå Univ, Dept Pharmacol & Clin Neurosci, Clin Pharmacol, Umeå, Sweden.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Natl Vet Inst (SVA), Dept Chem Environm & Feed Hyg, Uppsala, Sweden.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Natl Vet Inst (SVA), Dept Chem Environm & Feed Hyg, Uppsala, Sweden.
    Wikström, Gerhard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Rådegran, Göran
    Lund Univ, Dept Clin Sci Lund, Cardiol, Lund, Sweden; Skåne Univ Hosp, Sect Heart Failure & Valvular Dis, Hemodynam Lab, Heart & Lung Clin, Lund, Sweden.
    Alterations in plasma L-arginine and methylarginines in heart failure and after heart transplantation2018Inngår i: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 52, nr 4, s. 196-204Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Endothelial function, including the nitric oxide (NO)-pathway, has previously been extensively investigated in heart failure (HF). In contrast, studies are lacking on the NO pathway after heart transplantation (HT). We therefore investigated substances in the NO pathway prior to and after HT in relation to hemodynamic parameters.

    Design: 12 patients (median age 50.0 yrs, 2 females), heart transplanted between June 2012 and February 2014, evaluated at our hemodynamic lab, at rest, prior to HT, as well as four weeks and six months after HT were included. All patients had normal left ventricular function post-operatively and none had post-operative pulmonary hypertension or acute cellular rejection requiring therapy at the evaluations. Plasma concentrations of ADMA, SDMA, L-Arginine, L-Ornithine and L-Citrulline were analyzed at each evaluation.

    Results: In comparison to controls, the plasma L-Arginine concentration was low and ADMA high in HF patients, resulting in low L-Arginine/ADMA-ratio pre-HT. Already four weeks after HT L-Arginine was normalized whereas ADMA remained high. Consequently the L-Arginine/ADMA-ratio improved, but did not normalize. The biomarkers remained unchanged at the six-month evaluation and the L-Arginine/ADMA-ratio correlated inversely to pulmonary vascular resistance (PVR) six months post-HT.

    Conclusions: Plasma L-Arginine concentrations normalize after HT. However, as ADMA is unchanged, the L-Arginine/ADMA-ratio remained low and correlated inversely to PVR. Together these findings suggest that (i) the L-Arginine/ADMA-ratio may be an indicator of pulmonary vascular tone after HT, and that (ii) NO-dependent endothelial function is partly restored after HT. Considering the good postoperative outcome, the biomarker levels may be considered “normal” after HT.

  • 8. Paul, Prasanta
    et al.
    Sänger - van de Griend, Cari
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Kantisto BV, Calenburglaan, Netherlands.
    Adams, Erwin
    Van Schepdael, Ann
    A simple, low-cost and robust capillary zone electrophoresis method with capacitively coupled contactless conductivity detection for the routine determination of four selected penicillins in money-constrained laboratories.2018Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 39, nr 20, s. 2521-2529Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A simple and robust capillary zone electrophoresis method was developed and validated for the determination of amoxicillin and clavulanate, ampicillin, phenoxymethyl penicillin (Pen V) as well as flucloxacillin. Capacitively coupled contactless conductivity detection was employed as detection mode that makes CE a simple and economic tool for money-constrained laboratories. The developed method is straightforward and user-friendly. It offers good sensitivity and sufficient selectivity for the routine assay of the selected penicillins. The repeatabilities were <1.9% RSD for relative peak areas and <1% RSD for migration times for all the analytes. The method showed good linearity (R2  > 0.995) within the 80-120% range of the target concentration (0.5 mg/mL) for each antibiotic. The accuracy of the method, evaluated by standard fortification at three levels, was good for all the analytes. An extended robustness study was performed by varying ±10% of the optimum value of TRIS concentration, l-histidine concentration and temperature in a full factorial design at two levels. This was to evaluate larger than usual variability of factors on the assay value, in order to better cover potential global variance in lab conditions and equipment. Finally, the method was applied for the determination of percent (%) content of all antibiotics in available formulations.

