Characterization of interactions of simvastatin, pravastatin, fluvastatin, and pitavastatin with bovine serum albumin: multiple spectroscopic and molecular docking.

PubMed

Shi, Jie-Hua; Wang, Qi; Pan, Dong-Qi; Liu, Ting-Ting; Jiang, Min

2017-05-01

The binding interactions of simvastatin (SIM), pravastatin (PRA), fluvastatin (FLU), and pitavastatin (PIT) with bovine serum albumin (BSA) were investigated for determining the affinity of four statins with BSA through multiple spectroscopic and molecular docking methods. The experimental results showed that SIM, PRA, FLU, and PIT statins quenched the intrinsic fluorescence of BSA through a static quenching process and the stable stains-BSA complexes with the binding constants in the order of 10 4  M -1 at 298 K were formed through intermolecular nonbond interaction. The values of ΔH 0 , ΔS 0 and ΔG 0 in the binding process of SIM, PRA, FLU, and PIT with BSA were negative at the studied temperature range, suggesting that the binding process of four statins and BSA was spontaneous and the main interaction forces were van der Waals force and hydrogen-bonding interactions. Moreover, the binding of four statins with BSA was enthalpy-driven process due to |ΔH°|>|TΔS°| under the studied temperature range. From the results of site marker competitive experiments and molecular docking, subdomain IIIA (site II) was the primary binding site for SIM, PRA, FLU, and PIT on BSA. The results of UV-vis absorption, synchronous fluorescence, 3D fluorescence and FT-IR spectra proved that the slight change in the conformation of BSA, while the significant changes in the conformation of SIM, PRA, FLU, and PIT drug in statin-BSA complexes, indicating that the flexibility of statin molecules plays an important role in increasing the stability of statin-BSA complexes.

Quantitative assessment of the contribution of sodium-dependent taurocholate co-transporting polypeptide (NTCP) to the hepatic uptake of rosuvastatin, pitavastatin and fluvastatin.

PubMed

Bi, Yi-an; Qiu, Xi; Rotter, Charles J; Kimoto, Emi; Piotrowski, Mary; Varma, Manthena V; Ei-Kattan, Ayman F; Lai, Yurong

2013-11-01

Hepatic uptake transport is often the rate-determining step in the systemic clearance of drugs. The ability to predict uptake clearance and to determine the contribution of individual transporters to overall hepatic uptake is therefore critical in assessing the potential pharmacokinetic and pharmacodynamic variability associated with drug-drug interactions and pharmacogenetics. The present study revisited the interaction of statin drugs, including pitavastatin, fluvastatin and rosuvastatin, with the sodium-dependent taurocholate co-transporting polypeptide (NTCP) using gene transfected cell models. In addition, the uptake clearance and the contribution of NTCP to the overall hepatic uptake were assessed using in vitro hepatocyte models. Then NTCP protein expression was measured by a targeted proteomics transporter quantification method to confirm the presence and stability of NTCP expression in suspended and cultured hepatocyte models. It was concluded that NTCP-mediated uptake contributed significantly to active hepatic uptake in hepatocyte models for all three statins. However, the contribution of NTCP-mediated uptake to the overall active hepatic uptake was compound-dependent and varied from about 24% to 45%. Understanding the contribution of individual transporter proteins to the overall hepatic uptake and its functional variability when other active hepatic uptake pathways are interrupted could improve the current prediction practice used to assess the pharmacokinetic variability due to drug-drug interactions, pharmacogenetics and physiopathological conditions in humans. Copyright © 2013 John Wiley & Sons, Ltd.

Total hepatocellular disposition profiling of rosuvastatin and pitavastatin in sandwich-cultured human hepatocytes.

PubMed

Kanda, Katsuhiro; Takahashi, Ryosuke; Yoshikado, Takashi; Sugiyama, Yuichi

2018-04-09

This study describes the total disposition profiling of rosuvastatin (RSV) and pitavastatin (PTV) using a single systematic procedure called D-PREX (Disposition Profile Exploration) in sandwich-cultured human hepatocytes (SCHH). The biliary excretion fractions of both statins were clearly observed, which were significantly decreased dependent on the concentration of Ko143, an inhibitor for breast cancer resistance protein (BCRP). Ko143 also decreased the basolateral efflux fraction of RSV, whereas that of PTV was not significantly affected. To understand these phenomena, effects of Ko143 on biliary excretion (BCRP and multidrug resistance-associated protein (MRP) 2) and basolateral efflux (MRP3 and MRP4) transporters were examined using transporter-expressing membrane vesicles. BCRP, MRP3 and MRP4-mediated transport of RSV was observed, and Ko143 inhibited these transporters except MRP3. BCRP and MRP4 also mediated the transport of PTV, but the Ko143-mediated inhibition was only clear for BCRP. These results might explain the Ko143-mediated complete and partial inhibition of the biliary excretion and the basolateral efflux of RSV, respectively, in SCHH. In conclusion, D-PREX with sequential sampling of supernatants prior to cell lysis enables the evaluation of total drug disposition profiles resulting from complex interplays of intracellular pathways, which would provide high-throughput evaluation of drug disposition during drug discovery. Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion.

