Achievement of LDL-cholesterol goal with statins after an st segment elevation myocardial infarction.

BACKGROUND: In patients with very high cardiovascular risk, low-density lipoprotein cholesterol (LDL-C) less than 70 mg/dL or at least 50% reduction of LDL-C are recommended targets. High-dose atorvastatin has been shown to reduce death and ischemic events among patients with acute coronary syndrome. OBJECTIVE: To evaluate the proportion of STEMl patients that achieve LDL-C goal after hospital discharge from a real-world setting in Thailand To determine if the formulation of statin prescribed affected the LDL-C goal achievement. MATERIAL AND METHOD: The authors analyzed data from a cohort of patients with STEMI enrolled from June 1, 2008 through May 31, 2011. Patients who survived, were prescribed astatin on discharge and had LDL-C data at follow-up were analyzed. The formulation of statin was categorized as simvastatin or other statins (atorvastatin or rosuvastatin) group. RESULTS: Ninety-seven percent (n = 265 of 272) of patients were prescribed a statin at discharge. Of these, 216 patients had LDL-C data during a 3-month follow-up period, 75% were men, the mean age was 60.5 ± 12.2 years old and the mean baseline LDL-C was 118.1 ± 41.2 mg/dL. 73% (n = 157) of patients received simvastatin and 27% (n = 59) received other statins. At discharge, the median daily dose of simvastatin, atorvastatin and rosuvastatin were 20, 20 and 10 mg respectively. At follow-up, target LDL-C < 70 mg/dL or LDL-C reduction ≥ 50% was achieved in 30.1% (n = 65) of patients, 27.4% (n = 43) on simvastatin and 37.3% (n = 22) on other statins, (p = 0.158, simvastatin versus other statins). When stratified by the dose intensity of statin, a significantly greater proportion of patients on moderate to high intensity statin attained LDL-C goals than those on low intensity statin: (36.3% versus 24.3%, p = 0.038). CONCLUSION: Most patients with STEMI are prescribed statin therapy at discharge. Despite this, the target LDL-C is attained in a minority of the patients due to suboptimal statin dosing. The formulation of statin did not affect LDL-C goal attainment. High-dose statin therapy is underused in real-world clinical practice. These findings emphasize the opportunities to improve outcomes of STEMI patients with evidence-based therapies.

Protective effects of rosuvastatin in a rat model of lung contusion: Stimulation of the cyclooxygenase 2-prostaglandin E-2 pathway.

BACKGROUND: Lung contusion, which can occur in patients with blunt thoracic trauma, is a leading risk factor for development of acute lung injury (ALI) and acute respiratory distress syndrome. Statins are lipid-lowering drugs with many beneficial antiinflammatory and antioxidative effects. We therefore hypothesized that the administration of statins immediately after trauma will inhibit the production of inflammatory mediators, and thereby alleviate the severity of lung injury. METHODS: A model of blunt chest injury in rat was employed. The effects of statins (rosuvastatin) and cyclooxygenase-2 (COX-2) inhibitors (meloxicam) on ALI were assessed by measuring inflammatory mediator levels in the serum and in the bronchoalveolar space. Animals were killed at the end of day 3. Histologic evaluation of lung tissue was performed to confirm the presence and severity of lung contusion as well as the effects of statins, nonsteroidal antiinflammatory drugs, and their combination. RESULTS: Administration of meloxicam after lung contusion decreased the amount of neutrophil infiltration; however, marked hemorrhage and edema were still noticed. Administration of rosuvastatin decreased significantly cytokine levels that were increased after the blunt chest trauma. Rosuvastatin increased the expression of inducible nitric oxide (iNOS), COX-2, heme oxygenase-1 (HO-1), and prostaglandin E2 (PGE-2) in the bronchoalveolar lavage fluid of the rat contused lungs. Coadministration of meloxicam prevented these changes. CONCLUSION: Rosuvastatin treatment after lung contusion attenuated several features of ALI. The enhanced activity of iNOS, COX-2, and HO-1 in the lung may reflect the advent of protective processes that took place in the contused lung. To our knowledge, this is the first demonstration that prostaglandin pathways play an essential role in the effects of statins in lung injury.