  • 9.
    Paul, Prasanta
    et al.
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N2, PB 923,Herestr 49, B-3000 Leuven, Belgium..
    Sänger - van de Griend, Cari
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Kantisto BV, Callenburglaan 22, NL-3742 MV Baarn, Netherlands..
    Adams, Erwin
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N2, PB 923,Herestr 49, B-3000 Leuven, Belgium..
    Van Schepdael, Ann
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N2, PB 923,Herestr 49, B-3000 Leuven, Belgium..
    Recent advances in the capillary electrophoresis analysis of antibiotics with capacitively coupled contactless conductivity detection2018Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 158, s. 405-415Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    This review describes briefly the high rate of counterfeiting of antimicrobial drugs with focus upon its immediate health consequences. The major part of this review encompasses accounts of the improvements achieved in the domain of miniaturization of capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-(CD)-D-4). The application of this principle into the development of portable devices as well as its application to counter the health-system-crippling phenomenon of counterfeit antibiotic formulations, are discussed in the context of developing countries. 

  • 10.
    Roos, Carl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dahlgren, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjöblom, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditionsInngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pharmaceutical industry, prescribers, and patients have all traditionally preferred oral administration of drug products. In recent years there has been an increase in drug candidates with low solubility and/or low permeability, which may limit the use of oral administration. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed, with the aim of increasing the fraction of dose absorbed. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulphate. For the poorly permeating compounds enalaprilat and atenolol, the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen, the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol was not affected by any of the excipients. The changes in magnitude in the compounds’ absorptions were in general smaller in FeSSIF than in FaSSIF, possibly due to differences in colloidal structures present in FeSSIF that made the AMEs less available. The results in FeSSIF were similar to those from bolus-dosing in rat, which further suggests that the effect of AMEs on permeability is strongly affected by interactions between AMEs and colloidal structures in the intestinal lumen. The results suggest that, when investigating the effects of AMEs, the biorelevance of the SPIP method can be increased by the addition of intraluminal constituents to the perfusate.

  • 11.
    Roos, Carl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dahlgren, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjöblom, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.2018Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, s. 222-230, artikkel-id S0939-6411(18)30760-4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The number of highly lipophilic active pharmaceutical ingredients (APIs) in pharmaceutical development has been constantly increasing over recent decades. These APIs often have inherent issues with solubility and dissolution, limiting their oral bioavailability. Traditionally, a reduction in particle size to the micrometer range has been used to improve dissolution. More recently, size reduction to the nanometer range has been introduced, which further increases the dissolution rate, but may also involve other mechanisms for increasing bioavailability. The effect of particle size on the absorption of aprepitant was investigated using the single-pass intestinal perfusion (SPIP) model in the rat jejunum. Phosphate buffer, fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) were used as perfusion media to increase understanding of the processes involved and the effects of colloidal structures. The role of mucus on intestinal absorption was investigated by adding the mucolytic agent N-acetyl-cysteine (NAC). The absorption of aprepitant from the nanosuspensions was similar with all perfusion media (buffer = FaSSIF = FeSSIF), whereas food had a pronounced effect on absorption from the microsuspensions (FeSSIF > FaSSIF > buffer). The colloidal structures hence contributed to absorption from the microsuspensions. Partitioning of aprepitant from the nanosuspension into the colloidal structures decreased the amount of nanoparticles available, which offset the effect of food. The appearance flux of aprepitant in blood was non-significantly decreased for nanosuspensions of aprepitant with NAC versus without NAC in buffer (ratio of 2:1), indicating that particle deposition in the mucus may have been decreased as the layer thinned, with subsequently reduced intestinal absorption. The study also showed that the SPIP model is suitable for investigating detailed absorption mechanisms using complex perfusion media, which increase the biorelevance of the model.

