Research Article
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The dose-dependent antiangiogenic potential of apixaban: an experimental outlook

Year 2022, Volume: 6 Issue: 2, 179 - 184, 20.08.2022

Özgür Akkaya Eyüp Aydoğan

https://doi.org/10.30565/medalanya.1129978

Abstract

Aim: Direct oral anticoagulants (DOACs) are good alternatives to conventional medical regimens for the treatment and prevention of thromboembolism. Apixaban is one of the more popular variations of these newly developed drugs. Aside from its anticoagulant potential, possible cellular effects remain a topic for future studies. The object of this study was to investigate the possible antiangiogenic effects of apixaban in the chorioallantoic membrane (CAM) model.

Method: Drug pellets were prepared at 10-4, 10-5, and 10-6 M concentrations of apixaban and were placed in the chorioallantoic membrane on the fourth day of egg incubation. On the eighth day, all vascular densities of the membranes were compared with a 10-6 M concentration of bevacizumab, which is a known monoclonal, humanized, vascular endothelial growth-factor inhibitor.

Results: We find that a 10-4 M concentration of apixaban has strong antiangiogenic potential similar to that of bevacizumab. However, there was moderate antiangiogenic potential at a lower dose of apixaban (10-5 M, 10-6 M). A comparison of the higher doses of antiangiogenic potential (10-4 M concentration) with lower doses of apixaban (10-5 M, 10-6 M) revealed significant statistical differences (p < 0.05).

Conclusion: Our results indicate that a high dose of apixaban has strong antiangiogenic potential. The exact mechanism of this effect remains unknown. These pilot results should be confirmed with further studies to obtain an updated look at DOACs.

