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Disposition and effect of intra-articularly administered dexamethasone on lipopolysaccharide induced equine synovitis
Swedish Univ Agr Sci, Fac Vet Med & Anim Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7058, S-75007 Uppsala, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden. (Analytisk farmaceutisk kemi)
Romerike Hesteklin, Riisveien 75, N-2007 Kjeller, Norway.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden. (Analytisk farmaceutisk kemi)ORCID iD: 0000-0001-8962-2815
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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. Vol. 61, article id 28
Keywords [en]
Corticosteroids, Pharmacokinetics, Pharmacodynamics, Quantitative pharmacology
National Category
Clinical Science
Identifiers
URN: urn:nbn:se:uu:diva-390093DOI: 10.1186/s13028-019-0464-2ISI: 000472470900001PubMedID: 31221173OAI: oai:DiVA.org:uu-390093DiVA, id: diva2:1340355
Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-08-05Bibliographically approved

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