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Bondesson, Ulf
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Publications (10 of 80) Show all publications
Hansson, A., Knych, H., Stanley, S., Berndtson, E., Jackson, L., Bondesson, U., . . . Hedeland, M. (2018). Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.. Journal of chromatography. B, 1074-1075, 91-98
Open this publication in new window or tab >>Equine in vivo-derived metabolites of the SARM LGD-4033 and comparison with human and fungal metabolites.
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2018 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1074-1075, p. 91-98Article in journal (Refereed) 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.

Keywords
Doping, LGD-4033, Horse, Mass Spectrometry, Metabolite, SARM, Selective Androgen Receptor Modulator
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-344303 (URN)10.1016/j.jchromb.2017.12.010 (DOI)000425204900013 ()29334634 (PubMedID)
Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-05-07Bibliographically approved
Sandqvist, A., Schneede, J., Kylhammar, D., Henrohn, D., Lundgren, J., Hedeland, M., . . . Wikström, G. (2018). Plasma l-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction. Heart and Vessels, 33(3), 255-263
Open this publication in new window or tab >>Plasma l-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction
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2018 (English)In: Heart and Vessels, ISSN 0910-8327, E-ISSN 1615-2573, Vol. 33, no 3, p. 255-263Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
Pulmonary arterial hypertension, Left heart failure, Systolic dysfunction, L-Arginine, Dimethylarginines
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-350494 (URN)10.1007/s00380-017-1055-7 (DOI)000426278900005 ()28975394 (PubMedID)
Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2018-05-09Bibliographically approved
Dubbelboer, I. R., Lilienberg, E., Karalli, A., Axelsson, R., Brismar, T. B., Ebeling Barbier, C., . . . Lennernäs, H. (2018). Reply to "Comment on 'In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma'". Molecular Pharmaceutics, 15(1), 336-340
Open this publication in new window or tab >>Reply to "Comment on 'In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma'"
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 1, p. 336-340Article in journal (Refereed) Published
Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Lipiodol, doxorubicin, drug-eluting beads, hepatocelluar carcinoma, image-guided transarterial tumor therapy, interventional radiology, liver cancer, local therapy, transarterial chemoembolization (TACE)
National Category
Pharmacology and Toxicology Pharmaceutical Sciences Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-335507 (URN)10.1021/acs.molpharmaceut.7b00840 (DOI)000419419800033 ()29185767 (PubMedID)
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2018-05-04Bibliographically approved
Garg, N., Hansson, A., Knych, H. K., Stanley, S. D., Thevis, M., Bondesson, U., . . . Globisch, D. (2018). Structural elucidation of major selective androgen receptor modulator (SARM) metabolites for doping control. Organic and biomolecular chemistry, 16(5), 698-702
Open this publication in new window or tab >>Structural elucidation of major selective androgen receptor modulator (SARM) metabolites for doping control
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2018 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 16, no 5, p. 698-702Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2018
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-345712 (URN)10.1039/c7ob03030d (DOI)000423787600004 ()29319101 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-03-14 Created: 2018-03-14 Last updated: 2018-03-14Bibliographically approved
Hansson, A., Thevis, M., Cox, H., Miller, G., Eichner, D., Bondesson, U. & Hedeland, M. (2017). 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. Journal of Pharmaceutical and Biomedical Analysis, 134, 228-236
Open this publication in new window or tab >>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
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2017 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 134, p. 228-236Article in journal (Refereed) 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.

Keywords
FG-4592, Drug metabolism, High resolution mass spectrometry
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317588 (URN)10.1016/j.jpba.2016.11.041 (DOI)000392909900029 ()27918992 (PubMedID)
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2018-03-14Bibliographically approved
Knych, H. K., Stanley, S. D., McKemie, D. S., Arthur, R. M., Bondesson, U., Hedeland, M., . . . Kass, P. H. (2017). Pharmacokinetics and pharmacodynamics of meldonium in exercised thoroughbred horses. Drug Testing and Analysis, 9(9), 1392-1399
Open this publication in new window or tab >>Pharmacokinetics and pharmacodynamics of meldonium in exercised thoroughbred horses
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2017 (English)In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 9, no 9, p. 1392-1399Article in journal (Refereed) Published
Abstract [en]