  • 12.
    Sandqvist, Anna
    et al.
    Umea Univ, Clin Pharmacol, Dept Pharmacol & Clin Neurosci, S-90187 Umea, Sweden..
    Schneede, Jörn
    Umea Univ, Clin Pharmacol, Dept Pharmacol & Clin Neurosci, S-90187 Umea, Sweden..
    Kylhammar, David
    Lund Univ, Dept Clin Sci Lund, Cardiol, Lund, Sweden.;Skane Univ Hosp, Sect Heart Failure & Valvular Dis, Lund, Sweden..
    Henrohn, D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Lundgren, Jakob
    Lund Univ, Dept Clin Sci Lund, Cardiol, Lund, Sweden.;Skane Univ Hosp, Sect Heart Failure & Valvular Dis, Lund, Sweden..
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Natl Vet Inst SVA, Dept Chem, Uppsala, Sweden..
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Natl Vet Inst SVA, Dept Chem, Uppsala, Sweden..
    Rådegran, Göran
    Lund Univ, Dept Clin Sci Lund, Cardiol, Lund, Sweden.;Skane Univ Hosp, Sect Heart Failure & Valvular Dis, Lund, Sweden..
    Wikström, Gerhard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala Univ, Dept Med Sci, Cardiol, Uppsala, Sweden..
    Plasma l-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction2018Inngår i: Heart and Vessels, ISSN 0910-8327, E-ISSN 1615-2573, Vol. 33, nr 3, s. 255-263Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from l-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, l-arginine, l-ornithine, and l-citrulline were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma levels of ADMA and SDMA were higher, whereas l-arginine and l-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of l-arginine than patients with LVSD (p < 0.05). l-Arginine correlated to 6 min walking distance (6MWD) (r (s) = 0.58, p = 0.006) and l-arginine/ADMA correlated to WHO functional class (r (s) = -0.46, p = 0.043) in PAH. In conclusion, l-arginine levels were significantly lower in treatment na < ve PAH patients compared to patients with LVSD. Furthermore, l-arginine correlated with 6MWD in PAH. l-arginine may provide useful information in differentiating PAH from LVSD.

  • 13.
    van Tricht, Ewoud
    et al.
    Janssen Vaccines & Prevent Pharmaceut & Analyt De, Newtonweg 1, NL-2333 CP Leiden, Netherlands.
    de Raadt, Pascal
    Janssen Vaccines & Prevent Pharmaceut & Analyt De, Newtonweg 1, NL-2333 CP Leiden, Netherlands.
    Verwilligen, Annemiek
    Janssen Vaccines & Prevent Pharmaceut & Analyt De, Newtonweg 1, NL-2333 CP Leiden, Netherlands.
    Schenning, Martijn
    Janssen Vaccines & Prevent Pharmaceut & Analyt De, Newtonweg 1, NL-2333 CP Leiden, Netherlands.
    Backus, Harold
    Janssen Vaccines & Prevent Pharmaceut & Analyt De, Newtonweg 1, NL-2333 CP Leiden, Netherlands.
    Germano, Marta
    Janssen Vaccines & Prevent Pharmaceut & Analyt De, Newtonweg 1, NL-2333 CP Leiden, Netherlands.
    Somsen, Govert W.
    Vrije Univ Amsterdam, Div Biomol Anal, Amsterdam Inst Mol Med & Syst, Boelelaan 1083, NL-1081 HV Amsterdam, Netherlands.
    Sänger - van de Griend, Cari
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap. Kantisto BV, Callenburglaan 22, NL-3742 MV Baarn, Netherlands.
    Fast, selective and quantitative protein profiling of adenovirus-vector based vaccines by ultra-performance liquid chromatography2018Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1581-1582, s. 25-32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A method for the quantitative determination of the protein composition of adenovirus-vector based vaccines was developed. The final method used RP-UPLC with UV absorbance detection, a C4 column (300 angstrom, 1.7 mu m, 2.1 x 150 mm), and a water- acetonitrile (ACN) gradient containing trifluoroacetic acid (TFA) as ion-pairing agent. The chromatographic resolution between the various adenovirus proteins was optimized by studying the effect of the TFA concentration and the column temperature, applying a full factorial design of experiments. A reproducible baseline separation of all relevant adenovirus proteins could be achieved within 17 min run time. Samples containing adenovirus particles could be directly injected into the UPLC system without sample pretreatment. The viruses reproducibly dissociate into proteins in the UPLC system upon contact with the mobile phase containing ACN. The new RP-UPLC method was successfully validated for protein profiling and relative quantification of proteins in vaccine products based on adenovirus vector types 26 and 35. The intermediate precision of the relative peak areas of all proteins was between 1% and 14% RSD, except for the peak assigned to protein V (26% RSD). The method proved to be stability indicating with respect to thermal and oxidation stress of the adenovirus-vector based vaccine and was successfully implemented for the characterization of adenovirus-based products.

