Antioxidative Effects of Rosuvastatin in Low-to-Moderate Cardiovascular Risk Subjects.

Background: Although vast clinical evidence supports the oxidative CVD hypothesis, little is known on the effects of statins on LDL/HDL oxidative functionality. Therefore, the aim of this study was to evaluate the antioxidative effects of rosuvastatin by monitoring the susceptibility of LDL to oxidation and the antioxidative HDL potential in low-to-moderate CV risk subjects. Methods: 40 adult ambulatory patients (aged 53.8±10.9 years, 27 women and 13 men) were included in the study. Data was collected from patients' records, physical examination, and blood sampling. Subjects were prescribed rosuvastatin at 20mg/day. Traditional risk-factors/indicators, lipid parameters, inflammatory/immune markers, LDL susceptibility to oxidation and HDL antioxidative potential were monitored and statistically analyzed with t-test, Chi-square test, one-way ANOVA, Mann-Whitney, and Kruskal-Wallis tests. Multivariate logistic regression analyses were made. Results were considered significant when p≤0.05. Results: 67% of the patients showed lower susceptibility of LDL to oxidation after rosuvastatin treatment (p=0.03), with no significant effect on baseline LDL oxidation and lag time. All three LDL oxidative indices were seen to be dependent on the subjects' lipid profile, hemoglobin levels and the IL-1α and IL-8 pro-inflammatory marker levels. 53% of the patients showed higher HDL antioxidative capacity after treatment, but without statistical significance (p=0.07). Increased antioxidative potential of HDL with rosuvastatin treatment was more likely in males (OR=9.350; p=0.010), and subjects achieving lower post-treatment CV relative risk levels (higher CV risk reduction) (OR=0.338; p=0.027). Conclusions: This study suggests the need of a comprehensive approach when investigating oxidative stress and LDL/HDL functions, especially in low-to-moderate CVD risk subjects.

Comparison of efficiency between Rosuvastatin and Atorvastatin in reducing low-density lipoprotein (LDL-C) in patients with diabetes mellitus.

The study was designed to compare Rosuvastatin with Atorvastatin in terms of their efficacy to reduce low-density lipoproteins (LDL-C) in patients with type 2 diabetes mellitus. For this purpose, a cross-sectional analytical study was conducted in the OPD of Nishtar Medical Hospital, Multan, for six months. The study enrolled 66 patients who were consecutively allocated for double-blind therapy with 10mg Atorvastatin (n = 33) and 10mg Rosuvastatin (n = 33) for one month. The doses titration was carried up to four months in certain patients who failed to achieve 1998 European LDL-C level in the first month. A significant number of patients who were given 10mg Rosuvastatin matched the 1998 LDL-C goal in compared to the patients with 10mg dose of atorvastatin at one month (51% vs 46%, p< 0.0001) and at four months (94% vs 88%, p<0.05). Conclusively, Rosuvastatin was significantly more efficacious than Atorvastatin in its ability to reduce LDL-C.

Measuring effects on intima-media thickness: an evaluation of rosuvastatin in Chinese subjects with subclinical atherosclerosis-design, rationale, and methodology of the METEOR-China study.

BACKGROUND: The beneficial effect of statins on atherosclerosis and cardiovascular outcomes has been well established. The Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) global study demonstrated that a 2-year orally administered treatment with rosuvastatin 40 mg daily significantly slowed the progression of carotid intima-media thickness (CIMT) compared to placebo. The current METEOR-China study is designed to evaluate the effect of rosuvastatin 20 mg daily versus placebo on the progression of atherosclerosis measured by CIMT in asymptomatic Chinese subjects. METHODS: This is a phase 3, randomised, double-blind, placebo-controlled, multicentre parallel-group study. Asymptomatic Chinese subjects with a 10-year ischaemic cardiovascular disease (ICVD) risk < 10% will be recruited at 25 study sites. They will be treated with rosuvastatin 20 mg or placebo for 104 weeks. The primary endpoint is the annualised rate of change in CIMT measured by B-mode ultrasonography. Secondary endpoints include the annualised rate of change in CIMT at three different sections of the carotid artery and changes in the serum lipid profile. Safety parameters will also be assessed. CONCLUSION: The study will evaluate whether rosuvastatin 20 mg slows the progression of CIMT in asymptomatic Chinese subjects at low risk of ICVD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02546323 . Registered on September 10, 2015.

Safety and Optimal Neuroprotection of neu2000 in acute Ischemic stroke with reCanalization: study protocol for a randomized, double-blinded, placebo-controlled, phase-II trial.

BACKGROUND: The potential of neuroprotective agents should be revisited in the era of endovascular thrombectomy (EVT) for acute large-artery occlusion because their preclinical effects have been optimized for ischemia and reperfusion injury. Neu2000, a derivative of sulfasalazine, is a multi-target neuroprotectant. It selectively blocks N-methyl-D-aspartate receptors and scavenges for free radicals. This trial aimed to determine whether neuroprotectant administration before EVT is safe and leads to a more favorable outcome. METHODS: This trial is a phase-II, multicenter, three-arm, randomized, double-blinded, placebo-controlled, blinded-endpoint drug trial that enrolled participants aged ≥ 19 years undergoing an EVT attempt less than 8 h from symptom onset, with baseline National Institutes of Health Stroke Scale (NIHSS) score ≥ 8, Alberta Stroke Program Early CT score ≥ 6, evidence of large-artery occlusion, and at least moderate collaterals on computed tomography angiography. EVT-attempted patients are randomized into control, low-dose (2.75 g), and high-dose (5.25 g) Neu2000KWL over 5 days. Seventy participants per group are enrolled for 90% power, assuming that the treatment group has a 28.4% higher proportion of participants with functional independence than the placebo group. The primary outcome, based on intention-to-treat criteria is the improvement of modified Rankin Scale (mRS) scores at 3 months using a dichotomized model. Safety outcomes include symptomatic intracranial hemorrhage within 5 days. Secondary outcomes are distributional change of mRS, mean differences in NIHSS score, proportion of NIHSS score 0-2, and Barthel Index > 90 at 1 and 4 weeks, and 3 months. DISCUSSION: The trial results may provide information on new therapeutic options as multi-target neuroprotection might mitigate reperfusion injury in patients with acute ischemic stroke before EVT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02831088 . Registered on 13 July 2016.

Oral Delivery of Highly Lipophilic, Poorly Water-Soluble Drugs: Self-Emulsifying Drug Delivery Systems to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a Cholesteryl Ester Transfer Protein Inhibitor in Preclinical Species.

BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in preclinical studies in nonrodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients, and prototype formulations were developed. In vitro tests showed that fine/microemulsions were formed after aqueous dilution of lipid formulations, and BMS-A was transferred from oil phase to aqueous phase with enhanced solubility following lipid digestion. When dosed in dogs at 200 mg/kg, a Gelucire-based formulation exhibited more than 10-fold higher exposure compared to the solution formulation and was thus selected for toxicology studies in dogs. For monkeys, an olive oil formulation was developed, and the exposure was about 7-fold higher than that from the solution. In summary, lipid-based drug delivery could be applied in early stages of drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic compounds, while facilitating the candidate selection of a molecule which is more specifically designed for bioperformance in a lipid-based drug delivery strategy.

Transient azoospermia following rosuvastatin medication for hypercholesterolemia.

The authors report a case of transient azoospermia following hydroxymethylglutaryl-coenzyme A reductase (HMGCR) inhibitor rosuvastatin medication for hypercholesterolemia. While a primary infertile couple with oligoasthenospermia was preparing for an in vitro fertilization program, the male partner had been diagnosed with hypercholesterolemia in a medical check-up and prescribed four-week oral administration of rosuvastatin. No motile spermatozoa were found in the ejaculated semen and urine on the day of follicular aspiration. Azoospermia was confirmed by reexamination in weeks 3 and 7. Spermatozoa appeared in the ejaculated semen in two weeks of drug withdrawal. In week 16, the sperm count and motility increased to the level where intracytoplasmic sperm injection was available.

Takotsubo cardiomyopathy with involvement of delayed-onset rhabdomyolysis and acute kidney injury after rosuvastatin treatment.

Takotsubo cardiomyopathy is a disorder characterized by left ventricular apical ballooning with preceding emotional and/or physical stressors. This condition is also an important differential diagnosis of acute coronary syndrome. We herein describe a case of Takotsubo cardiomyopathy, a significant clinical phenomenon, triggered by delayed-onset rhabdomyolysis following the administration of long-term statin treatment, without any preceding stressors or changes in the patient's medical condition, in association with complaints of non-specific muscle-related symptoms. Although an electrocardiogram showed remarkable ST-segment elevation, a careful reading of the electrocardiogram findings revealed the features of Takotsubo cardiomyopathy. Withdrawing the statin therapy improved the patient's cardiac function.

Statins for primary prevention of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is common in clinical practice. The efficacy of statins in the primary prevention of VTE remains unproven. This is an update of the review first published in 2011. OBJECTIVES: To assess the efficacy of statins in the primary prevention of VTE. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases (PVD) Group Trials Search Co-ordinator searched the Specialised Register (last searched February 2014) and CENTRAL (2014, Issue 1). SELECTION CRITERIA: Randomised controlled trials (RCTs) that assessed statins in the primary prevention of VTE were considered. The outcomes we evaluated were the rates of VTE, cardiovascular and cerebrovascular events, death and adverse events. Two authors (L Li, JH Tian) independently selected RCTs against the inclusion criteria. Disagreements were resolved by discussion with a third author (KH Yang). DATA COLLECTION AND ANALYSIS: Data extraction was independently carried out by two authors (L Li, JH Tian). Disagreements were resolved by discussion with a third author (PZ Zhang). Two authors (L Li, JH Tian) independently assessed the risk of bias according to a standard quality checklist provided by the PVD Group. MAIN RESULTS: For this update we included one RCT with 17,802 participants that assessed rosuvastatin compared with placebo for the prevention of VTE. The quality of the evidence was moderate because of imprecision, as the required sample size for the outcomes of this review was not achieved. Analysis showed that when compared with placebo rosuvastatin reduced the incidence of VTE (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.37 to 0.86) and deep vein thrombosis (DVT) (OR 0.45, 95% CI 0.25 to 0.79), the risk of any (fatal and non-fatal) myocardial infarction (MI) (OR 0.45, 95% CI 0.30 to 0.69), and any (fatal and non-fatal) stroke (OR 0.51, 95% CI 0.34 to 0.78). There was no difference in the incidence of pulmonary embolism (PE) (OR 0.77, 95% CI 0.41 to 1.46), fatal MI (OR 1.50, 95% CI 0.53 to 4.22), fatal stroke (OR 0.30, 95% CI 0.08 to 1.09) or death after VTE (OR 0.50, 95% CI 0.20 to 1.24). The incidence of any serious adverse events was no different between the rosuvastatin and placebo groups (OR 1.07, 95% CI 0.95 to 1.20). AUTHORS' CONCLUSIONS: Available evidence showed that rosuvastatin was associated with a reduced incidence of VTE, but the evidence was limited to a single RCT and any firm conclusions and suggestions could be not drawn. Randomised controlled trials of statins (including rosuvastatin) are needed to evaluate their efficacy in the prevention of VTE.

A generalised sensation of coldness following introduction of rosuvastatin therapy.

Rosuvastatin is the most potent 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor commercially available to lower low-density lipoprotein cholesterol. Rosuvastatin has been associated with several adverse effects, including rhabdomyolysis and arthralgias. Here, we report an unusual adverse effect occurring on treatment with rosuvastatin, a 'continuous sensation of coldness'. A 60-year-old man began experiencing this peculiar feeling shortly after introduction of rosuvastatin treatment. The gentleman had to wear extra pair of socks and cover himself with blankets while reading, even during summer with surrounding temperature above 30°C. The abnormal sensation persisted for the 26 months during which he was treated with rosuvastatin, and disappeared within a week after discontinuing treatment. Physical examination, including thorough neurological examination, was entirely normal, as were haematological and biochemical parameters. While the pathophysiology of this phenomenon remains unknown, we hope that this case will encourage others to report similar symptomatology, perhaps enabling to gain more insight on the condition.

PTEN upregulation may explain the development of insulin resistance and type 2 diabetes with high dose statins.

PURPOSE: Statins increase the incidence of new onset diabetes. Prolonged statin therapy upregulates PTEN expression. PTEN levels are also elevated in diabetic animals. Activation of protein kinase A by cAMP decreases PTEN expression. We assessed whether prolonged treatment with rosuvastatin (ROS) induces glucose intolerance by upregulating Phosphatase and Tensin Homologue on Chromosome 10 (PTEN) in mice receiving normal (ND) or Western Diet (WD) and whether concomitant treatment with cilostazol (CIL, a phosphodiesterase-3 inhibitor) attenuates the effects. METHODS: PTEN(loxp/cre) or PTEN(+/-) mice received ND or WD without or with ROS (10 mg/kg/day). Wild-type mice received ND or WD without or with ROS, CIL (10 mg/kg/day), or ROS+CIL for 30 days. Fasting insulin and glucose tolerance test were measured as well as PTEN and P-AKT levels in skeletal muscle. RESULTS: Serum glucose after intraperitoneal injection of glucose was higher in PTEN(loxp/cre) mice receiving WD or ROS and especially WD+ROS. Levels were lower in PTEN(+/-) mice compared to PTEN(loxp/cre) in each treatment group. CIL decreased glucose levels in mice receiving WD, ROS and their combination. Insulin levels were higher in the WD+ROS group. CIL decreased insulin in mice receiving WD+ROS. WD, ROS and especially their combination increased PTEN and decreased P-AKT levels. CIL attenuated the effect of WD, ROS and their combination. CONCLUSIONS: Long-term ROS can induce diabetes by upregulating PTEN. CIL attenuates these changes. Partial knockdown of PTEN also ameliorates ROS-induced insulin resistance. Further studies are needed to assess the effects of increasing cAMP levels to prevent the induction of diabetes by statins.

Incidence of skeletal muscle disorders after statins' treatment: consequences in clinical and EMG picture.

OBJECTIVES: The goal of this clinical trial was to determine the incidence of undesirable side effects, and to ascertain any occurrence of genetic polymorphisms. MATERIAL AND METHODS: Clinically, we looked for manifestations of a benign myositis and of serious rhabdomyolysis. We observed a group 198 patients treated with statins, primarially fluvastatin and rosuvastatin. There were 126 (mean age = 58.3 ± 4.1; male 91, mean age = 57.4 ± 5.9; female 35, mean age = 60.5 ± 6.5) patients in a subgroup where we administered rosuvastatin. Undesirable muscular signs and symptoms were present in 32 patients (25.39%). In 11 (8.73% of the total 126) CK level increased maximally to 4 times ULN, in 6 (4.7%) statins were excluded because of very intense subjective suffering. CK levels 2-5 times ULN were present in 9 (7.14%). CK blood levels over 10 times ULN or higher indicated statins exclusion in 2 (1.58%). Increased levels of the further muscular enzyme AST by 5 times ULN were present in 16 (12.69%), up to 10 times ULN in 2 (1.58%), and over 10 times ULN also in 2 (1.58%). RESULTS: We observed rhabdomyolysis in 6 patients (3.03% of the total 198 patients group) using other types of statins (three of them undergo chronic hemodialysis). In this group we performed molecular-genetic analysis of the following proteins relating to statin myopathy: SLCO1B1(388AA/AG-521TT) - (discovered polymorphism in 1 patient), further cytochroms Cyp 2C9 (in 1 patient), 2C8 (in 1 patient), Cyp SA/4 (non discovered positivity) and finally UGT1A1*2B (discovered in 2 patients). CONCLUSIONS: In the group of patients treated by rosuvastatin, we discovered not one case of rhabdomyolysis. In each patient with rhabdomyolysis (brown urine discoloration, mal-odorous urine, painful muscle cramps, muscle weakness, fatigue) at least one polymorphism of "statins´ genes" was present.

Dietary supplementation with essential amino acids boosts the beneficial effects of rosuvastatin on mouse kidney.

The effects of high-potency statins on renal function are controversial. To address the impact of statins on renal morpho-functional aspects, normotensive young mice were treated with rosuvastatin (Rvs). Moreover, because statins may impair mitochondrial function, mice received either dietary supplementation with an amino acid mixture enriched in essential amino acids (EAAm), which we previously demonstrated to increase mitochondrial biogenesis in muscle or an unsupplemented control diet for 1 month. Mitochondrial biogenesis and function, apoptosis, and insulin signaling pathway events were studied, primarily in cortical proximal tubules. By electron microscopy analysis, mitochondria were more abundant and more heterogeneous in size, with dense granules in the inner matrix, in Rvs- and Rvs plus EAAm-treated animals. Rvs administration increased protein kinase B and endothelial nitric oxide synthase phosphorylation, but the mammalian target of rapamycin signaling pathway was not affected. Rvs increased the expression of sirtuin 1, peroxisome proliferator-activated receptor γ coactivator-1α, cytochrome oxidase type IV, cytochrome c, and mitochondrial biogenesis markers. Levels of glucose-regulated protein 75 (Grp75), B-cell lymphoma 2, and cyclin-dependent kinase inhibitor 1 were increased in cortical proximal tubules, and expression of the endoplasmic reticulum-mitochondrial chaperone Grp78 was decreased. EAAm supplementation maintained or enhanced these changes. Rvs promotes mitochondrial biogenesis, with a probable anti-apoptotic effect. EAAm boosts these processes and may contribute to the efficient control of cellular energetics and survival in the mouse kidney. This suggests that appropriate nutritional interventions may enhance the beneficial actions of Rvs, and could potentially prevent chronic renal side effects.