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Erngren, I., Haglöf, J., Engskog, M. K., Nestor, M., Hedeland, M., Arvidsson, T. & Pettersson, C. (2019). Adduct formation in electrospray ionisation-mass spectrometry with hydrophilic interaction liquid chromatography is strongly affected by the inorganic ion concentration of the samples. Journal of Chromatography A, 1600, 174-182
Open this publication in new window or tab >>Adduct formation in electrospray ionisation-mass spectrometry with hydrophilic interaction liquid chromatography is strongly affected by the inorganic ion concentration of the samples
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2019 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1600, p. 174-182Article in journal (Refereed) Published
Abstract [en]

Hydrophilic interaction liquid chromatography (HILIC)/electrospray ionisation-mass spectrometry (ESI-MS) has gained interest for the analysis of polar analytes in bioanalytical applications in recent years. However, ESI-MS is prone to adduct formation of analytes. In contrast to reversed phase chromatography, small inorganic ions have retention in HILIC, i.e. analytes and inorganic ions may co-elute, which could influence the adduct formation. In the present paper, it was demonstrated that the co-elution of sodium ions or potassium ions and analytes in HILIC/ESI-MS affect the adduct formation and that different concentrations of sodium ions and potassium ions in biological samples could have an impact on the quantitative response of the respective adducts as well as the quantitative response of the protonated adduct. The co-elution also lead to cluster formation of analytes and sodium formate or potassium formate, causing extremely complicated spectra. In analytical applications using HILIC/ESI-MS where internal standards are rarely used or not properly matched, great care needs to be taken to ensure minimal variation of inorganic ion concentration between samples. Moreover, the use of alkali metal ion adducts as quantitative target ions in relative quantitative applications should be made with caution if proper internal standards are not used.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2019
Keywords
Adduct formation, Hydrophilic interaction liquid chromatography, Mass spectrometry, Screening, Metabolomics, Cluster formation
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-390383 (URN)10.1016/j.chroma.2019.04.049 (DOI)000472687800021 ()31047661 (PubMedID)
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Balgoma, D., Pettersson, C. & Hedeland, M. (2019). Common Fatty Markers in Diseases with Dysregulated Lipogenesis. Trends in endocrinology and metabolism, 30(5), 283-285
Open this publication in new window or tab >>Common Fatty Markers in Diseases with Dysregulated Lipogenesis
2019 (English)In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 30, no 5, p. 283-285Article in journal, Editorial material (Other academic) Published
Abstract [en]

Recent studies have reported the upregulation of a subgroup of triacylglycerides as markers of different diseases with dysregulated lipogenesis, which means that these markers are not selective. This observation has a deep impact on their use as diagnostic tools in clinical practice (e.g., markers of risk of type 2 diabetes).

Place, publisher, year, edition, pages
ELSEVIER SCIENCE LONDON, 2019
National Category
Endocrinology and Diabetes Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-383044 (URN)10.1016/j.tem.2019.02.008 (DOI)000465043400001 ()30926249 (PubMedID)
Available from: 2019-05-13 Created: 2019-05-13 Last updated: 2019-05-13Bibliographically approved
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
Henrohn, D., Björkstrand, K., Lundberg, J. O., Granstam, S.-O., Baron, T., Ingimarsdóttir, I. J., . . . Wikström, G. (2018). 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.. Journal of Cardiac Failure, 24(10), 640-653
Open this publication in new window or tab >>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.
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2018 (English)In: Journal of Cardiac Failure, ISSN 1071-9164, E-ISSN 1532-8414, Vol. 24, no 10, p. 640-653Article in journal (Refereed) Published
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.

Keywords
Pulmonary arterial hypertension, beetroot juice, nitrate, nitric oxide, nitrite
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-366975 (URN)10.1016/j.cardfail.2018.09.010 (DOI)000452812400004 ()30244181 (PubMedID)
Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2019-04-17Bibliographically 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
Roos, C., Dahlgren, D., Sjögren, E., Sjöblom, M., Hedeland, M. & Lennernäs, H. (2018). Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.. European journal of pharmaceutics and biopharmaceutics, 132, 222-230, Article ID S0939-6411(18)30760-4.
Open this publication in new window or tab >>Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.
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2018 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, p. 222-230, article id S0939-6411(18)30760-4Article in journal (Refereed) Published
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.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-363157 (URN)10.1016/j.ejpb.2018.09.022 (DOI)000449127600022 ()30266667 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-013
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2019-01-07Bibliographically approved
Haglind, A., Hedeland, M., Arvidsson, T. & Pettersson, C. E. (2018). Major signal suppression from metal ion clusters in SFC/ESI-MS: Cause and Effects. Journal of chromatography. B, 1084, 96-105
Open this publication in new window or tab >>Major signal suppression from metal ion clusters in SFC/ESI-MS: Cause and Effects
2018 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1084, p. 96-105Article in journal (Refereed) 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.

Keywords
SFC-MS, matrix effect, alkali metal, ion cluster, Supercritical fluid chromatography, ESI
National Category
Analytical Chemistry
Research subject
Analytical Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-345978 (URN)10.1016/j.jchromb.2018.03.024 (DOI)000430524400012 ()29579734 (PubMedID)
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-06-26Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-8962-2815

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