Keywords

angiogenesis anticoagulation apixaban DOACs

Supporting Institution

none

Project Number

none

Thanks

none

References

  • 1. Alquwaizani M, Buckley L, Adams C, Fanikos J. Anticoagulants: A Review of the Pharmacology, Dosing, and Complications Curr Emerg Hosp Med Rep. 2013;1(2):83–97. doi: 10.1007/s40138-013-0014-6.
  • 2. Nowak-Göttl U, Bidlingmaier C, Krümpel A, Göttl L, Kenet G. Pharmacokinetics, efficacy, and safety of LMWHs in venous thrombosis and stroke in neonates, infants and children Br J Pharmacol. 2008;153(6):1120–7. doi: 10.1038/sj.bjp.0707447.
  • 3. Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National Trends in Ambulatory Oral Anticoagulant Use. Am J Med. 2015;128(12):1300-5.e2. doi: 10.1016/j.amjmed.2015.05.044.
  • 4. Hansen PW, Sehested TSG, Fosbøl EL, Torp-Pedersen C, Køber L, Andersson C, et al. Trends in warfarin use and its associations with thromboembolic and bleeding rates in a population with atrial fibrillation between 1996 and 2011 PLoS One. 2018;13(3):e0194295. doi: 10.1371/journal.pone.0194295.
  • 5. Kamuren Z, Kigen G, Keter A, Maritim A. Characteristics of patients with thromboembolic disorders on warfarin therapy in resource limited settings. BMC Health Serv Res. 2018; 18: 723. doi: 10.1186/s12913-018-3537-4.
  • 6. Loo SY, Dell'Aniello S, Huiart L, Renoux C. Trends in the prescription of novel oral anticoagulants in UK primary care. Br J Clin Pharmacol. 2017;83(9):2096–106. doi: 10.1111/bcp.13299.
  • 7. Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag. 2015;11:967-77. doi: 10.2147/TCRM.S84210.
  • 8. Zalpour A, Oo TH. Clinical utility of apixaban in the prevention and treatment of venous thromboembolism: current evidence. Drug Des Devel Ther. 2014;8:2181–91. doi: 10.2147/DDDT.S51006.
  • 9. Dogan OT, Polat ZA, Karahan O, Epozturk K, Altun A, Akkurt I, Cetin A. Antiangiogenic activities of bemiparin sodium, enoxaparin sodium, nadroparin calcium and tinzaparin sodium. Thromb Res. 2011;128(4):e29-32. doi: 10.1016/j.thromres.2011.05.005.
  • 10. Katrancioglu N, Karahan O, Kilic AT, Altun A, Katrancioglu O, Polat ZA. Comparison of the antiangiogenic effects of heparin sodium, enoxaparin sodium, and tinzaparin sodium by using chorioallantoic membrane assay. Blood Coagul Fibrinolysis. 2012;23(3):218-21. doi: 10.1097/MBC.0b013e3283504132.
  • 11. Yavuz C, Caliskan A, Karahan O, Yazici S, Guclu O, Demirtas S, et al. Investigation of the antiangiogenic behaviors of rivaroxaban and low molecular weight heparins. Blood Coagul Fibrinolysis. 2014;25(4):303-8. doi: 10.1097/MBC.0000000000000019.
  • 12. Browne C, Lanitis T, Hamilton M, Li X, Horbyluk R, Mardekian J, et al. Impact of apixaban vs low molecular weight heparin/vitamin k antagonist on hospital resource use in patients with venous thromboembolism. J Med Econ. 2017;20(1):98-106. doi: 10.1080/13696998.2016.1258365.
  • 13. Gómez-Outes A, Suárez-Gea ML, Lecumberri R, Terleira-Fernández AI, Vargas-Castrillón E, Rocha E. Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients. Vasc Health Risk Manag. 2013;9:207-28. doi: 10.2147/VHRM.S35843.
  • 14. Karahan O, Yavuz C, Demirtas S, Caliskan A, Atahan E. The Investigation of the Antiangiogenic Potential of Amiodarone HCl in the Chick Embryo Chorioallantoic Membrane Model. Biomedical Research 2013;24(1):131-4.
  • 15. Katrancioglu N, Karahan O, Kilic AT, Altun A, Katrancioglu O, Polat ZA. The antiangiogenic effects of levosimendan in a CAM assay. Microvasc Res. 2012;83(3):263-6. doi: 10.1016/j.mvr.2012.01.002.
  • 16. Bürgermeister J, Paper DH, Vogl H, Linhardt RJ, Franz G. LaPSvS1, a (1-->3)-beta-galactan sulfate and its effect on angiogenesis in vivo and in vitro. Carbohydr Res. 2002;337(16):1459-66. doi: 10.1016/s0008-6215(02)00163-5.
  • 17. Demirci B, Dadandi MY, Paper DH, Franz G, Baser KH. Chemical composition of the essential oil of Phlomis linearis Boiss.&Bal., and biological effects on the CAM assay: a safety evaluation. Z Naturforsch C. 2003;58(11–12):826–9. doi: 10.1515/znc-2003-11-1214.
  • 18. Liu FD, Zhao R, Feng XY, Shi YH, Wu YL, Shen XL, et al. Rivaroxaban does not influence hemorrhagic transformation in a diabetes ischemic stroke and endovascular thrombectomy model. Sci Rep. 2018;8(1):7408. doi: 10.1038/s41598-018-25820-y.
  • 19. Pavlidis ET, Pavlidis TE. Role of bevacizumab in colorectal cancer growth and its adverse effects: a review World J Gastroenterol. 2013;19(31):5051-60. doi: 10.3748/wjg.v19.i31.5051.
  • 20. Rema RB, Rajendran K, Ragunathan M. Angiogenic efficacy of Heparin on chick chorioallantoic membrane. Vasc Cell. 2012;4(1):8. doi: 10.1186/2045-824X-4-8.
  • 21. Hwang HH, Lee DY. Antiangiogenic Actions of Heparin Derivatives for Cancer Therapy. Macromol Res. 2016;24(9):767-72. doi: 10.1007/s13233-016-4111-8.
  • 22. Wu TC, Chan JS, Lee CY, Leu HB, Huang PH, Chen JS, et al. Rivaroxaban, a factor Xa inhibitor, improves neovascularization in the ischemic hindlimb of streptozotocin-induced diabetic mice. Cardiovasc Diabetol. 2015;14:81. doi: 10.1186/s12933-015-0243-y.
  • 23. Cohen AT, Hamilton M, Mitchell SA, Phatak H, Liu X, Bird A, Tushabe D, 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(12):e0144856. doi: 10.1371/journal.pone.0144856.
  • 24. Kubat E, Gurpinar OA, Karasoy D, Onur MA. A link between cytotoxicity in cell culture and gastrointestinal side effects of oral anticoagulants: bench-to-bedside.Bratisl Lek Listy. 2018;119(11):706-12. doi: 10.4149/BLL_2018_126.
  • 25. Guasti L, Squizzato A, Moretto P, Vigetti D, Ageno W, Dentali F, et al. In vitro effects of Apixaban on 5 different cancer cell lines. PLoS One. 2017;12(10):e0185035. doi: 10.1371/journal.pone.0185035.

Apıxaban'ın Doza Bağlı Antianjiyojenik Potansiyeli: Deneysel Bir Bakış

Year 2022, Volume: 6 Issue: 2, 179 - 184, 20.08.2022

Özgür Akkaya Eyüp Aydoğan

https://doi.org/10.30565/medalanya.1129978

Abstract

Amaç: Direkt oral antikoagülanlar (DOAK'lar), tromboembolizmin tedavisi ve önlenmesi için geleneksel tıbbi rejimlere iyi alternatiflerdir. Apixaban, bu yeni geliştirilen ilaçların daha popüler varyasyonlarından biridir. Antikoagülan potansiyelinin yanı sıra, olası hücresel etkiler gelecekteki çalışmaların konusu olmaya devam etmektedir. Bu çalışmanın amacı, korioallantoik membran (CAM) modelinde apiksaban'ın olası antianjiyogenik etkilerini araştırmaktı.

