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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: 2019-01-16Bibliographically 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
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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8962-2815

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