  • 14.
    Yao, Han
    et al.
    Univ Ghent, Dept Pharmaceut Anal, Fac Pharmaceut Sci, Drug Qual & Registrat DruQuaR Grp, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
    Vandenbossche, Jana
    Univ Ghent, Dept Pharmaceut Anal, Fac Pharmaceut Sci, Drug Qual & Registrat DruQuaR Grp, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
    Sänger - van de Griend, Cari
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Janssens, Yorick
    Univ Ghent, Dept Pharmaceut Anal, Fac Pharmaceut Sci, Drug Qual & Registrat DruQuaR Grp, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
    Fernandez, Cristina Soto
    Univ Ghent, Dept Pharmaceut Anal, Fac Pharmaceut Sci, Drug Qual & Registrat DruQuaR Grp, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
    Xu, Xiaolong
    Univ Ghent, Dept Pharmaceut Anal, Fac Pharmaceut Sci, Drug Qual & Registrat DruQuaR Grp, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
    Wynendaele, Evelien
    Univ Ghent, Dept Pharmaceut Anal, Fac Pharmaceut Sci, Drug Qual & Registrat DruQuaR Grp, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
    Somsen, Govert Willem
    Vrije Univ Amsterdam, AIMMS Res Grp BioMol Anal, Div BioAnalyt Chem, De Boelelaan 1085, NL-1081 HV Amsterdam, Netherlands.
    Haselberg, Rob
    Vrije Univ Amsterdam, AIMMS Res Grp BioMol Anal, Div BioAnalyt Chem, De Boelelaan 1085, NL-1081 HV Amsterdam, Netherlands.
    De Spiegeleer, Bart
    Univ Ghent, Dept Pharmaceut Anal, Fac Pharmaceut Sci, Drug Qual & Registrat DruQuaR Grp, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
    Development of a capillary zone electrophoresis method to quantify E. coli L-asparaginase and its acidic variants2018Inngår i: Talanta: The International Journal of Pure and Applied Analytical Chemistry, ISSN 0039-9140, E-ISSN 1873-3573, Vol. 182, s. 83-91Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A capillary zone electrophoresis (CZE) method with UV detection was developed for the quantification of the E.coli L-asparaginase (L-ASNase) and its acidic variants. During the initial method development, a variety of experimental conditions were screened. Subsequently, a Design of Experiments (DoE) was used to optimize the pH and concentration of the selected background electrolyte (BGE) containing both TRIS and boric acid. Optimization was performed taking into account both the separation efficiency of L-ASNase and its acidic variants as well as overall method robustness. A repeatable separation between E.coli L-ASNase and its acidic variants was achieved on a bare fused silica capillary in combination with a BGE consisting of both 400 mM TRIS and boric acid. The method was validated for linearity, accuracy, precision, LOD, LOQ and robustness. The recovery for L-ASNase was 97.9-104.4% with a precision RSD of 1.5-3.2%, while the recovery of impurities was 92.1-109.8% with a RSD of 1.7-4.6%. The quantification limit was 1.9% (m/m). Moreover, the CZE-UV method was applied to determine the degradation rate in the presence of ammonium bicarbonate, confirming the suitability of the method. The degraded, partially charged L-ASNase was evaluated for its in-vitro enzymatic activity showing an insignificant different enzyme activity compared to the unmodified sample.

1 - 14 of 14
RefereraExporteraLink til resultatlisten
Permanent link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf