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Balgoma, D., Zelleroth, S., Grönbladh, A., Hallberg, M., Pettersson, C. & Hedeland, M. (2020). Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver. Metabolomics, 16(1), Article ID 12.
Open this publication in new window or tab >>Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver
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2020 (English)In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 16, no 1, article id 12Article in journal (Refereed) Published
Abstract [en]

Introduction: The abuse of anabolic androgenic steroids (AASs) is a source of public concern because of their adverse effects. Supratherapeutic doses of AASs are known to be hepatotoxic and regulate the lipoproteins in plasma by modifying the metabolism of lipids in the liver, which is associated with metabolic diseases. However, the effect of AASs on the profile of lipids in plasma is unknown.

Objectives: To describe the changes in the plasma lipidome exerted by AASs and to discuss these changes in the light of previous research about AASs and de novo lipogenesis in the liver.

Methods: We treated male Wistar rats with supratherapeutic doses of nandrolone decanoate and testosterone undecanoate. Subsequently, we isolated the blood plasma and performed lipidomics analysis by liquid chromatography-high resolution mass spectrometry.

Results: Lipid profiling revealed a decrease of sphingolipids and glycerolipids with palmitic, palmitoleic, stearic, and oleic acids. In addition, lipid profiling revealed an increase in free fatty acids and glycerophospholipids with odd-numbered chain fatty acids and/or arachidonic acid.

Conclusion: The lipid profile presented herein reports the imprint of AASs on the plasma lipidome, which mirrors the downregulation of de novo lipogenesis in the liver. In a broader perspective, this profile will help to understand the influence of androgens on the lipid metabolism in future studies of diseases with dysregulated lipogenesis (e.g. type 2 diabetes, fatty liver disease, and hepatocellular carcinoma).

Place, publisher, year, edition, pages
SPRINGER, 2020
Keywords
Androgens, Androgen receptor, Estrogen receptors, Lipidomics, Liver X receptors
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-407500 (URN)10.1007/s11306-019-1632-0 (DOI)000516536100002 ()31925559 (PubMedID)
Available from: 2020-03-26 Created: 2020-03-26 Last updated: 2020-03-26Bibliographically approved
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
Pirttilä, K., Pierre, P. V., Haglöf, J., Engskog, M., Hedeland, M., Laurell, G., . . . Pettersson, C. (2019). An LCMS-based untargeted metabolomics protocol for cochlear perilymph: highlighting metabolic effects of hydrogen gas on the inner ear of noise exposed Guinea pigs. Metabolomics, 15(10), Article ID 138.
Open this publication in new window or tab >>An LCMS-based untargeted metabolomics protocol for cochlear perilymph: highlighting metabolic effects of hydrogen gas on the inner ear of noise exposed Guinea pigs
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2019 (English)In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 15, no 10, article id 138Article in journal (Refereed) Published
Abstract [en]

Introduction

Noise-induced hearing loss (NIHL) is an increasing problem in society and accounts for a third of all cases of acquired hearing loss. NIHL is caused by formation of reactive oxygen species (ROS) in the cochlea causing oxidative stress. Hydrogen gas (H-2) can alleviate the damage caused by oxidative stress and can be easily administered through inhalation.

Objectives

To present a protocol for untargeted metabolomics of guinea pig perilymph and investigate the effect of H-2 administration on the perilymph metabolome of noise exposed guinea pigs.

Methods

The left ear of guinea pigs were exposed to hazardous impulse noise only (Noise, n = 10), noise and H-2 (Noise + H2, n = 10), only H-2 (H2, n = 4), or untreated (Control, n = 2). Scala tympani perilymph was sampled from the cochlea of both ears. The polar component of the perilymph metabolome was analyzed using a HILIC-UHPLC-Q-TOF-MS-based untargeted metabolomics protocol. Multivariate data analysis (MVDA) was performed separately for the exposed- and unexposed ear.

Results

MVDA allowed separation of groups Noise and Noise + H2 in both the exposed and unexposed ear and yielded 15 metabolites with differentiating relative abundances. Seven were found in both exposed and unexposed ear data and included two osmoprotectants. Eight metabolites were unique to the unexposed ear and included a number of short-chain acylcarnitines.

Conclusions

A HILIC-UHPLC-Q-TOF-MS-based protocol for untargeted metabolomics of perilymph is presented and shown to be fit-for-purpose. We found a clear difference in the perilymph metabolome of noise exposed guinea pigs with and without H-2 treatment.

