Necati KAPLAN, Numan KARAASLAN, İbrahim YILMAZ, Özkan ATEŞ, Feride SİNEM AKGÜN, Duygu Yaşar ŞİRİN, Abdullah Talha ŞİMŞEK, Hanefi ÖZBEK

Evaluation of the effect of apixaban on the primary intact intervertebral disc cell cultures

Aim: Apixaban is a frequently preferred pharmacological agent in clinics to prevent deep vein thrombosis and pulmonary embolism.Such new oral anticoagulants may cause hemorrhage’s in tissues and/or organs or may cause gastrointestinal symptoms withoutbleeding. It is also reported in the literature that it may lead to mental disorders, unwanted disorders in the urinary tract and skeletalmuscle system. However, when the literature is examined, there are no studies, which are of high-evidential value, evaluating theefficacy of apixaban on healthy, intact intervertebral disc tissue, and matrix-like structures. In this pharmaco-molecular study, itwas aimed to investigate the effects of a new oral anticoagulant agent containing the active ingredient apixaban on the intactintervertebral disc tissue cells, extracellular matrix (ECM) structure and to evaluate its positive and / or negative effects on geneexpressions of cartilage oligo matrix protein (COMP), chondroadherin (CHAD), and Matrix Metalloproteinase (MMP)s.Material and Methods: The primary cell cultures were prepared from the intact tissues of the patients with the traumatic intervertebraldisc herniation. Apixaban was administered to the cultures and molecular analyses were performed for 21 days. The data obtainedfrom the apixaban-administered and non-apixaban-administered samples were evaluated statistically and the significance valuewas accepted as P