PubMed

Zheng, Chunyu; Azcutia, Veronica; Aikawa, Elena; Figueiredo, Jose-Luiz; Croce, Kevin; Sonoki, Hiroyuki; Sacks, Frank M; Luscinskas, Francis W; Aikawa, Masanori

2013-02-01

Activation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid-independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo. Physiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor κB (NF-κB) mediated apoCIII-induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-κB activation. Furthermore, in the aorta of hypercholesterolaemic Ldlr(-/-) mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect. These findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII.

Dual Incorporation of the in vitro Data (IC50) and in vivo (Cmax) Data for the Prediction of Area Under the Curve (AUC) for Statins using Regression Models Developed for Either Pravastatin or Simvastatin.

PubMed

Srinivas, N R

2016-08-01

Linear regression models utilizing a single time point (Cmax) has been reported for pravastatin and simvastatin. A new model was developed for the prediction of AUC of statins that utilized the slopes of the above 2 models, with pharmacokinetic (Cmax) and a pharmacodynamic (IC50 value) components for the statins. The prediction of AUCs for various statins (pravastatin, atorvastatin, simvastatin and rosuvastatin) was carried out using the newly developed dual pharmacokinetic and pharmacodynamic model. Generally, the AUC predictions were contained within 0.5 to 2-fold difference of the observed AUC suggesting utility of the new models. The root mean square error predictions were<45% for the 2 models. On the basis of the present work, it is feasible to utilize both pharmacokinetic (Cmax) and pharmacodynamic (IC50) data for effectively predicting the AUC for statins. Such a new concept as described in the work may have utility in both drug discovery and development stages. © Georg Thieme Verlag KG Stuttgart · New York.

Relationships of Changes in Pharmacokinetic Parameters of Substrate Drugs in Drug-Drug Interactions on Metabolizing Enzymes and Transporters.

PubMed

Yamazaki, Shinji

2018-05-03

A general objective of drug-drug interaction (DDI) studies is to determine whether potential interactions of new molecular entities with concomitantly administered other drugs exist and, if DDIs occur, whether dosage adjustments are required. A typical end point for DDI evaluations is the ratio of area under the plasma concentration-time curve (AUC) of substrate drugs (AUCR), whereas the ratios of maximal plasma concentration (C max ) and terminal half-life (t 1/2 ) are also important to understand DDI mechanisms (C max R and t 1/2 R, respectively). Because changes in substrate AUC by precipitant drugs ultimately result from alterations of C max and t 1/2 , AUCR can be considered a hybrid parameter of C max R and t 1/2 R, for example, AUCR ≈ C max R  ×  t 1/2 R. The primary objective of this study was to investigate the relationships between AUCR, C max R, and t 1/2 R in physiologically based pharmacokinetic model-predicted and clinically observed DDI results. First, the model-predicted results showed the excellent proportional relationship between AUCR and (C max R × t 1/2 R) in DDI results of virtual substrates having a wide range of oral bioavailability with coadministration of ketoconazole, ritonavir, and rifampin. Second, the reasonable proportional relationships were also observed in the clinically observed DDI results of midazolam and statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) with various inhibitors and inducers. Finally, these results suggest that utilization of the proportional relationship between AUCR and (C max R × t 1/2 R) can provide an additional framework to further interpret DDI results reasonably and clearly. Furthermore, the proportional relationship can be purposely used to assess study design and pharmacokinetic analyses in DDI studies. © 2018, The American College of Clinical Pharmacology.

ATP-dependent transport of statins by human and rat MRP2/Mrp2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellis, Lucy C.J., E-mail: Luc_ellis@yahoo.co.uk; Hawksworth, Gabrielle M.; Weaver, Richard J.

2013-06-01

Multidrug resistance associated protein-2, MRP2 (human), Mrp2 (rat) are an efflux transporter, responsible for the transport of numerous endogenous and xenobiotic compounds including taurocholate, methotrexate and carboxydichlorofluorescein (CDF). The present study aims to characterise transport of statins by human and rat MRP2/Mrp2 using membrane and vesicle preparations. All statins tested (simvastatin, pravastatin, pitavastatin, fluvastatin, atorvastatin, lovastatin and rosuvastatin) stimulated vanadate-sensitive ATPase activity in membranes expressing human or rat MRP2/Mrp2, suggesting that all statins are substrates of human and rat MRP2/Mrp2. The substrate affinity (Km) of all statins for MRP2/Mrp2 was comparable and no correlation between lipophilicity (logD{sub 7.0}) and Kmmore » was seen. All statins also inhibited uptake of the fluorescent Mrp2 substrate, CDF (1 μM) into vesicles expressing human or rat MRP2/Mrp2 with similar IC{sub 50} values. Fitting of the inhibitory data to the hill slope equation, gave hill coefficients (h) of greater than one, suggesting that transport involved more than one binding site for inhibitors of MPR2 and Mrp2. We conclude that statins were transported by both human and rat MRP2/Mrp2 with similar affinity. Statins were also shown to compete with other substrates for transport by MRP2/Mrp2 and that this transport involved more than one binding site on the Mrp2/MRP2 protein. - Highlights: • We characterised MRP2 (human)/Mrp2 (rat)-mediated transport of statins. • We show statins were transported by human and rat MRP2/Mrp2. • Statins competed with a known substrate for transport by MRP2/Mrp2. • Competition involved more than one binding site on the MRP2/Mrp2 protein.« less

Statin-associated muscular and renal adverse events: data mining of the public version of the FDA adverse event reporting system.

PubMed

Sakaeda, Toshiyuki; Kadoyama, Kaori; Okuno, Yasushi

2011-01-01

Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to assess the muscular and renal adverse events induced by the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and to attempt to determine the rank-order of the association. After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving pravastatin, simvastatin, atorvastatin, or rosuvastatin were analyzed. Authorized pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Myalgia, rhabdomyolysis and an increase in creatine phosphokinase level were focused on as the muscular adverse events, and acute renal failure, non-acute renal failure, and an increase in blood creatinine level as the renal adverse events. Based on 1,644,220 AERs from 2004 to 2009, signals were detected for 4 statins with respect to myalgia, rhabdomyolysis, and an increase in creatine phosphokinase level, but these signals were stronger for rosuvastatin than pravastatin and atorvastatin. Signals were also detected for acute renal failure, though in the case of atorvastatin, the association was marginal, and furthermore, a signal was not detected for non-acute renal failure or for an increase in blood creatinine level. Data mining of the FDA's adverse event reporting system, AERS, is useful for examining statin-associated muscular and renal adverse events. The data strongly suggest the necessity of well-organized clinical studies with respect to statin-associated adverse events.

A crossover study of rosuvastatin and pitavastatin in patients with type 2 diabetes.

PubMed

Yanagi, Kazunori; Monden, Tsuyoshi; Ikeda, Shiori; Matsumura, Mihoko; Kasai, Kikuo

2011-02-01

The effects of a low dose of rosuvastatin (ROS) and pitavastatin (PIT) on lipid profiles and inflammation markers were assessed in subjects with type 2 diabetes mellitus. A total of 90 Japanese type 2 diabetes patients with hyperlipidemia (low-density lipoprotein cholesterol [LDL-C] ≥140 mg/dL) were enrolled in this study. They were randomly assigned to four groups with open-label treatment with ROS (2.5 mg daily) or PIT (2 mg daily); two groups were sequentially treated with both drugs, with crossover of medication after 12 weeks, and the other two groups underwent treatment with either ROS or PIT for 24 weeks. The primary endpoints were the percentage changes in LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglyceride, and the LDL-C/HDL-C ratio. Both ROS and PIT lowered LDL-C and triglyceride, and increased HDL-C. In particular, significantly greater reduction in LDL-C was seen with ROS (-44.1%) than with PIT (-36.9%, P<0.01) in the crossover group from ROS to PIT, and the same result was detected in the crossover group from PIT (-34.8%) to ROS (-44.7%). The ratio of LDL-C/HDL-C was significantly reduced with ROS treatment (from 3.45 to 1.85) compared with that with PIT (from 3.45 to 2.22, P<0.01). Both ROS and PIT lowered plasma levels of high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF)-alpha, and plasminogen activator inhibitor-1 (PAI-1). In addition, the hsCRP level with the administration of ROS was significantly improved compared with the administration of PIT. There was no significant correlation between changes in LDL-C and hsCRP, TNF-alpha, and PAI-1 levels. ROS and PIT did not have an adverse effect on glycemic control in type 2 diabetes patients. Therapy with both statins improved lipid profiles and reduced proinflammatory responses; however, 2.5 mg of ROS have a potent LDL-C-lowering and hsCRP-lowering effect compared with 2 mg of PIT in patients with diabetes.

Impact of statin therapy on plasma adiponectin concentrations: A systematic review and meta-analysis of 43 randomized controlled trial arms.

PubMed

Chruściel, Piotr; Sahebkar, Amirhossein; Rembek-Wieliczko, Magdalena; Serban, Maria-Corina; Ursoniu, Sorin; Mikhailidis, Dimitri P; Jones, Steven R; Mosteoru, Svetlana; Blaha, Michael J; Martin, Seth S; Rysz, Jacek; Toth, Peter P; Lip, Gregory Y H; Pencina, Michael J; Ray, Kausik K; Banach, Maciej

2016-10-01

The effect of statin therapy on plasma adiponectin levels has not been conclusively studied. Therefore, we aimed to evaluate this effect through a systematic review and meta-analysis of available randomized controlled trials (RCTs). Quantitative data synthesis was performed using a random-effects model with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics. In 30 studies (43 study arms) with 2953 participants, a significant increase in plasma adiponectin levels was observed after statin therapy (WMD: 0.57 μg/mL, 95% CI: 0.18, 0.95, p = 0.004). In subgroup analysis, atorvastatin, simvastatin, rosuvastatin, pravastatin and pitavastatin were found to change plasma adiponectin concentrations by 0.70 μg/mL (95% CI: -0.26, 1.65), 0.50 μg/mL (95% CI: -0.44, 1.45), -0.70 μg/mL (95% CI: -1.08, -0.33), 0.62 μg/mL (95% CI: -0.12, 1.35), and 0.51 μg/mL (95% CI: 0.30, 0.72), respectively. With respect to duration of treatment, there was a significant increase in the subset of trials lasting ≥12 weeks (WMD: 0.88 μg/mL, 95% CI: 0.19, 1.57, p = 0.012) but not in the subset of <12 weeks of duration (WMD: 0.18 μg/mL, 95% CI: -0.23, 0.58, p = 0.390). Random-effects meta-regression suggested a significant association between statin-induced elevation of plasma adiponectin and changes in plasma low density lipoprotein cholesterol levels (slope: 0.04; 95% CI: 0.01, 0.06; p = 0.002). The meta-analysis showed a significant increase in plasma adiponectin levels following statin therapy. Although statins are known to increase the risk for new onset diabetes mellitus, our data might suggest that the mechanism for this is unlikely to be due to a reduction in adiponectin expression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Trends in Statin Use in Seniors 1999 to 2013: Time Series Analysis.

PubMed

Minard, Laura V; Corkum, Amber; Sketris, Ingrid; Fisher, Judith; Zhang, Ying; Saleh, Ahmed

2016-01-01

To examine HMG-CoA reductase inhibitor (statin) drug dispensing patterns to Nova Scotia Seniors' Pharmacare program (NSSPP) beneficiaries over a 14-year period in response to: 1) rosuvastatin market entry in 2003, 2) JUPITER trial publication in 2008, and 3) generic atorvastatin availability in 2010. All NSSPP beneficiaries who redeemed at least one prescription for a statin from April 1, 1999 to March 31, 2013 were included. Aggregated, anonymous monthly prescription counts were extracted by the Nova Scotia Department of Health and Wellness (Nova Scotia, Canada) and changes in dispensing patterns of statins were measured. Data were analyzed using descriptive analyses and interrupted time series methods. The percentage of NSSPP beneficiaries dispensed any statin increased from 5.3% in April 1999 to 20.7% in March 2013. In 1999, most NSSPP beneficiaries were dispensed either simvastatin (29.5%) or atorvastatin (28.7%). When rosuvastatin was added to the NSSPP Formulary in August 2003, prescriptions dispensed for simvastatin, lovastatin, pravastatin, and fluvastatin declined significantly (slope change, -0.0027; 95% confidence interval (CI), (-0.0046, -0.0009)). This significant decline continued following the publication of JUPITER (level change, -0.1974; 95% CI, (-0.2991, -0.0957)) and the availability of generic atorvastatin (level change, -0.2436; 95% CI, (-0.3314, -0.1558)). Atorvastatin was not significantly affected by any of the three interventions, although it maintained an overall decreasing trend. Only upon the availability of generic atorvastatin did the upward trend in rosuvastatin use decrease significantly (slope change, -0.0010, 95% CI, (-0.0015, -0.0005)). The type and rate of statins dispensed to NSSPP beneficiaries changed from 1999 to 2013 in response to the availability of new agents and publication of the JUPITER trial. The overall proportion of NSSPP beneficiaries dispensed a statin increased approximately 4-fold during the study period. In 2013, rosuvastatin was the most commonly dispensed statin (44.1%) followed by atorvastatin (39.1%).

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-06-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate, fluvastatin sodium, fondaparinux sodium; Gaboxadol, gamma-hydroxybutyrate sodium, gefitinib, gelclair, gemcitabine, gemfibrozil, glibenclamide, glyminox; Haloperidol, heparin sodium, HPV 16/HPV 18 vaccine, human insulin, human insulin; Icatibant, imatinib mesylate, indium 111 (111In) ibritumomab tiuxetan, infliximab, INKP-100, iodine (I131) tositumomab, IoGen, ipratropium bromide, ixabepilone; L-870810, lamivudine, lapatinib, laquinimod, latanoprost, levonorgestrel, licochalcone a, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, lorazepam, lovastatin; Maraviroc, maribavir, matuzumab, MDL-100907, melphalan, methotrexate, methylprednisolone, mitomycin, mitoxantrone hydrochloride, MK-0431, MN-001, MRKAd5 HIV-1 gag/pol/nef, MRKAd5gag, MVA.HIVA, MVA-BN Nef, MVA-Muc1-IL-2, mycophenolate mofetil; Nelfinavir mesilate, nesiritide, NSC-330507; Olanzapine, olmesartan medoxomil, omalizumab, oral insulin, osanetant; PA-457, paclitaxel, paroxetine, paroxetine hydrochloride, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, perillyl alcohol, pexelizumab, pimecrolimus, pitavastatin calcium, porfiromycin, prasterone, prasugrel, pravastatin sodium, prednisone, pregabalin, prinomastat, PRO-2000, propofol, prostate cancer vaccine; Rasagiline mesilate, rhBMP-2/ACS, rhBMP-2/BCP, rhC1, ribavirin, rilpivirine, ritonavir, rituximab, Ro-26-9228, rosuvastatin calcium, rosuvastatin sodium, rubitecan; Selodenoson, simvastatin, sirolimus, sitaxsentan sodium, sorafenib, SS(dsFv)-PE38, St. John's Wort extract, stavudine; Tacrolimus, tadalafil, tafenoquine succinate, talaglumetad, tanomastat, taxus, tegaserod maleate, telithromycin, tempol, tenofovir, tenofovir disoproxil fumarate, testosterone enanthate, TH-9507, thalidomide, tigecycline, timolol maleate, tiotropium bromide, tipifarnib, torcetrapib, trabectedin, travoprost, travoprost/timolol, treprostinil sodium; Valdecoxib, vardenafil hydrochloride hydrate, varenicline, VEGF-2 gene therapy, venlafaxine hydrochloride, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine. Copyright (c) 2005 Prous Science. All rights reserved.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-06-01

(+)-Dapoxetine hydrochloride; Abatacept, Adalimumab, Agalsidase beta, Alemtuzumab, Alglucosidase alfa, Aliskiren fumarate, Ambrisentan, Amlodipine, Aripiprazole, Atrasentan, Azacitidine, Azelnidipine; Belotecan hydrochloride, Bevacizumab, Bilastine, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, CG-100649, Cinacalcet hydrochloride, Clindamycin phosphate/ benzoyl peroxide; Dasatinib, Denosumab, Duloxetine hydrochloride, Dutasteride, Dutasteride/tamsulosin; Ecogramostim, Eculizumab, Eltrombopag olamine, EndoTAG-1, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe; FAHF-2, Fondaparinux sodium; Gefitinib, Golimumab; HEV-239, HSV-TK; Imatinib mesylate, Indium 111 ((111)In) ibritumomab tiuxetan, Influenza vaccine(surface antigen, inactivated, prepared in cell culture), Insulin glargine; Kisspeptin-54; Lidocaine/prilocaine, Lomitapide; Maraviroc, Mirodenafil hydrochloride, MK-8141, MVA-Ag85A; Nilotinib hydrochloride monohydrate; Olmesartan medoxomil; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pitavastatin calcium, Prasugrel; Recombinant human relaxin H2, RHAMM R3 peptide, Rivaroxaban, Rosuvastatin calcium, RRz2; Sagopilone, Salinosporamide A, SB-509, Serlopitant, Sirolimus-eluting stent, Sorafenib, Sunitinib malate; Tadalafil, Temsirolimus, Teriparatide, TG-4010, Tositumomab/iodine (I131) tositumomab; Velusetrag Hydrochloride; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Dyslipidemia and its therapeutic challenges in renal transplantation.

PubMed

Riella, L V; Gabardi, S; Chandraker, A

2012-08-01

Cardiovascular disease is the leading cause of mortality in kidney transplant recipients. Dyslipidemia is a common finding after renal transplantation and a significant risk factor in the development of coronary heart disease. Although a causal relationship with cardiovascular mortality has not been proven in the transplant population, it is reasonable to extrapolate data from the general population and aggressively treat posttransplant dyslipidemia. Statins are considered the agents of choice, though their use may be complicated by drug misadventures. Pravastatin, fluvastatin and pitavastatin are considered to be the safest statins to use in this population; however, given their low-potency, a high-potency statin, such as atorvastatin, may be necessary in patients with significant dyslipidemia. In this article, we discuss the etiology of and treatment strategies for dyslipidemia in renal transplant recipients based on a literature review of potential therapeutic adverse effects and benefits in this population. We will also evaluate the reasons for and consequences of the latest Food and Drug Administration (FDA) warnings regarding the use of simvastatin. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

[Medication management: Simvastatin and Amlodipin - a clinically relevant drug-interaction?

PubMed

Schröder, Jane; Goltz, Lisa; Knoth, Holger

2016-10-01

The clinical relevance of the drug-drug interaction simvastatin and amlodipine is appraised controversially by german simvastatin Summary of Product Characteristics (SPCs) and different drug interaction databases. Results of clinical trials have shown that simultaneous administration of simvastatin and amlodipine can increase simvastatin bioavailability. However, it is unclear whether this increase is associated with a higher risk for adverse drug events. So far there is no evidence that the combination might increase cases of myopathy or rhabdomyolysis. Therefore combined treatment with amlodipine and up to 40 mg simvastatin daily seems clinically justifiable if the patient does not report adverse events. If myopathy or muscle weakness occur, simvastatin dose should be reduced to 20 mg daily or the patient should be switched to pravastatin, fluvastatin or rosuvastatin. The highest approved dose of simvastatin (80 mg) is generally not recommended in new patients because of increased risk of muscle damage. © Georg Thieme Verlag KG Stuttgart · New York.