Although developed as a therapeutic medication, meldonium has found widespread use in human sports and was recently added to the World Anti-Doping Agency's list of prohibited substances. Its reported abuse potential in human sports has led to concern by regulatory authorities about the possible misuse of meldonium in equine athletics. The potential abuse in equine athletes along with the limited data available regarding the pharmacokinetics and pharmacodynamics of meldonium in horses necessitates further study. Eight exercised adult thoroughbred horses received a single oral dose of 3.5, 7.1, 14.3 or 21.4 mg/kg of meldonium. Blood and urine samples were collected and analyzed using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using non-compartmental analysis. Maximum serum concentrations ranged from 440.2 to 1147 ng/mL and the elimination half-life from 422 to 647.8 h. Serum concentrations were below the limit of quantitation by days 4, 7, 12 and 12 for doses of 3.5, 7.1, 14.3 and 21.4 mg/kg, respectively. Urine concentrations were below the limit of detection by day 44 following administration of 3.5 mg/kg and day 51 for all other dose groups. No adverse effects were observed following meldonium administration. While the group numbers were small, changes in heart rate were observed in the 3.5 mg/kg dose group (n = 1). Glucose concentrations changed significantly in all dose groups studied (n = 2 per dose group). Similar to that reported for humans, the detection time of meldonium in biological samples collected from horses is prolonged, which should allow for satisfactory regulation in performance horses. Copyright (C) 2017 John Wiley & Sons, Ltd.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
doping, horse, horse racing, LC-MS, meldonium, pharmacodynamics, pharmacokinetics
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-336486 (URN)10.1002/dta.2214 (DOI)000411747700012 ()28513092 (PubMedID)
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-01-13Bibliographically approved
Salomonsson, M. L., Bondesson, U. & Hedeland, M. (2017). Quantification of dimethylsulfoxide (DMSO) in equine plasma and urine using HILIC-MS/MS. Drug Testing and Analysis, 9(6), 935-941
Open this publication in new window or tab >>Quantification of dimethylsulfoxide (DMSO) in equine plasma and urine using HILIC-MS/MS
2017 (English)In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 9, no 6, p. 935-941Article in journal (Refereed) Published
Abstract [en]

This paper describes quantitative methods for the determination of dimethylsulfoxide (DMSO) in equine plasma and urine based on simple precipitation and dilution followed by hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry (HILIC-MS/MS). DMSO is a polar solvent with analgesic and anti-inflammatory properties. Its pharmacological features make it prohibited in horse racing. However, since DMSO is naturally present in the horses' environment, international threshold values have been implemented for plasma and urine (1 and 15 mu g/mL, respectively). Previously presented quantitative methods for the determination of DMSO are based on gas chromatography, thus demanding a tedious extraction step to transfer the analyte from the aqueous bodily fluid to an injectable organic solvent. The column used in the presented method was an Acquity BEH HILIC and the mobile phase was a mixture of ammonium acetate buffer and acetonitrile delivered as a gradient. Hexadeuterated DMSO (H-2(6)-DMSO) was used as the internal standard. Validation was performed in the range of the international thresholds concerning selectivity, carry-over, linearity, precision, accuracy, stability and inter-individual matrix variation. The results fulfilled the predefined criteria and the methods were considered fit for purpose. Successful applications on real equine doping control samples were carried out with determined DMSO concentrations exceeding the international thresholds.

