Plasma and synovial fluid concentration of doxycycline following low-dose, low-frequency administration, and resultant inhibition of matrix metalloproteinase-13 from interleukin-stimulated equine synoviocytes.
Abstract: To determine whether low-dose, low-frequency doxycycline administration is capable of achieving chondroprotective concentrations within synovial fluid (SF) while remaining below minimum inhibitory concentration 90 (MIC90 ) of most equine pathogens and would be an option in the management of osteoarthritis. Objective: To determine whether low-dose, low-frequency oral administration of doxycycline can attain in vivo SF concentrations capable of chondroprotective effects through reduction of matrix metalloproteinase (MMP)-13 activity, while remaining below MIC90 of most equine pathogens. Methods: Descriptive pharmacokinetic study with crossover design. Methods: Two groups of 6 horses received oral doxycycline. Plasma and SF doxycycline concentrations were measured using high performance liquid chromatography. Group 1 received 5 mg/kg bwt q. 24 h with 21 blood and 8 SF samples collected over 120 h; Group 2 received 5 mg/kg bwt q. 48 h with 27 blood and 11 SF samples collected over 192 h. Cultured synoviocytes were treated with interleukin-1α (1 ng/ml) for 24 h to stimulate MMP synthesis, and then SF was added to the culture medium for 96 h. MMP-13 protein and mRNA were measured in synoviocyte culture medium and synoviocytes, respectively. Results: Mean doxycycline concentration ≥0.043 μg/ml (previously demonstrated to inhibit MMP-13) was achieved in plasma by t = 0.25 h and SF by t = 48 h in Group 1, and in plasma by t = 0.17 h and SF by t = 1 h in Group 2. Synoviocyte culture medium containing doxycycline from Groups 1 and 2 had significantly decreased active MMP-13 protein concentration, and synoviocytes cultured in this medium had significantly decreased MMP-13 gene expression compared to controls. Plasma doxycycline concentration in both groups and SF doxycycline concentration in Group 2 demonstrated a cumulative effect. Conclusions: Low-dose orally administered doxycycline achieves SF concentrations in vivo capable of diminishing MMP-13 expression. This study supports the use of doxycycline as a disease modifying osteoarthritic drug.
© 2013 EVJ Ltd.
Publication Date: 2013-12-05 PubMed ID: 23855565DOI: 10.1111/evj.12139Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The study investigates the effects of low-dose, low-frequency doxycycline administration on synovial fluid concentrations and the resultant inhibition of matrix metalloproteinase-13 (MMP-13) in horses. It concludes that such treatments achieve synovial fluid concentrations that can reduce MMP-13 expression, suggesting the potential use of doxycycline as a disease modifying osteoarthritic drug.
Objective of the Research
The primary aim of this study was to test the effectiveness of low-dose, low-frequency doxycycline administration in achieving protective concentrations within the synovial fluid. This approach was intended to maintain levels below the minimum inhibitory concentration 90 (MIC90), preventing most equine pathogens from proliferating and potentially providing a strategy for managing osteoarthritis.
Research Methodology
- The study deployed a descriptive pharmacokinetic approach with a crossover design involving two groups of six horses.
- Each horse received an oral dose of doxycycline, and the concentrations in their plasma and synovial fluid were measured using high performance liquid chromatography.
- The first group received a dosage of 5 mg/kg of body weight every 24 hours, while the second group received the same dose every 48 hours.
- Samples from the first group were collected over 120 hours and those from the second group over 192 hours.
- Synoviocytes in-vitro were treated with an interleukin-1α stimulant for MMP synthesis, followed by adding synovial fluid to the culture medium for further observation.
Key Findings
- The results demonstrated that mean doxycycline concentration in plasma and synovial fluid, enough to inhibit MMP-13, was achieved faster in the second group.
- Reduced active MMP-13 protein concentration was found in the culture medium where doxycycline was present, indicating an inhibitory effect of the drug on MMP-13 production.
- Additionally, synoviocytes cultured in doxycycline-containing medium exhibited significant decrease in MMP-13 gene expression compared to the controls, further substantiating the inhibitory effect of the drug.
Conclusion
The study found that low-dose, orally administered doxycycline can achieve synovial fluid concentrations in-vivo capable of reducing MMP-13 expression. This suggests significant promise for the potential use of doxycycline as a drug that can modify the course of osteoarthritis. The evidence supports the continued investigation into doxycycline as a treatment option for osteoarthritis in equines.