Statin Lactonization by Uridine 5'-Diphospho-glucuronosyltransferases (UGTs).

PubMed

Schirris, Tom J J; Ritschel, Tina; Bilos, Albert; Smeitink, Jan A M; Russel, Frans G M

2015-11-02

Statins are cholesterol-lowering drugs that have proven to be effective in lowering the risk of major cardiovascular events. Although well tolerated, statin-induced myopathies are the most common side effects. Compared to their pharmacologically active acid form, statin lactones are more potent inducers of toxicity. They can be formed by glucuronidation mediated by uridine 5'-diphospho-glucuronosyltransferases (UGTs), but a systematic characterization of subtype specificity and kinetics of lactonization is lacking. Here, we demonstrate for six clinically relevant statins that only UGT1A1, 1A3, and 2B7 contribute significantly to their lactonization. UGT1A3 appeared to have the highest lactonization capacity with marked differences in statin conversion rates: pitavastatin ≫ atorvastatin > cerivastatin > lovastatin > rosuvastatin (simvastatin not converted). Using in silico modeling we could identify a probable statin interaction region in the UGT binding pocket. Polymorphisms in these regions of UGT1A1, 1A3, and 2B7 may be a contributing factor in statin-induced myopathies, which could be used in personalization of statin therapy with improved safety.

Anticonvulsant and Antioxidant Effects of Pitavastatin Against Pentylenetetrazol-Induced Kindling in Mice.

PubMed

Faghihi, Nastaran; Mohammadi, Mohammad Taghi

2017-06-01

Purpose: The pleiotropic effects of statins (antioxidant and anti-inflammation) have been reported by previous studies. Therefore, we aimed to determine whether pitavastatin has protective effects against pentylenetetrazol (PTZ)-induced kindling in mice and also whether pitavastatin improves the brain antioxidant capacity and attenuates the oxidative injuries in kindled mice. Methods: Twenty-four mice were randomly divided into four groups (each group n=6); control, PTZ-kindling and PTZ-kindled rats treated with pitavastatin (1&4 mg/kg). PTZ kindling seizures were induced by repetitive intraperitoneal injections of PTZ (65 mg/kg) every 48 hours till day twenty-one. Animals received daily oral pitavastatin for twenty-one days. Latency, score and duration of the seizures were recorded. The activities of catalase (CAT) ad superoxide dismutase (SOD), and likewise the contents of malondialdehyde (MDA) and nitrate were assessed in the brains of all rats. Results: There was a progressive reduction in latency of the kindled rats in the next injections of PTZ. Pitavastatin reduced this value (latency) particularly at higher dose. Seizures duration and score also decreased in treatment groups. SOD and CAT activities significantly decreased in PTZ-kindling group by 62% and 64%, respectively, but pitavastatin did not significantly change the SOD and CAT activities. Brain MDA and nitrate significantly increased in PTZ-kindling group by 53% and 30%, respectively. Pitavastatin at higher dose significantly decreased the MDA and nitrate contents of PTZ-kindling rats by 45% and 32%, respectively. Conclusion: Our findings revealed that pitavastatin can improve the behavioral expression of the PTZ-kindling rats and attenuate the seizure-induced oxidative/nitrosative damage.

Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia.

PubMed

Oda, Shinichiro; Nagahama, Ryoji; Nakano, Kaku; Matoba, Tetsuya; Kubo, Mitsuki; Sunagawa, Kenji; Tominaga, Ryuji; Egashira, Kensuke

2010-08-01

We recently demonstrated in a murine model that nanoparticle-mediated delivery of pitavastatin into vascular endothelial cells effectively increased therapeutic neovascularization. For the development of a clinically applicable approach, further investigations are necessary to assess whether this novel system can induce the development of collateral arteries (arteriogenesis) in a chronic ischemia setting in larger animals. Chronic hind limb ischemia was induced in rabbits. They were administered single injections of nanoparticles loaded with pitavastatin (0.05, 0.15, and 0.5 mg/kg) into ischemic muscle. Treatment with pitavastatin nanoparticles (0.5 mg/kg), but not other nanoparticles, induced angiographically visible arteriogenesis. The effects of intramuscular injections of phosphate-buffered saline, fluorescein isothiocyanate (FITC)-loaded nanoparticles, pitavastatin (0.5 mg/kg), or pitavastatin (0.5 mg/kg) nanoparticles were examined. FITC nanoparticles were detected mainly in endothelial cells of the ischemic muscles for up to 4 weeks. Treatment with pitavastatin nanoparticles, but not other treatments, induced therapeutic arteriogenesis and ameliorated exercise-induced ischemia, suggesting the development of functional collateral arteries. Pretreatment with nanoparticles loaded with vatalanib, a vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor, abrogated the therapeutic effects of pitavastatin nanoparticles. Separate experiments with mice deficient for VEGF receptor tyrosine kinase demonstrated a crucial role of VEGF receptor signals in the therapeutic angiogenic effects. The nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients. Copyright (c) 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Inhibiting prenylation augments chemotherapy efficacy in renal cell carcinoma through dual inhibition on mitochondrial respiration and glycolysis.