Place, publisher, year, edition, pages
WILEY, 2017
Keywords
DMSO, HILIC, MS, horse urine, horse plasma, dimethylsulfoxide
National Category
Veterinary Science
Identifiers
urn:nbn:se:uu:diva-327452 (URN)10.1002/dta.2098 (DOI)000403226400011 ()
Available from: 2017-08-11 Created: 2017-08-11 Last updated: 2017-08-11Bibliographically approved
Ekstrand, C., Ingvast-Larsson, C., Olsen, L., Hedeland, M., Bondesson, U. & Gabrielsson, J. (2016). A quantitative approach to analysing cortisol response in the horse. Journal of Veterinary Pharmacology and Therapeutics, 39(3), 255-263
Open this publication in new window or tab >>A quantitative approach to analysing cortisol response in the horse
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2016 (English)In: Journal of Veterinary Pharmacology and Therapeutics, ISSN 0140-7783, E-ISSN 1365-2885, Vol. 39, no 3, p. 255-263Article in journal (Refereed) Published
Abstract [en]

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

National Category
Pharmacology and Toxicology Veterinary Science
Identifiers
urn:nbn:se:uu:diva-297103 (URN)10.1111/jvp.12276 (DOI)000374349500005 ()26542753 (PubMedID)
Available from: 2016-06-22 Created: 2016-06-21 Last updated: 2018-01-10Bibliographically approved
Hansson, A., Knych, H., Stanley, S., Thevis, M., Bondesson, U. & Hedeland, M. (2016). Investigation of the selective androgen receptor modulators S1, S4 and S22 and their metabolites in equine plasma using high-resolution mass spectrometry. Rapid Communications in Mass Spectrometry, 30(7), 833-842
Open this publication in new window or tab >>Investigation of the selective androgen receptor modulators S1, S4 and S22 and their metabolites in equine plasma using high-resolution mass spectrometry
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2016 (English)In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 30, no 7, p. 833-842Article in journal (Refereed) 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. 

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-286622 (URN)10.1002/rcm.7512 (DOI)000372508100006 ()26969924 (PubMedID)
Available from: 2016-04-28 Created: 2016-04-21 Last updated: 2018-03-14Bibliographically approved
Thevis, M., Machnik, M., Schenk, I., Krug, O., Piper, T., Schaenzer, W., . . . Hedeland, M. (2016). Nickel in equine sports drug testing - pilot study results on urinary nickel concentrations. Rapid Communications in Mass Spectrometry, 30(7), 982-984
Open this publication in new window or tab >>Nickel in equine sports drug testing - pilot study results on urinary nickel concentrations
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2016 (English)In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 30, no 7, p. 982-984Article in journal (Refereed) Published
Abstract [en]

RationaleThe issue of illicit performance enhancement spans human and animal sport in presumably equal measure, with prohibited substances and methods of doping conveying both ways. Due to the proven capability of unbound ionic cobalt (Co2+) to stimulate erythropoiesis in humans, both human and equine anti-doping regulations have listed cobalt as a banned substance, and in particular in horse drug testing, thresholds for cobalt concentrations applying to plasma and urine have been suggested or established. Recent reports about the finding of substantial amounts of undeclared nickel in arguably licit performance- and recovery-supporting products raised the question whether the ionic species of this transition metal (Ni2+), which exhibits similar prolyl hydroxylase inhibiting properties to Co2+, has been considered as a substitute for cobalt in doping regimens. MethodsTherefore, a pilot study with 200 routine post-competition doping control horse urine samples collected from animals participating in equestrian, gallop, and trotting in Europe was conducted to provide a first dataset on equine urinary Ni2+ concentrations. All specimens were analyzed by conventional inductively coupled plasma mass spectrometry (ICP-MS) to yield quantitative data for soluble nickel. ResultsConcentrations ranging from below the assay's limit of quantification (LOQ, 0.5 ng/mL) up to 33.4 ng/mL with a mean value ( standard deviation) of 6.1 (+/- 5.1) ng/mL were determined for the total nickel content. ConclusionsIn horses, nickel is considered a micronutrient and feed supplements containing nickel are available; hence, follow-up studies are deemed warranted to consolidate potential future threshold levels concerning urine and blood nickel concentrations in horses using larger sets of samples for both matrices and to provide in-depth insights by conducting elimination studies with soluble Ni2+-salt species.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-286623 (URN)10.1002/rcm.7528 (DOI)000372508100023 ()26969941 (PubMedID)
Available from: 2016-04-28 Created: 2016-04-21 Last updated: 2017-11-30Bibliographically approved
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