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Bondesson, Ulf
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Publications (10 of 84) Show all publications
Ekstrand, C., Bondesson, U., Giving, E., Hedeland, M., Ingvast-Larsson, C., Jacobsen, S., . . . Ranheim, B. (2019). Disposition and effect of intra-articularly administered dexamethasone on lipopolysaccharide induced equine synovitis. Acta Veterinaria Scandinavica, 61, Article ID 28.
Open this publication in new window or tab >>Disposition and effect of intra-articularly administered dexamethasone on lipopolysaccharide induced equine synovitis
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2019 (English)In: Acta Veterinaria Scandinavica, ISSN 1751-0147, E-ISSN 1751-0147, Vol. 61, article id 28Article in journal (Refereed) Published
Abstract [en]

Background: Dexamethasone is used for the intra-articular route of administration in management of aseptic arthritis in horses. Despite its widespread use there is very little quantitative data of the disposition and response to dexamethasone. The aim of this study was to investigate and describe the synovial fluid and plasma dexamethasone concentration over time and to explore the relation between synovial fluid concentration and response using clinical endpoints as response biomarkers after IA injection of dexamethasone disodium salt solution in an equine model of synovitis.

Results: Inflammation was induced in the radiocarpal joint of six horses by injection of 2ng lipopolysaccharide (LPS). Two hours later either saline or dexamethasone was injected in the same joint in a two treatment cross over design. Each horse was treated once with one of the six doses dexamethasone used (0.01, 0.03, 0.1, 0.3, 1 or 3mg) and once with saline. Dexamethasone was quantified by means of UHPLC-MS/MS. Dexamethasone disposition was characterised by means of a non-linear mixed effects model. Lameness was evaluated both objectively with an inertial sensor based system and subjectively scored using a numerical scale (0-5). Joint circumference, skin temperature over the joint and rectal temperature were also recorded. The LPS-challenge induced lameness in all horses with high inter-individual variability. Dexamethasone significantly decreased lameness compared with saline. Other variables were not statistically significant different between treatments. Objective lameness scoring was the most sensitive method used in this study to evaluate the lameness response. A pharmacokinetic/pharmacodynamic model was successfully fitted to experimental dexamethasone and lameness data. The model allowed characterization of the dexamethasone synovial fluid concentration-time course, the systemic exposure to dexamethasone after intra-articular administration and the concentration-response relation in an experimental model of synovitis.

Conclusions: The quantitative data improve the understanding of the pharmacology of dexamethasone and might serve as input for future experiments and possibly contribute to maintain integrity of equine sports.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Corticosteroids, Pharmacokinetics, Pharmacodynamics, Quantitative pharmacology
National Category
Clinical Science
Identifiers
urn:nbn:se:uu:diva-390093 (URN)10.1186/s13028-019-0464-2 (DOI)000472470900001 ()31221173 (PubMedID)
Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-08-05Bibliographically approved
Lundgren, J., Sandqvist, A., Hedeland, M., Bondesson, U., Wikström, G. & Rådegran, G. (2018). Alterations in plasma L-arginine and methylarginines in heart failure and after heart transplantation. Scandinavian Cardiovascular Journal, 52(4), 196-204
Open this publication in new window or tab >>Alterations in plasma L-arginine and methylarginines in heart failure and after heart transplantation
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2018 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 52, no 4, p. 196-204Article in journal (Refereed) Published
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.

Keywords
Nitric Oxide, ADMA, L-Arginine, heart transplantation, heart failure, right heart catheterization
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-358210 (URN)10.1080/14017431.2018.1459823 (DOI)000436583700005 ()29648475 (PubMedID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2018-09-20Bibliographically approved
Ekstrand, C., Ingvast-Larsson, C., Bondesson, U., Hedeland, M. & Olsen, L. (2018). Cetirizine per os: exposure and antihistamine effect in the dog. Acta Veterinaria Scandinavica, 60, Article ID 77.
Open this publication in new window or tab >>Cetirizine per os: exposure and antihistamine effect in the dog
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2018 (English)In: Acta Veterinaria Scandinavica, ISSN 1751-0147, E-ISSN 1751-0147, Vol. 60, article id 77Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
BMC, 2018
Keywords
Anti-inflammatory, Efficacy, Pharmacodynamics, Pharmacokinetics, Potency
National Category
Medical Bioscience
Identifiers
urn:nbn:se:uu:diva-372332 (URN)10.1186/s13028-018-0431-3 (DOI)000451251500001 ()30477556 (PubMedID)
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Akhter, T., Wikström, G., Larsson, M., Bondesson, U., Hedeland, M. & Naessén, T. (2018). Dimethylarginines correlate to common carotid artery wall layer dimensions and cardiovascular risk factors in pregnant women with and without preeclampsia. Paper presented at 86th Congress of the European-Atherosclerosis-Society (EAS), MAY 05-08, 2018, Lisbon, PORTUGAL. Atherosclerosis, 275, E69-E70
Open this publication in new window or tab >>Dimethylarginines correlate to common carotid artery wall layer dimensions and cardiovascular risk factors in pregnant women with and without preeclampsia
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2018 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 275, p. E69-E70Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2018
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-367146 (URN)10.1016/j.atherosclerosis.2018.06.192 (DOI)000442512600206 ()
Conference
86th Congress of the European-Atherosclerosis-Society (EAS), MAY 05-08, 2018, Lisbon, PORTUGAL
Available from: 2018-11-28 Created: 2018-11-28 Last updated: 2018-11-28Bibliographically approved
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
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