Risk of Stroke in Chronic Heart Failure Patients Without Atrial Fibrillation: Analysis of the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) Trials.

BACKGROUND: Our aim was to describe the incidence and predictors of stroke in patients who have heart failure without atrial fibrillation (AF). METHODS AND RESULTS: We pooled 2 contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca-Heart Failure trial (GISSI-HF). Of the 9585 total patients, 6054 did not have AF. Stroke occurred in 165 patients (4.7%) with AF and in 206 patients (3.4%) without AF (rates 16.8/1000 patient-years and 11.1/1000 patient-years, respectively). Using Cox proportional-hazards models, we identified the following independent predictors of stroke in patients without AF (ranked by χ(2) value): age (hazard ratio, 1.34; 95% confidence interval, 1.18-1.63 per 10 years), New York Heart Association class (1.60, 1.21-2.12 class III/IV versus II), diabetes mellitus treated with insulin (1.87, 1.22-2.88), body mass index (0.74, 0.60-0.91 per 5 kg/m(2) up to 30), and previous stroke (1.81, 1.19-2.74). N-terminal pro B-type natriuretic peptide (available in 2632 patients) was also an independent predictor of stroke (hazard ratio, 1.31; 1.11-1.57 per log unit) when added to this model. With the use of a risk score formulated from these predictors, we found that patients in the upper third of risk had a rate of stroke that approximated the risk in patients with AF. CONCLUSIONS: A small number of demographic and clinical variables identified a subset of patients who have heart failure without AF at a high risk of stroke.

Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial.

BACKGROUND: The role of lipid-lowering treatments in renoprotection for patients with diabetes is debated. We studied the renal effects of two statins in patients with diabetes who had proteinuria. METHODS: PLANET I was a randomised, double-blind, parallel-group trial done in 147 research centres in Argentina, Brazil, Bulgaria, Canada, Denmark, France, Hungary, Italy, Mexico, Romania, and the USA. We enrolled patients with type 1 or type 2 diabetes aged 18 years or older with proteinuria (urine protein:creatinine ratio [UPCR] 500-5000 mg/g) and taking stable angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or both. We randomly assigned participants to atorvastatin 80 mg, rosuvastatin 10 mg, or rosuvastatin 40 mg for 52 weeks. The primary endpoint was change from baseline to week 52 of mean UPCR in each treatment group. The study is registered with ClinicalTrials.gov, number NCT00296374. FINDINGS: We enrolled 353 patients: 118 were assigned to rosuvastatin 10 mg, 124 to rosuvastatin 40 mg, and 111 to atorvastatin 80 mg; of these, 325 were included in the intention-to-treat population. UPCR baseline:week 52 ratio was 0·87 (95% CI 0·77-0·99; p=0·033) with atorvastatin 80 mg, 1·02 (0·88-1·18; p=0·83) with rosuvastatin 10 mg, and 0·96 (0·83-1·11; p=0·53) with rosuvastatin 40 mg. In a post-hoc analysis to compare statins, we combined data from PLANET I with those from PLANET II (a similar randomised parallel study of 237 patients with proteinuria but without diabetes; registered with ClinicalTrials.gov, NCT00296400). In this analysis, atorvastatin 80 mg lowered UPCR significantly more than did rosuvastatin 10 mg (-15·6%, 95% CI -28·3 to -0·5; p=0·043) and rosuvastatin 40 mg (-18·2%, -30·2 to -4·2; p=0·013). Adverse events occurred in 69 (60%) of 116 patients in the rosuvastatin 10 mg group versus 79 (64%) of 123 patients in the rosuvastatin 40 mg group versus 63 (57%) of 110 patients in the atorvastatin 80 mg group; renal events occurred in nine (7·8%) versus 12 (9·8%) versus five (4·5%). INTERPRETATION: Despite high-dose rosuvastatin lowering plasma lipid concentrations to a greater extent than did high-dose atorvastatin, atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population. FUNDING: AstraZeneca.