Keywords
Metabolomics, NIHL, In vivo, Noise-induced hearing loss, LCMS, Perilymph
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-396660 (URN)10.1007/s11306-019-1595-1 (DOI)000488961300002 ()31587113 (PubMedID)
Available from: 2019-11-12 Created: 2019-11-12 Last updated: 2019-11-12Bibliographically 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 (Refereed) 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: 2020-01-31Bibliographically 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
Roos, C., Dahlgren, D., Sjögren, E., Sjöblom, M., Hedeland, M. & Lennernäs, H. (2019). Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions. European journal of pharmaceutics and biopharmaceutics, 142, 387-395
Open this publication in new window or tab >>Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions
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2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 387-395Article in journal (Refereed) Published
Abstract [en]

Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396543 (URN)10.1016/j.ejpb.2019.07.012 (DOI)000488654000040 ()31306752 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Lindell Jonsson, E., Erngren, I., Engskog, M., Haglöf, J., Arvidsson, T., Hedeland, M., . . . Nestor, M. (2019). Exploring Radiation Response in Two Head and Neck Squamous Carcinoma Cell Lines Through Metabolic Profiling. Frontiers in Oncology, 9, Article ID 825.
Open this publication in new window or tab >>Exploring Radiation Response in Two Head and Neck Squamous Carcinoma Cell Lines Through Metabolic Profiling
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2019 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, article id 825Article in journal (Refereed) Published
Abstract [en]

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common form of cancer worldwide. Radiotherapy, with or without surgery, represents the major approach to curative treatment. However, not all tumors are equally sensitive to irradiation. It is therefore of interest to apply newer system biology approaches (e.g., metabolic profiling) in squamous cancer cells with different radiosensitivities in order to provide new insights on the mechanisms of radiation response. In this study, two cultured HNSCC cell lines from the same donor, UM-SCC-74A and UM-SCC-74B, were first genotyped using Short Tandem Repeat (STR), and assessed for radiation response by the means of clonogenic survival and growth inhibition assays. Thereafter, cells were cultured, irradiated and collected for subsequent metabolic profiling analyses using liquid chromatography-mass spectrometry (LC-MS). STR verified the similarity of UM-SCC-74A and UM-SCC-74B cells, and three independent assays proved UM-SCC-74B to be clearly more radioresistant than UM-SCC-74A. The LC-MS metabolic profiling demonstrated significant differences in the intracellular metabolome of the two cell lines before irradiation, as well as significant alterations after irradiation. The most important differences between the two cell lines before irradiation were connected to nicotinic acid and nicotinamide metabolism and purine metabolism. In the more radiosensitive UM-SCC-74A cells, the most significant alterations after irradiation were linked to tryptophan metabolism. In the more radioresistant UM-SCC-74B cells, the major alterations after irradiation were connected to nicotinic acid and nicotinamide metabolism, purine metabolism, the methionine cycle as well as the serine, and glycine metabolism. The data suggest that the more radioresistant cell line UM-SCC-74B altered the metabolism to control redox-status, manage DNA-repair, and change DNA methylation after irradiation. This provides new insights on the mechanisms of radiation response, which may aid future identification of biomarkers associated with radioresistance of cancer cells.

Keywords
radioresistance, radiosensitivity, metabolomics, mass spectrometry, redox status
National Category
Otorhinolaryngology Pharmaceutical Sciences Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-393266 (URN)10.3389/fonc.2019.00825 (DOI)000483315200001 ()31544064 (PubMedID)
Funder
Swedish Cancer Society, CAN 2018/494Swedish Cancer Society, CAN 2015/1080Swedish Cancer Society, CAN 2015/385Swedish Research Council, 201330876-104113-30
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2019-09-18 Created: 2019-09-18 Last updated: 2019-12-09Bibliographically approved
Stenholm, Å., Hedeland, M., Arvidsson, T. & Pettersson, C. E. (2019). Removal of diclofenac from a non-sterile aqueous system using Trametes versicolor with an emphasis on adsorption and biodegradation mechanisms. Environmental technology, 40(19), 2460-2472
Open this publication in new window or tab >>Removal of diclofenac from a non-sterile aqueous system using Trametes versicolor with an emphasis on adsorption and biodegradation mechanisms
2019 (English)In: Environmental technology, ISSN 0959-3330, E-ISSN 1479-487X, Vol. 40, no 19, p. 2460-2472Article in journal (Refereed) Published
Abstract [en]

This paper describes the search for procedures through which the xenobiotic pollutant diclofenac can be removed from non-sterile aquatic systems. Specifically, adsorption to solid supports (carriers) in combination with biodegradation by non-immobilized and immobilized white rot fungus Trametes versicolor were investigated. Batch experiments using polyurethane foam (PUF)-carriers resulted in 99.9% diclofenac removal after 4 h, with monolayer adsorption of diclofenac to carrier and glass surfaces accounting for most of the diclofenac decrease. Enzymatic reactions contributed less, accounting for approximately < 0.5% of this decrease. In bioreactor experiments using PUF-carriers, an initial 100% removal was achieved with biodegradation contributing approximately 7%. In batch experiments that utilized polyethylene-carriers with negligible immobilization of Trametes versicolor, a 98% total diclofenac removal was achieved after one week, with a biodegradation contribution of approximately 14%. Five novel enzyme-catalyzed biodegradation products were tentatively identified in the batch-wise and bioreactor experiments using full scan ultra-high-performance liquid chromatography-quadrupole/time of flight mass spectrometry. Both reduction and oxidation products were found, with the contents estimated to be at µg L-1 concentration levels.

Keywords
Diclofenac, UHPLC-Q-TOF MS, adsorption, biodegradation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-401666 (URN)10.1080/09593330.2018.1444098 (DOI)000501810600001 ()29464996 (PubMedID)
Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-01-17Bibliographically 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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8962-2815

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