PubMed

Huang, Jiangrong; Yang, Xiaoyu; Peng, Xiaochun; Huang, Wei

2017-11-18

Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of pitavastatin in different SLCO1B1 backgrounds on repaglinide pharmacokinetics and pharmacodynamics in healthy Chinese males.

PubMed

Zhu, Jie; Song, Min; Tan, Hong-Yi; Huang, Li-Hua; Huang, Zhi-Jun; Liu, Chang; Fu, Zhi-Min; Huang, Yuan-Yuan; Tan, Zhi-Rong; Chen, Xiao-Ping; Yuan, Hong; Yang, Guo-Ping

2013-05-01

The effect of pitavastatin and SLCO1B1 genetic background on the pharmacokinetic and pharmacodynamic properties of repaglinide was investigated. In this randomized, placebo-controlled, crossover study, twelve healthy Chinese males were administered with pitavastatin 4 mg/d or the placebo for 5 d followed by repaglinide 4 mg given orally on d 5. Plasma repaglinide and glucose levels were measured by liquid chromatography-tandem mass spectrometry (LC/MS/MS) and the glucose oxidase method, respectively. Treatment with pitavastatin significantly increased the peak plasma concentration (Cmax) of repaglinide (P=0.003) in SLCO1B1*1b homozygotes (P=0.015) and SLCO1B1*15 carriers (P=0.031). Treatment with pitavastatin led to a marginal increase in the area under plasma concentration-time curve from 0 h to infinity (AUC0⇒∞) of repaglinide (P=0.091). There was no significant difference in pharmacokinetic parameters or hypoglycemic effects of repaglinide among SLCO1B1 genotypes in either the pitavastatin or control group. Pitavastatin increased the Cmax of the plasma concentration of repaglinide in an SLCO1B1 genotype dependent manner, but had no apparent effect on the pharmacodynamics of repaglinide in healthy volunteers. The p values for this statement were not reported.

Improvement of endothelial function by pitavastatin: a meta-analysis.

PubMed

Katsiki, Niki; Reiner, Željko; Tedeschi Reiner, Eugenia; Al-Rasadi, Khalid; Pirro, Matteo; Mikhailidis, Dimitri P; Sahebkar, Amirhossein

2018-02-01

Dyslipidemia is commonly associated with endothelial dysfunction and increased cardiovascular risk. Pitavastatin has been shown to reduce total and low-density lipoprotein cholesterol, to increase high-density lipoprotein (HDL)-cholesterol and improve HDL function. Furthermore, several trials explored its effects on flow-mediated dilation (FMD), as an index of endothelial function. The authors evaluated the effect of pitavastatin therapy on FMD. The authors performed a systematic review and meta-analysis of all clinical trials exploring the impact of pitavastatin on FMD. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Six eligible studies comprising 7 treatment arms were selected for this meta-analysis. Overall, WMD was significant for the effect of pitavastatin on FMD (2.45%, 95% CI: 1.31, 3.60, p < 0.001) and the effect size was robust in the leave-one-out sensitivity analysis. This meta-analysis of all available clinical trials revealed a significant increase of FMD induced by pitavastatin.

Effect of Pitavastatin Treatment on ApoB-48 and Lp-PLA₂ in Patients with Metabolic Syndrome: Substudy of PROspective Comparative Clinical Study Evaluating the Efficacy and Safety of PITavastatin in Patients with Metabolic Syndrome.

PubMed

Lee, Hyo Sun; Jung, Chang Hee; Kim, Sung Rae; Jang, Hak Chul; Park, Cheol Young

2016-03-01

Apolipoprotein (Apo) B-48 is an intestinally derived lipoprotein that is expected to be a marker for cardiovascular disease (CVD). Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a vascular-specific inflammatory marker and important risk predictor of CVD. The aim of this study was to explore the effect of pitavastatin treatment and life style modification (LSM) on ApoB-48 and Lp-PLA₂ levels in metabolic syndrome (MS) patients at relatively low risk for CVD, as a sub-analysis of a previous multi-center prospective study. We enrolled 75 patients with MS from the PROPIT study and randomized them into two treatment groups: 2 mg pitavastatin daily+intensive LSM or intensive LSM only. We measured the change of lipid profiles, ApoB-48 and Lp-PLA₂ for 48 weeks. Total cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and ApoB-100/A1 ratio were significantly improved in the pitavastatin+LSM group compared to the LSM only group (P≤0.001). Pitavastatin+LSM did not change the level of ApoB-48 in subjects overall, but the level of ApoB-48 was significantly lower in the higher mean baseline value group of ApoB-48. The change in Lp-PLA₂ was not significant after intervention in either group after treatment with pitavastatin for 1 year. Pitavastatin treatment and LSM significantly improved lipid profiles, ApoB-100/A1 ratio, and reduced ApoB-48 levels in the higher mean baseline value group of ApoB-48, but did not significantly alter the Lp-PLA₂ levels.