The beneficial effects of rosuvastatin are independent of zinc supplementation in patients with atherosclerosis.

BACKGROUND: Statins have multiple antiatherosclerotic effects, but can reduce blood plasma concentrations of minerals, including zinc. As zinc possesses antiinflammatory and antioxidant effects, low zinc status can promote injuries or inadequate tissue repair in endothelial cells. Metallothionein (MT) expression might modulate responses induced by statins in patients with atherosclerosis. However, research regarding mineral status and the use of statins is scarce. This study evaluated the effects of zinc supplementation on zinc status and expression of the zinc-dependent MT1F and MT2A genes in patients with atherosclerosis treated with rosuvastatin. METHODS: A double-blind, randomized clinical trial was performed with 54 participants treated with 10mg rosuvastatin for 4 months with or without zinc supplementation (30mg/day). Diet, lipid profile, high-sensitivity reactive protein C (hs-CRP), plasma and erythrocyte zinc concentrations, erythrocyte superoxide dismutase (SOD) activity, and MT1F and MT2A genes expression were analyzed before and after intervention. RESULTS: Rosuvastatin therapy was effective in reducing low- and non-high-density lipoprotein, total cholesterol, triglycerides, and hs-CRP levels, independent of zinc supplementation. Additionally, zinc treatment had no effect on SOD enzyme activity (P=0.201), plasma (P>0.671) and erythrocyte (P>0.123) zinc concentrations, or the pattern of MT1F and MT2A genes expression (P=0.088 and P=0.229, respectively). CONCLUSIONS: The effectiveness of rosuvastatin treatment is independent of the effects of zinc supplementation. Moreover, rosuvastatin treatment did not have a significant impact on zinc status or MT1F and MT2A genes expression in patients with atherosclerosis.

Comparison of atorvastatin, pitavastatin and rosuvastatin for residual cardiovascular risk using non-fasting blood sampling.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk. However, some patients show symptoms of coronary heart disease (CHD) even though their LDL-C is strictly controlled. Therefore, it is important to treat other risk factors. METHODS: Some 129 outpatients with dyslipidemia who were treated with either atorvastatin 10 mg/day (ATO), pitavastatin 2 mg/day (PIT), or rosuvastatin 2.5 mg/day (ROS) were enrolled. After informed consent was obtained, these patients were switched to another statin. Lipid profiles and lipoprotein fraction by polyacrylamide gel electrophoresis (PAGE) were compared between before and after 3 months of treatment with non-fasting blood sample. RESULTS: LDL-C did not show any significant changes after switching and was maintained around 2.59 mmol/L in all groups. High-density lipoprotein cholesterol (HDL-C) was significantly increased in group ATO→PIT (1.43→1.54 mmol/L, p = 0.0010) and ROS→PIT (1.46→1.57 mmol/L, p = 0.0004), and was significantly decreased in group PIT→ATO (1.44→1.36 mmol/L, p = 0.0290). Apolipoprotein A-I (Apo A-I) and preheparin lipoprotein lipase (LPL) mass showed similar changes in HDL-C. Changes in HDL-C showed a significant positive correlation with those in Apo A-I and preheparin LPL mass, and a little but significant negative correlation with changes in Lp(a) and intermediate density lipoprotein (IDL) fraction. CONCLUSIONS: ATO, PIT, and ROS have comparable effect on LDL-C lowering. Changes in HDL-C were similar to those in Apo A-I and preheparin LPL mass, and PIT was the most effective treatment in increasing HDL-C, Apo A-I, and preheparin LPL mass.

Beneficial effects of black yeast derived 1-3, 1-6 Beta Glucan-Nichi Glucan in a dyslipidemic individual of Indian origin--a case report.

Dyslipidemia is a major risk factor for the development of cardiovascular diseases and statins are the common drugs used to correct dyslipidemia. Herein, we report a case where the subject was a nondiabetic, dyslipidemia patient on medication with Rosuvastatin. After the intake of Rosuvastatin, his triglycerides decreased to a minimum of 220 mg/dL. In order to augment the action of Rosuvastatin, he was advised to take 1.5 mg of Nichi Glucan food supplement, which is a 1,3-1,6 Beta Glucan derived from the black yeast, Aureobasidium pullulans, daily for 2 months. At the end of 2 months, his triglyceride levels decreased from 523 mg/dL (at start of the study) to 175 mg/dL. His VLDL levels, which were 104.6 mg/dL at the start of the study decreased to 35 mg/dL and the HDL cholesterol levels increased from 27 to 38 mg/dL. This is a first of its kind report on the effect of the black yeast derived 1,3-1,6 Beta Glucans on dyslipidemia not associated with diabetes. Thus supplementation of Nichi Glucan, 1,3- 1,6 Beta Glucan derived from the black yeast along with the routine medications was beneficial to treat dyslipidemia and a larger trial is needed to confirm the effects.

Evaluation of the pharmacokinetics and drug interactions of the two recently developed statins, rosuvastatin and pitavastatin.

INTRODUCTION: Statins are the cornerstone of lipid-lowering therapy to reduce the risk of coronary heart disease. Rosuvastatin and pitavastatin are the two recently developed statins with less potential for drug interaction resulting in improved safety profiles. AREAS COVERED: This review summarizes the pharmacokinetics and drug interactions of rosuvastatin and pitavastatin. The materials reviewed were identified by searching PubMed for publications using 'rosuvastatin', 'pitavastatin', 'statins', 'pharmacokinetics' and 'drug interaction' as the search terms. EXPERT OPINION: Rosuvastatin and pitavastatin have favorable pharmacokinetic and safety profiles as their disposition does not depend on or is only marginally influenced by cytochrome P450 (CYP) enzymes, thus potentially reducing the risk of drug-drug interactions of these two statins with other drugs known to inhibit CYP enzymes. However, drug transporters play a significant role in the disposition of rosuvastatin and pitavastatin and drug interactions may occur through these. Genetic polymorphisms in drug transporters may also affect the pharmacokinetics, drug interactions and/or the lipid-lowering effect of these statins to a different extent.

Rosuvastatin calcium in acute coronary syndromes.

INTRODUCTION: Low-density lipoprotein cholesterol (LDL-C) reduction using 3-hydroxy-3-methyl glutaryl coenzyme A (HMGCoA) reductase inhibitors (statins) has a proven survival benefit in patients presenting with acute coronary syndromes (ACS). Patients presenting with ACS remain at significant risk of subsequent cardiovascular death and non-fatal myocardial infarction despite high compliance with current guideline indicated secondary prevention therapies. There remains, therefore, a need to consider the potential benefits of more intensive LDL-C lowering after presentation with ACS. Rosuvastatin is the most potent of the currently available statins and has some unique pharmacological properties that may be advantageous in such patients. AREAS COVERED: We conducted a Medline literature search to identify rosuvastatin papers and papers on statin use in ACS published in English. In this review, we outline the pharmacology of rosuvastatin and examine its efficacy and safety. We also evaluate the published trials of statin therapy in ACS and offer an opinion on the use of rosuvastatin in ACS. EXPERT OPINION: There is adequate clinical trial evidence confirming the LDL-C lowering efficacy and safety of high-dose rosuvastatin in ACS. Whilst there are sound theoretical reasons to consider early use of high-dose rosuvastatin in ACS, the available level of evidence is insufficient to justify a wholesale change from the current standard of care.

Rosuvastatin in experimental brain trauma: improved capillary patency but no effect on edema or cerebral blood flow.

