Original Article

Ezetimibe Therapy and Its Influence on Oxidative Stress and Fibrinolytic Activity

Authors: Nurver Turfaner, MD, PhD, Hafize Uzun, MD, Huriye Balci, PhD, Meltem A. Ercan, MD, Yesari H. Karter, MD, Metin Caner, MD, Fikret Sipahioglu, MD, Habibe Genc, MD

Abstract


Objective: The effect of ezetimibe on blood lipids, oxidative stress, and fibrinolytic activity in hyperlipidemic patients was investigated after three months of therapy.


Methods: Thirty hyperlipidemic patients were treated for twelve weeks with ezetimibe 10 mg/day. A healthy control group with matching age and gender was also included. Fasting blood glucose, lipid parameters, paraoxonase (PON1), protein carbonyl (PCO), oxidized LDL (oxLDL), 8-isoprostane (ISOPR), total antioxidant capacity (TAC) levels, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type-1 (PAI-1), and PAI-1/t-PA levels were evaluated.


Results: Ezetimibe therapy for twelve weeks led to changes in lipid profile in accordance with the literature. Fibrinolytic activity parameters, PAI-1/tPA and tPA-1 decreased, whereas PAI-1 levels did not change significantly. Antioxidant parameters, serum PON1 activity, and TAC levels increased significantly compared with the basal values. Oxidant parameters, oxLDL, ISOPR, and PCO (which is an indicator of oxidative protein damage) decreased significantly after therapy.


Conclusions: Ezetimibe therapy has beneficial effects on fibrinolytic activity and homeostasis between oxidant and antioxidant activity in hyperlipidemic patients This may be through lowering lipid levels or other mechanisms such as decreasing insulin resistance and the pleiotropic effects of the drug.



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References

1. Jeu L, Cheng JW. Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor. Clin Ther 2003;25:2352–2387.
 
2. Landin K, Tengborn L, Smith U. Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular diseases. J Intern Med 1990;227:273–278.
 
3. Landin K, Stigendal L, Eriksson E, et al. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism 1990;39:1044–1048.
 
4. Juhan-Vague I, Alessi MC, Vague P. Thrombogenic and fibrinolytic factors and cardiovascular risk in non-insulin-dependent diabetes mellitus. Ann Med 1996;28:371–380.
 
5. Schneider DJ, Absher PM, Neimane D, et al. Fibrinolysis and atherogenesis in the JCR: LA-cp rat in relation to insulin and triglyceride concentrations in blood. Diabetologia 1998;41:141–147.
 
6. Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 1997;272:20313–20316.
 
7. Stadtman ER. Role of oxidant species in aging. Curr Med Chem 2004;11:1105–1112.
 
8. Basarici I, Altekin RE, Demir I, et al. Associations of isoprostanes-related oxidative stress with surrogate subclinical indices and angiographic measures of atherosclerosis. Coron Artery Dis 2007;18:615–620.
 
9. Cakatay U, Kayali R, Uzun H. Relation of plasma protein oxidation parameters and paraoxonase activity in the ageing population. Clin Exp Med 2008;8:51–57.
 
10. Fuhrman B, Koren L, Volkova N, et al. Atorvastatin therapy in hypercholesterolemic patients suppresses cellular uptake of oxidized-LDL by differentiating monocytes. Atherosclerosis 2002;164:179–185.
 
11. Paragh G, Törocsik D, Seres I, et al. Effect of short term treatment with simvastatin and atorvastatin on lipids and paraoxonase activity in patients with hyperlipoproteinaemia. Curr Med Res Opin 2004;20:1321–1327.
 
12. Tomás M, Sentí M, García-Faria F, et al. Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2000;20:2113–2119.
 
13. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001;37:1053–1059.
 
14. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8–15.
 
15. Sawamura T, Kume N, Aoyama T, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature 1997;386:73–77.
 
16. Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet 2005;44:467–494.
 
17. Davidson MH, Ballantyne CM, Kerzner B, et al; Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia. Int J Clin Pract 2004;58:746–755.
 
18. Davis HR Jr, Pula KK, Alton KB, et al. The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs. Metabolism 2001;50:1234–1241.
 
19. Masuda D, Nakagawa-Toyama Y, Nakatani K, et al. Ezetimibe improves postprandial hyperlipidaemia in patients with type IIb hyperlipidaemia. Eur J Clin Invest 2009;39:689–698.
 
20. Bays HE, Ose L, Fraser N, et al. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004;26:1758–1773.
 
21. Hasselwander O, Savage DA, McMaster D, et al. Paraoxonase polymorphisms are not associated with cardiovascular risk in renal transplant recipients. Kidney Int 1999;56:289–298.
 
22. Bolayirli IM, Aslan M, Balci H, et al. Effects of atorvastatin therapy on hypercholesterolemic rabbits with respect to oxidative stress, nitric oxide pathway and homocysteine. Life Sci 2007;8:121–127.
 
23. Nakou ES, Filippatos TD, Kiortsis DN, et al. The effects of ezetimibe and orlistat, alone or in combination, on high-density lipoprotein (HDL) subclasses and HDL-associated enzyme activities in overweight and obese patients with hyperlipidaemia. Expert Opin Pharmacother 2008;9:3151–3158.
 
24. Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. London, United Kingdom, Oxford University Press, 1999.
 
25. Martino F, Loffredo L, Carnevale R, et al. Oxidative stress is associated with arterial dysfunction and enhanced intima-media thickness in children with hypercholesterolemia: the potential role of nicotinamide-adenine dinucleotide phosphate oxidase. Pediatrics 2008;12:e648–e55.
 
26. Shacter E. Quantification and significance of protein oxidation in biological samples. Drug Metab Rev 2000;32:307–326.
 
27. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998;1643–1650.
 
28. Koh KK. Effects of HMG-CoA inhibitor on hemostasis. Int J Cardiol 2000;76:23–32.
 
29. Wiesbauer F, Kaun C, Zorn G, et al. HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins. Br J Pharmacol 2002;135:284–292.