Yöntem: Apixaban'ın 10-4, 10-5 ve 10-6 M konsantrasyonlarında ilaç peletleri hazırlandı ve yumurta inkübasyonunun dördüncü gününde korioallantoik membrana yerleştirildi. Sekizinci günde, membranların tüm vasküler yoğunlukları, bilinen bir monoklonal, insanlaştırılmış, vasküler endotelyal büyüme faktörü inhibitörü olan 10-6 M'lik bir bevacizumab konsantrasyonu ile karşılaştırıldı.

Bulgular: 10-4 M apiksaban konsantrasyonunun, bevacizumabınkine benzer güçlü bir antianjiyogenik potansiyele sahip olduğunu bulduk. Bununla birlikte, daha düşük bir apiksaban dozunda (10-5 M, 10-6 M) orta düzeyde antianjiyogenik potansiyel vardı. Daha yüksek antianjiyogenik potansiyel dozlarının (10-4 M konsantrasyon) daha düşük dozlarda apiksaban (10-5 M, 10-6 M) ile karşılaştırılması, önemli istatistiksel farklılıklar ortaya çıkardı (p <0.05).

Sonuç: Sonuçlarımız, yüksek doz apiksaban'ın güçlü antianjiyogenik potansiyele sahip olduğunu göstermektedir. Bu etkinin kesin mekanizması bilinmemektedir. Bu pilot sonuçlar, DOAK'lara yeni bir bakış elde etmek için daha ileri çalışmalarla doğrulanmalıdır.