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1. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis 2011;31:326-43.
2. Anderson I, Cifu AS. Management of Bleeding in Patients Taking Oral Anticoagulants.JAMA 2018;319:2032-33.
3. Hawcutt DB, Ghani AA, Sutton L, et al. Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects. Pharmacogenomics 2014;14:542-48.
4. Cohen AT, Hamilton M, Mitchell SA, et al. Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis. PloS One 2015;10:0144856.
5. Priyanka P, Kupec JT, Krafft M, et al. Newer Oral Anticoagulants in the Treatment of Acute Portal Vein Thrombosis in Patients with and without Cirrhosis. Int J Hepatol 2018;2018:8432781.
6. Hellfritzsch M, Rasmussen L, Hallas J, et al. Using the Symmetry Analysis Design to Screen for Adverse Effects of Non-vitamin K Antagonist Oral Anticoagulants. Drug Saf 2018;41:685-95.
7. Karaarslan N, Yilmaz I, Ozbek H, et al. Are specific gene expressions of extracellular matrix and nucleus pulposus affected by primary cell cultures prepared from intact or degenerative intervertebral disc tissues? Turk Neurosurg. 2018.
8. Karaarslan N, Yilmaz I, Sirin DY, et al. Do we damage nucleus pulposus tissue while treating cerebrovascular ischemic neurological deficits. Ann Med Res 2018;25:266-73.
9. Karaarslan N, Yilmaz I, Sirin DY, et al. Pregabalin treatment for neuropathic pain may damage intervertebral disc tissue. Exp Ther Med 2018;16:1259- 65.
10. Sirin DY, Kaplan N, Yilmaz I, et al. The association between different molecular weights of hyaluronic acid and CHAD, HIF-1α, COL2A1 expression in chondrocyte cultures. Exp Ther Med 2018;15:4205-12.
11. Sirin D and Karaarslan N. Evaluation of the effects of pregabalin on chondrocyte proliferation and CHAD, HIF-1α, and COL2A1 gene expression. Arc Med Sci 2018;14:1340-47.
12. Schulz JN, Nüchel J, Niehoff A, et al. COMP-assisted collagen secretion--a novel intracellular function required for fibrosis. J Cell Sci 2016;129:706-16.
13. Zhu J, Tang H, Zhang Z, et al. Kaempferol slows intervertebral disc degeneration by modifying LPSinduced osteogenesis/adipogenesis imbalance and inflammation response in BMSCs. Int Immunopharmacol 2017;43:236-42.
14. Frost CE, Byon W, Song Y, et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol 2015;79:838-46.
15. Alastruey-Izquierdo A, Cadranel J, Flick H, et al. Treatment of Chronic Pulmonary Aspergillosis: Current Standards and Future Perspectives. Respiration 2018;96:159-70.
16. Loffredo L, Perri L, Violi F. Impact of new oral anticoagulants on gastrointestinal bleeding in atrial fibrillation: A meta-analysis of interventional trials. Dig Liver Dis 2015;47:429-31.
17. Maruyama K, Yamamoto T, Aoyagi H, et al. Difference between the Upper and the Lower Gastrointestinal Bleeding in Patients Taking Nonvitamin K Oral Anticoagulants. Biomed Res Int 2018;2018:7123607.
18. Dhar A, Sadiq F, Anstee QM, et al. Thrombin and factor Xa link the coagulation system with liver fibrosis. BMC Gastroenterol 2018;18:60.
19. Bastiaans J, Mulder VC, van Meurs JC, et al. Dabigatran inhibits intravitreal thrombin activity. Acta Ophthalmol 2018;96:452-58.
20. Vianello F, Sambado L, Goss A, et al. Dabigatran antagonizes growth, cell-cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines. Cancer Med 2016;5:2886-98.
21. Castle J, Farnie G, Kirwan CC. PO-11-Thrombin and cancer stem-like cells: in vitro support for breast cancer anticoagulation. Thromb Res 2016;140:180.
22. Simmers MB, Cole BK, Ogletree ML, et al. Hemodynamics associated with atrial fibrillation directly alters thrombotic potential of endothelial cells. Thromb Res 2016;143:34-39.
23. Liang Y, Fu Y, Qi R, et al. Cartilage oligomeric matrix protein is a natural inhibitor of thrombin. Blood 2015;126:905-14.
24. Yang CY, Chanalaris A, Troeberg L. ADAMTS and ADAM metalloproteinases in osteoarthritis- looking beyond the ‘usual suspects’. Osteoarthritis Cartilage 2017;25:1000-9.
25. Adams MA and Roughley PJ. What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976) 2006;31:2151-61.
26. Humzah MD and Soames RW. Human intervertebral disc: Structure and function. Anat Rec 1988;220:337- 56.
27. Hutton WC and Adams MA. Can the lumbar spine be crushed in heavy lifting? Spine (Phila Pa 1976) 1982;7:586-90.
28. Park EY and Park JB. Dose- and time-dependent effect of high glucose concentration on viability of notochordal cells and expression of matrix degrading and fibrotic enzymes. Int Orthop 2013;37:1179-86.
29. Yin XF, Jiang LB, Ma YQ, et al. Decreased Zn(2+) Influx Underlies the Protective Role of Hypoxia in Rat Nucleus Pulposus Cells. Biol Trace Elem Res 2015;168:196-05.
30. Melrose J, Smith SM, Appleyard RC, et al. Aggrecan, versican and type VI collagen are components of annular translamellar crossbridges in the intervertebral disc. Eur Spine J 2008;17:314-24.
31. Karaarslan N, Gurbuz MS, Caliskan T, et al. The Effect of Matrix Metalloproteinase-3 on the Prognosis and Biological Behaviour of Meningiomas. Turk Neurosurg 2016;26:678-83.
32. Nishijima T, Kawakami M, Kita I. A bout of treadmill exercise increases matrix metalloproteinase-9 activity in the rat hippocampus. Neurosci Lett 2015;594:144- 9.
33. Muphy G, Willenbrock F, Crabbe T. Regulation of matrix metalloproteinase activity. Ann Ny Acad Sci 1994;732:31-41.
34. Anderson DG, Li X, Balian G. A fibronectin fragment alters the metabolism by rabbit intervertebral disc cells in vitro. Spine (Phila Pa 1976) 2005;30:1242-6.
35. Aota Y, An HS, Homandberg G, et al. Differential effects of fibronectin fragment on proteoglycan metabolism by intervertebral disc cells: A comparison with articular chondrocytes. Spine (Phila Pa 1976) 2005;30:722-28.
36. Nagase H and Woessner JF Jr. Matrix metalloproteinases. J Biol Chem 1999;274:21491- 494.
37. Cal S, Obaya AJ, Llamazares M, et al. Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. Gene 2002;283:49-62.
38. Nagase H and Kashiwagi M. Aggrecanases and cartilage matrix degradation. Arthritis Res Ther 2003;5:94-103.
39. Somerville RP, Longpre JM, Jungers KA, et al. Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J Biol Chem 2003;278:9503-13.
40. Roberts S, Caterson B, Menage J, et al. Matrix metalloproteinases and aggrecanase: Their role in disorders of the human intervertebral disc. Spine (Phila Pa 1976) 2000;25:3005-13.
41. Sztrolovics R, Alini M, Roughley PJ, et al. Aggrecan degradation in human intervertebral disc and articular cartilage. Biochem J 1997;15:235-41.
42. Wang G, Huang K, Dong Y, et al. Lycorine Suppresses Endplate-Chondrocyte Degeneration and Prevents Intervertebral Disc Degeneration by Inhibiting NF-κB Signalling Pathway. Cell Physiol Biochem 2018;45:1252-69.
43. Gawri R, Moir J, Ouellet J, et al. Physiological loading can restore the proteoglycan content in a model of early IVD degeneration. PLoS One 2014;9:101233.
44. Son H, Lee D, Lim LA, Jet al. Development of a pharmacokinetic interaction model for coadministration of simvastatin and amlodipine. Drug Metab Pharmacokinet 2014;29:120-8.