BACKGROUND: Microvascular dysfunction, characterized by edema formation secondary to increased blood-brain barrier (BBB) permeability and decreased blood flow, contributes to poor outcome following brain trauma. Recent studies have indicated that statins may counteract edema formation following brain trauma but little is known about other circulatory effects of statins in this setting. The objective of this study was to investigate whether statin treatment improves brain microcirculation early after traumatic brain injury, and whether microvascular effects are associated with altered production of nitric oxide and prostacyclin. METHODS: After fluid percussion injury, rats were randomized to intravenous treatment with 20mg/kg of rosuvastatin or vehicle. Brain edema (wet/dry weight), BBB integrity ((51)Cr-EDTA blood to brain transfer), cerebral blood flow ((14)C-iodoantipyrine autoradiography), and number of perfused cortical capillaries (FITC-albumin fluorescence microscopy), were measured at 4 and 24h. NO and prostacyclin production was estimated from plasma concentration of the degradation products NO2- and NO3- (NOx) and 6-keto-PGF1-alpha, respectively. Sham injured animals were treated with vehicle and analyzed at 4h. RESULTS: Trauma resulted in brain edema, BBB dysfunction, and reduced cortical blood flow, with no effect of statin treatment. Trauma also induced a reduction in the number of perfused capillaries, which was improved by statin treatment. Statin treatment led to increased NOx levels and reduced mean arterial blood pressure. 6-Keto-PGF1-alpha levels tended to increase after trauma, and were significantly reduced by rosuvastatin. CONCLUSIONS: Rosuvastatin treatment may improve microcirculation after traumatic brain injury by preserved patency of cerebral capillaries. This effect is associated with increased NO and reduced prostacyclin production. No effect on brain edema or BBB integrity was found.

Usefulness of rosuvastatin to prevent periprocedural myocardial injury in patients undergoing elective coronary intervention.

The aim of the present study was to investigate whether percutaneous coronary intervention-related periprocedural myocardial infarction (MI) can be suppressed more significantly with high- compared with low-dose rosuvastatin. A total of 232 patients scheduled to undergo elective percutaneous coronary intervention within 5 to 7 days were assigned to groups that would receive either 2.5 or 20 mg/day of rosuvastatin (n = 116 each). The incidence of periprocedural MI did not significantly differ between the high and low-dose groups (8.7% vs 18.7%, p = 0.052). In patients who were not taking statins at the time of enrollment, high-dose rosuvastatin significantly suppressed periprocedural MI compared with the low dose (10.5% vs 30.0%, p = 0.037). The difference was not significant in patients who were already taking statins (high vs low dose 7.6% vs 10.6%, p = 0.582). In conclusion, the incidence of percutaneous coronary intervention-related periprocedural MI was reduced more effectively by high-dose than by low-dose rosuvastatin in statin-naive patients. However, low-dose rosuvastatin is sufficient for patients who are already taking statins.

Rosuvastatin enhances the therapeutic efficacy of adipose-derived mesenchymal stem cells for myocardial infarction via PI3K/Akt and MEK/ERK pathways.

The poor viability of transplanted stem cells hampers their therapeutic efficacy for treatment of myocardial infarction. The aim of this study was to investigate whether rosuvastatin improved survival of adipose-derived mesenchymal stem cells (AD-MSCs) after transplantation into infarcted hearts. AD-MSCs isolated from Tg(Fluc-egfp) mice which constitutively express both firefly luciferase (Fluc) and enhanced green fluorescent protein were transplanted into infarcted hearts with or without rosuvastatin administration. Longitudinal in vivo bioluminescence imaging and histological staining revealed that rosuvastatin enhanced the survival of engrafted AD-MSCs. Furthermore, combined therapy of AD-MSC and rosuvastatin reduced fibrosis, decreased cardiomyocyte apoptosis, and preserved heart function. AD-MSCs were then subjected to hypoxia and serum deprivation injury in vitro to mimic the ischemic environment. Rosuvastatin (10(-6) mmol/L) enhanced the viability and paracrine effect of AD-MSCs, and decreased their apoptotic rate. Western blotting revealed that rosuvastatin supplementation increased Akt and ERK phosphorylation, which resulted in FoxO3a phosphorylation and nuclear export. In addition, rosuvastatin administration decreased the pro-apoptotic proteins Bim and Bax, and increased the anti-apoptotic proteins Bcl-xL and Bcl-2. Furthermore, these effects were abolished by PI3K inhibitor LY294002 and MEK1/2 inhibitor U0126. This study demonstrates that rosuvastatin may improve the survival of engrafted AD-MSCs at least in part through the PI3K/Akt and MEK/ERK1/2 signaling pathways. Combination therapy with rosuvastatin and AD-MSCs has a synergetic effect on improving myocardial function after infarction.

