Pharmacological Research 107 (2016) 1–18

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Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs

Review

Rosuvastatin: Beyond the cholesterol-lowering effect Francesca Cortese a,∗ , Michele Gesualdo a , Annamaria Cortese b , Santa Carbonara a , Fiorella Devito a , Annapaola Zito a , Gabriella Ricci a , Pietro Scicchitano a , Marco Matteo Ciccone a a b

Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Bari, Italy Cerebrovascular Diseases and Neurorehabilitation Department, San Camillo Hospital, Venezia Lido, Italy

a r t i c l e

i n f o

Article history: Received 23 November 2015 Received in revised form 13 February 2016 Accepted 14 February 2016 Available online 2 March 2016 Chemical compounds studied in this article: Rosuvastatin (PubChem CID:446157) Cholesterol (PubChem CID: 5997) Mevalonate (PubChem CID: 4478250) Farnesylpyrophosphate (PubChem CID: 44134714) Geranylgeranylpyrophosphate (PubChem CID: 44134732) Nitric Oxide (PubChem CID: 145068) Coenzyme Q10 (PubChem CID: 5281915)

a b s t r a c t Rosuvastatin is a fully synthetic statin wich acts by interfering with the endogenous synthesis of cholesterol through competitively inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a liver enzyme responsible of the rate-limiting step in cholesterol synthesis. When compared to other molecules of the same class, it shows high efficacy in the improvement of lipid profile, and, thanks to its noncholesterol-lowering actions (anti-inflammatory, antioxidant and antithrombotic), represents a crucial tool for cardiovascular primary and secondary prevention. Moreover, recent data highlight rosuvastatin beneficial effects in several other fields. In this manuscript we analyzed literature sources in order to better define rosuvastatin features and discuss some critical issues. © 2016 Elsevier Ltd. All rights reserved.

Keywords: Rosuvastatin Cardiovascular disease Lipid-lowering effect Pleiotrophic effect

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Rosuvastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1. Chemistry and pharmacokinetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.2. The “pleiotropic effects” of rosuvastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.3. Coenzyme Q10 bioavailability and selenium protein synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.4. Rosuvastatin and adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.5. The concept of lipophilicity/hydrophilicity: what the literature says . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Main pharmacological effects of rosuvastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.1. Effect on lipid profile and atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.2. The improvement of endothelial function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.3. Anti-inflammatory actions of rosuvastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.4. Rosuvastatin in atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.5. Rosuvastatin in nonalcoholic fatty liver disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

∗ Corresponding author at: Piazza G. Cesare 11, 70124 Bari, Italy. E-mail address: [email protected] (F. Cortese). http://dx.doi.org/10.1016/j.phrs.2016.02.012 1043-6618/© 2016 Elsevier Ltd. All rights reserved.

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F. Cortese et al. / Pharmacological Research 107 (2016) 1–18

4.

5. 6.

3.6. Other properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Rosuvastatin in high cv risk patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.1. Rosuvastatin in patients with HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.2. Rosuvastatin in patients with chronic renal failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.3. Rosuvastatin in patients with DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.4. Risk of new DM development of rosuvastatin compared to other statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Safety of rosuvastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

1. Introduction Cardiovascular (CV) diseases secondary to atherosclerosis are the primary cause of early death and disability in Western countries, with an annual healthcare cost of about 192 billion euros in Europe, and it is becoming increasingly more common in developing countries [1]. Since they are associated to huge health and economic burden, considerable resources are used to reduce the incidence of fatal and nonfatal CV events (coronary artery disease, ischemic stroke and peripheral arterial disease), which mainly aim to act on the modifiable risk factors (lifestyle: tobacco smoking, physical activity and dietary habits, blood pressure, type 2 diabetes, and dyslipidaemia). As regard to dyslipidemias, within the broad spectrum of lipid abnormalities that define it, total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels represent the primary targets of therapy, since multiple randomized controlled trials (RCTs) have shown that their reduction can prevent CV disease. In particular, given the fact that the LDL-C levels have been used to monitor the lipid-lowering response to treatments in almost all related trials, it remains the primary target in the management of dyslipidaemias [1]. Current guidelines recommend LDL-C levels

Rosuvastatin: Beyond the cholesterol-lowering effect.

Rosuvastatin is a fully synthetic statin wich acts by interfering with the endogenous synthesis of cholesterol through competitively inhibiting the 3-...
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