Keywords

anjiyogenez antikoagülasyon apiksaban DOAK'lar

Project Number

none

References

  • 1. Alquwaizani M, Buckley L, Adams C, Fanikos J. Anticoagulants: A Review of the Pharmacology, Dosing, and Complications Curr Emerg Hosp Med Rep. 2013;1(2):83–97. doi: 10.1007/s40138-013-0014-6.
  • 2. Nowak-Göttl U, Bidlingmaier C, Krümpel A, Göttl L, Kenet G. Pharmacokinetics, efficacy, and safety of LMWHs in venous thrombosis and stroke in neonates, infants and children Br J Pharmacol. 2008;153(6):1120–7. doi: 10.1038/sj.bjp.0707447.
  • 3. Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National Trends in Ambulatory Oral Anticoagulant Use. Am J Med. 2015;128(12):1300-5.e2. doi: 10.1016/j.amjmed.2015.05.044.
  • 4. Hansen PW, Sehested TSG, Fosbøl EL, Torp-Pedersen C, Køber L, Andersson C, et al. Trends in warfarin use and its associations with thromboembolic and bleeding rates in a population with atrial fibrillation between 1996 and 2011 PLoS One. 2018;13(3):e0194295. doi: 10.1371/journal.pone.0194295.
  • 5. Kamuren Z, Kigen G, Keter A, Maritim A. Characteristics of patients with thromboembolic disorders on warfarin therapy in resource limited settings. BMC Health Serv Res. 2018; 18: 723. doi: 10.1186/s12913-018-3537-4.
  • 6. Loo SY, Dell'Aniello S, Huiart L, Renoux C. Trends in the prescription of novel oral anticoagulants in UK primary care. Br J Clin Pharmacol. 2017;83(9):2096–106. doi: 10.1111/bcp.13299.
  • 7. Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag. 2015;11:967-77. doi: 10.2147/TCRM.S84210.
  • 8. Zalpour A, Oo TH. Clinical utility of apixaban in the prevention and treatment of venous thromboembolism: current evidence. Drug Des Devel Ther. 2014;8:2181–91. doi: 10.2147/DDDT.S51006.
  • 9. Dogan OT, Polat ZA, Karahan O, Epozturk K, Altun A, Akkurt I, Cetin A. Antiangiogenic activities of bemiparin sodium, enoxaparin sodium, nadroparin calcium and tinzaparin sodium. Thromb Res. 2011;128(4):e29-32. doi: 10.1016/j.thromres.2011.05.005.
  • 10. Katrancioglu N, Karahan O, Kilic AT, Altun A, Katrancioglu O, Polat ZA. Comparison of the antiangiogenic effects of heparin sodium, enoxaparin sodium, and tinzaparin sodium by using chorioallantoic membrane assay. Blood Coagul Fibrinolysis. 2012;23(3):218-21. doi: 10.1097/MBC.0b013e3283504132.
  • 11. Yavuz C, Caliskan A, Karahan O, Yazici S, Guclu O, Demirtas S, et al. Investigation of the antiangiogenic behaviors of rivaroxaban and low molecular weight heparins. Blood Coagul Fibrinolysis. 2014;25(4):303-8. doi: 10.1097/MBC.0000000000000019.
  • 12. Browne C, Lanitis T, Hamilton M, Li X, Horbyluk R, Mardekian J, et al. Impact of apixaban vs low molecular weight heparin/vitamin k antagonist on hospital resource use in patients with venous thromboembolism. J Med Econ. 2017;20(1):98-106. doi: 10.1080/13696998.2016.1258365.
  • 13. Gómez-Outes A, Suárez-Gea ML, Lecumberri R, Terleira-Fernández AI, Vargas-Castrillón E, Rocha E. Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients. Vasc Health Risk Manag. 2013;9:207-28. doi: 10.2147/VHRM.S35843.
  • 14. Karahan O, Yavuz C, Demirtas S, Caliskan A, Atahan E. The Investigation of the Antiangiogenic Potential of Amiodarone HCl in the Chick Embryo Chorioallantoic Membrane Model. Biomedical Research 2013;24(1):131-4.
  • 15. Katrancioglu N, Karahan O, Kilic AT, Altun A, Katrancioglu O, Polat ZA. The antiangiogenic effects of levosimendan in a CAM assay. Microvasc Res. 2012;83(3):263-6. doi: 10.1016/j.mvr.2012.01.002.
  • 16. Bürgermeister J, Paper DH, Vogl H, Linhardt RJ, Franz G. LaPSvS1, a (1-->3)-beta-galactan sulfate and its effect on angiogenesis in vivo and in vitro. Carbohydr Res. 2002;337(16):1459-66. doi: 10.1016/s0008-6215(02)00163-5.
  • 17. Demirci B, Dadandi MY, Paper DH, Franz G, Baser KH. Chemical composition of the essential oil of Phlomis linearis Boiss.&Bal., and biological effects on the CAM assay: a safety evaluation. Z Naturforsch C. 2003;58(11–12):826–9. doi: 10.1515/znc-2003-11-1214.
  • 18. Liu FD, Zhao R, Feng XY, Shi YH, Wu YL, Shen XL, et al. Rivaroxaban does not influence hemorrhagic transformation in a diabetes ischemic stroke and endovascular thrombectomy model. Sci Rep. 2018;8(1):7408. doi: 10.1038/s41598-018-25820-y.
  • 19. Pavlidis ET, Pavlidis TE. Role of bevacizumab in colorectal cancer growth and its adverse effects: a review World J Gastroenterol. 2013;19(31):5051-60. doi: 10.3748/wjg.v19.i31.5051.
  • 20. Rema RB, Rajendran K, Ragunathan M. Angiogenic efficacy of Heparin on chick chorioallantoic membrane. Vasc Cell. 2012;4(1):8. doi: 10.1186/2045-824X-4-8.
  • 21. Hwang HH, Lee DY. Antiangiogenic Actions of Heparin Derivatives for Cancer Therapy. Macromol Res. 2016;24(9):767-72. doi: 10.1007/s13233-016-4111-8.
  • 22. Wu TC, Chan JS, Lee CY, Leu HB, Huang PH, Chen JS, et al. Rivaroxaban, a factor Xa inhibitor, improves neovascularization in the ischemic hindlimb of streptozotocin-induced diabetic mice. Cardiovasc Diabetol. 2015;14:81. doi: 10.1186/s12933-015-0243-y.
  • 23. Cohen AT, Hamilton M, Mitchell SA, Phatak H, Liu X, Bird A, Tushabe D, 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(12):e0144856. doi: 10.1371/journal.pone.0144856.
  • 24. Kubat E, Gurpinar OA, Karasoy D, Onur MA. A link between cytotoxicity in cell culture and gastrointestinal side effects of oral anticoagulants: bench-to-bedside.Bratisl Lek Listy. 2018;119(11):706-12. doi: 10.4149/BLL_2018_126.
  • 25. Guasti L, Squizzato A, Moretto P, Vigetti D, Ageno W, Dentali F, et al. In vitro effects of Apixaban on 5 different cancer cell lines. PLoS One. 2017;12(10):e0185035. doi: 10.1371/journal.pone.0185035.
There are 25 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research Article
Authors

Özgür Akkaya 0000-0001-6460-5066

Eyüp Aydoğan 0000-0003-3432-4946

Project Number none
Early Pub Date August 20, 2022
Publication Date August 20, 2022
Submission Date June 13, 2022
Acceptance Date July 7, 2022
Published in Issue Year 2022 Volume: 6 Issue: 2

Cite

Vancouver Akkaya Ö, Aydoğan E. The dose-dependent antiangiogenic potential of apixaban: an experimental outlook. Acta Med. Alanya. 2022;6(2):179-84.

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