Model-based approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond.

INTRODUCTION: Membrane transporters have been recognized to play a key role in determining the absorption, distribution and elimination processes of drugs. The organic anion-transporting polypeptide (OATP)1B1 and OATP1B3 isoforms are selectively expressed in the human liver and are known to cause significant drug-drug interactions (DDIs), as observed with an increasing number of drugs. It is evident that DDIs involving hepatic transporters are capable of altering systemic, as well as tissue-specific, exposure of drug substrates resulting in marked differences in drug safety and/or efficacy. It is therefore essential to quantitatively predict such interactions early in the drug development to mitigate clinical risks. AREAS COVERED: The role of hepatic uptake transporters in drug disposition and clinical DDIs has been reviewed with an emphasis on the current state of the models applicable for quantitative predictions. The readers will also gain insight into the in vitro experimental tools available to characterize transport kinetics, while appreciating the knowledge gaps in the in vitro-in vivo extrapolation (IVIVE), which warrant further investigation. EXPERT OPINION: Static and dynamic models can be convincingly applied to quantitatively predict drug interactions, early in drug discovery, to mitigate clinical risks as well as to avoid unnecessary clinical studies. Compared to basic models, which focus on individual processes, mechanistic models provide the ability to assess DDI potential for compounds with systemic disposition determined by both transporters and metabolic enzymes. However, complexities in the experimental tools and an apparent disconnect in the IVIVE of transport kinetics have limited the physiologically based pharmacokinetic modeling strategies. Emerging data on the expression of transporter proteins and tissue drug concentrations are expected to help bridge these gaps. In addition, detailed characterization of substrate kinetics can facilitate building comprehensive mechanistic models.

Alteration of relation of atherogenic lipoprotein cholesterol to apolipoprotein B by intensive statin therapy in patients with acute coronary syndrome (from the Limiting UNdertreatment of lipids in ACS With Rosuvastatin [LUNAR] Trial).

The low-density lipoprotein (LDL) cholesterol goal of <70 mg/dl, recommended for patients with acute coronary syndrome, typically requires intensive therapy with high-dose statins. The secondary goals of non-high-density lipoprotein (non-HDL) cholesterol <100 mg/dl and apolipoprotein B (ApoB) <80 mg/dl have been recommended to reduce excess cardiovascular risk not captured by LDL cholesterol. The present post hoc analysis from the Limiting UNdertreatment of lipids in Acute coronary syndrome with Rosuvastatin (LUNAR) study examined the relation of ApoB with LDL cholesterol and non-HDL cholesterol at baseline and during treatment with intensive statin therapy. The LUNAR participants had acute coronary syndrome and received rosuvastatin 40 mg/day or 20 mg/day or atorvastatin 80 mg/day for 12 weeks. Linear regression analyses were used to compare ApoB, direct LDL cholesterol, and non-HDL cholesterol at baseline and during therapy. Of the 682 patients included in the analysis, 220 had triglycerides ≥200 mg/dl. Linear regression analysis showed that correlation of ApoB and non-HDL cholesterol was stronger than that of ApoB and LDL cholesterol and stronger with statin therapy than at baseline (R(2) = 0.93 for ApoB vs non-HDL cholesterol with statins). The target of ApoB of 80 mg/dl correlated with LDL cholesterol of 90 mg/dl and non-HDL cholesterol of 110 mg/dl at baseline and with LDL cholesterol of 74 mg/dl and non-HDL cholesterol of 92 mg/dl with statin therapy. For high-triglyceride patients, the corresponding on-treatment targets were LDL cholesterol of 68 mg/dl and non-HDL cholesterol of 92 mg/dl. In conclusion, non-HDL cholesterol is an adequate surrogate of ApoB during statin therapy, independent of triglyceride status. However, to match LDL cholesterol and ApoB treatment goals in the very-high-risk category, the current non-HDL cholesterol goal should be lowered by 8 to 10 mg/dl.