Cite This Article
APA
Maher MC, Schnabel LV, Cross JA, Papich MG, Divers TJ, Fortier LA.
(2013).
Plasma and synovial fluid concentration of doxycycline following low-dose, low-frequency administration, and resultant inhibition of matrix metalloproteinase-13 from interleukin-stimulated equine synoviocytes.
Equine Vet J, 46(2), 198-202.
https://doi.org/10.1111/evj.12139 Publication
Researcher Affiliations
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, New York, USA.
MeSH Terms
- Animals
- Anti-Bacterial Agents / administration & dosage
- Anti-Bacterial Agents / chemistry
- Anti-Bacterial Agents / metabolism
- Anti-Bacterial Agents / pharmacokinetics
- Cells, Cultured
- Cross-Over Studies
- Dose-Response Relationship, Drug
- Doxycycline / administration & dosage
- Doxycycline / blood
- Doxycycline / chemistry
- Doxycycline / pharmacokinetics
- Drug Administration Schedule
- Gene Expression Regulation, Enzymologic / drug effects
- Horses
- Matrix Metalloproteinase 13 / genetics
- Matrix Metalloproteinase 13 / metabolism
- Matrix Metalloproteinase Inhibitors / administration & dosage
- Matrix Metalloproteinase Inhibitors / blood
- Matrix Metalloproteinase Inhibitors / chemistry
- Matrix Metalloproteinase Inhibitors / pharmacokinetics
- RNA, Messenger / genetics
- RNA, Messenger / metabolism
- Synovial Fluid / chemistry
- Synovial Membrane / cytology
Citations
This article has been cited 8 times.- Gilbertie JM, Schaer TP, Engiles JB, Seiler GS, Deddens BL, Schubert AG, Jacob ME, Stefanovski D, Ruthel G, Hickok NJ, Stowe DM, Frink A, Schnabel LV. A Platelet-Rich Plasma-Derived Biologic Clears Staphylococcus aureus Biofilms While Mitigating Cartilage Degeneration and Joint Inflammation in a Clinically Relevant Large Animal Infectious Arthritis Model. Front Cell Infect Microbiol 2022;12:895022.
- Shen C, Gao M, Chen H, Zhan Y, Lan Q, Li Z, Xiong W, Qin Z, Zheng L, Zhao J. Reactive oxygen species (ROS)-responsive nanoprobe for bioimaging and targeting therapy of osteoarthritis. J Nanobiotechnology 2021 Nov 27;19(1):395.
- Huang ZY, Perry E, Huebner JL, Katz B, Li YJ, Kraus VB. Biomarkers of inflammation - LBP and TLR- predict progression of knee osteoarthritis in the DOXY clinical trial. Osteoarthritis Cartilage 2018 Dec;26(12):1658-1665.
- Gilbertie JM, Long JM, Schubert AG, Berglund AK, Schaer TP, Schnabel LV. Pooled Platelet-Rich Plasma Lysate Therapy Increases Synoviocyte Proliferation and Hyaluronic Acid Production While Protecting Chondrocytes From Synoviocyte-Derived Inflammatory Mediators. Front Vet Sci 2018;5:150.
- Ghasemi S, Sardari K, Mirshokraei P, Hassanpour H. In vitro study of matrix metalloproteinases 1, 2, 9, 13 and serum amyloid A mRNAs expression in equine fibroblast-like synoviocytes treated with doxycycline. Can J Vet Res 2018 Apr;82(2):82-88.
- Divers TJ, Gardner RB, Madigan JE, Witonsky SG, Bertone JJ, Swinebroad EL, Schutzer SE, Johnson AL. Borrelia burgdorferi Infection and Lyme Disease in North American Horses: A Consensus Statement. J Vet Intern Med 2018 Mar;32(2):617-632.
- Joo NE, Miao D, Bermúdez M, Stallcup WB, Kapila YL. Shedding of NG2 by MMP-13 attenuates anoikis. DNA Cell Biol 2014 Dec;33(12):854-62.
- Guardabassi L, Apley M, Olsen JE, Toutain PL, Weese S. Optimization of Antimicrobial Treatment to Minimize Resistance Selection. Microbiol Spectr 2018 May;6(3).
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