Rosuvastatin attenuates inflammation, apoptosis and fibrosis in a rat model of cyclosporine-induced nephropathy.

BACKGROUND/AIM: Cyclosporine (CsA)-induced kidney injury is characterized by renal dysfunction with inflammatory cell infiltrations, apoptosis and fibrosis. Pleiotropic effects of statins may exert anti-inflammatory, antiapoptotic and antifibrotic actions beyond lipid control. The aim of this study is to investigate whether rosuvastatin (RUS) has anti-inflammatory, antiapoptotic and antifibrotic effects on chronic CsA-induced nephropathy in a rat model. METHODS: Male Sprague-Dawley rats fed a low-sodium diet were divided into three treatment groups: control (0.9% saline injection), CsA (15 mg/kg/day by subcutaneous injection), CsA + RUS (10 mg/kg/day by gastric gavage). Renal function, CsA level and lipid levels were measured at the end of 4 weeks. The expression of ED-1, transforming growth factor-ß(1) (TGF-ß(1)) and α-smooth muscle actin (α-SMA) for inflammation and fibrosis were examined by Western blot analysis. The expression levels of apoptosis-associated factors were examined by Western blot analysis. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling (TUNEL) method. RESULTS: Kidney function was decreased in CsA-treated rats compared with controls, which was attenuated by RUS. RUS did not affect the lipid level or the blood CsA level. TUNEL staining showed that RUS inhibited CsA-induced tubular apoptosis. RUS decreased CsA-induced increased expression of Bax/Bcl-2 ratio. The expressions of ED-1, α-SMA, TGF-ß(1), Smad2/3, Smad4 and p-JNK were increased in CsA-treated rats, which were attenuated by RUS. Tubular atrophy and interstitial fibrosis in CsA-treated rats were attenuated by RUS supplementation. CONCLUSION: RUS supplementation attenuates proinflammatory and apoptosis-related factors and inhibits the fibrotic pathways including the smad-dependent and smad-independent pathways in a rat model of CsA-induced nephropathy.

Systems biology analysis unravels the complementary action of combined rosuvastatin and ezetimibe therapy.

AIMS: Combination-drug therapy takes advantage of the complementary action of their individual components, thereby potentiating its therapeutic effect. Potential disadvantages include side effects that are not foreseen on basis of the data available from drug monotherapy. Here, we used a systems biology approach to understand both the efficacy and the side effects of a cholesterol-lowering drug-combination therapy on the basis of the biological pathways and molecular processes affected by each drug alone or in combination. METHODS AND RESULTS: ApoE*3Leiden transgenic mice, a mouse model with human-like cholesterol-lowering drug responses, were treated with rosuvastatin and ezetimibe, alone and in combination. Analyses included functional responses, viz. effects on cardiovascular risk factors, inflammation, and atherosclerosis, and measurement of global gene expression, and identification of enriched biological pathways and molecular processes. Combination therapy reduced plasma cholesterol, plasma inflammation markers, and atherosclerosis stronger than the single drugs did. Systems biology analysis at the level of biological processes shows that the therapeutic benefit of combined therapy is largely the result of additivity of the complementary mechanisms of action of the two single drugs. Importantly, combination therapy also exerted a significant effect on 16 additional and mostly NF-κB-linked signaling processes, 11 of which tended to be regulated in a similar direction with monotherapy. CONCLUSION: This study shows that gene expression analysis together with bioinformatics pathway analysis has the potential to help predict and identify drug combination-specific complementary and side effects.