Efficacy and Safety of Pitavastatin in Children and Adolescents with Familial Hypercholesterolemia in Japan and Europe.

PubMed

Harada-Shiba, Mariko; Kastelein, John J P; Hovingh, G Kees; Ray, Kausik K; Ohtake, Akira; Arisaka, Osamu; Ohta, Takao; Okada, Tomoo; Suganami, Hideki; Wiegman, Albert

2018-05-01

Children with Familial Hypercholesterolemia (FH) are widely prescribed statins, and it has been suggested that the effects of statins differ among ethnicities. We compared the efficacy and safety of pitavastatin in children and adolescents with FH in clinical trials conducted in Japan and Europe. Low-density lipoprotein cholesterol (LDL-C) reductions, adjusted for confounding factors, and safety were compared between the studies in Japan and Europe. In the Japanese study, 14 males with heterozygous FH, aged 11.8±1.6 years, were randomized to 52-week double-blind treatment with 1 or 2 mg/day pitavastatin. In the European study, 106 children and adolescents with high risk hyperlipidemia (103 heterozygous FH), aged 10.6±2.9 years, were randomized to 12-week double-blind treatment with 1, 2 or 4 mg/day pitavastatin or placebo; 84 of these patients and 29 new patients participated in a 52-week open-label extension study. Age, body weight and baseline LDL-C were identified as factors influencing LDL-C reduction. There were no significant differences in the adjusted mean percentage reduction in LDL-C in Japanese and European children by pitavastatin (24.5% and 23.6%, respectively at 1 mg/day and 33.5% and 30.8%, respectively at 2 mg/day). Pitavastatin was well tolerated without any difference in the frequency or nature of adverse events between the treatment groups, or between the studies. There were no significant differences between the efficacy or safety of pitavastatin in Japanese and European children and adolescents with FH, suggesting no relevant ethnic differences in the safety or efficacy of pitavastatin.

Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.

PubMed

Prueksaritanont, T; Tatosian, D A; Chu, X; Railkar, R; Evers, R; Chavez-Eng, C; Lutz, R; Zeng, W; Yabut, J; Chan, G H; Cai, X; Latham, A H; Hehman, J; Stypinski, D; Brejda, J; Zhou, C; Thornton, B; Bateman, K P; Fraser, I; Stoch, S A

2017-04-01

A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Pitavastatin attenuates monocyte activation in response to orthopedic implant-derived wear particles by suppressing the NF-κB signaling pathway.

PubMed

Zhang, Zehua; Dai, Fei; Cheng, Peng; Luo, Fei; Hou, Tianyong; Zhou, Qiang; Xie, Zhao; Deng, Moyuan; Xu, Jian-Zhong

2015-11-01

Aseptic loosening secondary to particle‑induced periprosthetic osteolysis is considered to be the primary cause of long‑term implant failure in orthopedic surgery. Implant‑derived wear particles activate and recruit macrophages and osteoclasts, which cause a persistent inflammatory response with bone destruction that is followed by a loosening of the implant. Thus, strategies for inhibiting macrophage and osteoclast function may provide a therapeutic benefit for preventing aseptic loosening. The aim of the present study was to determine the effects of pitavastatin on the activation and cytokine response of polymethyl methacrylate (PMMA) particle‑induced monocytes. Peripheral blood monocytes were obtained and treated with PMMA and pitavastatin. ELISA demonstrated that pitavastatin inhibited mRNA and protein expression of interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α. Western blot analysis and immunofluorescence staining demonstrated that pitavastatin downregulated inhibitor of κB phosphorylation and degradation, and nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) p65 translocation. Together, these results indicate that pitavastatin may attenuate monocyte activation in response to orthopedic implant wear particles by suppression of the NF‑κB signaling pathway.

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells.

PubMed

Al-Qatati, Abeer; Aliwaini, Saeb

2017-12-01

Melanoma is an aggressive skin cancer and its incidence is increasing faster than any other type of cancer. Whilst dacarbazine (DTIC) is the standard chemotherapy for metastatic melanoma, it has limited success. Statins, including pitavastatin, have been demonstrated to have a range of anti-cancer effects in a number of human cancer cell lines. The present study therefore explored the anti-cancer activity of combined DTIC and pitavastatin in A375 and WM115 human melanoma cells. Cell survival assays demonstrated that combined DTIC and pitavastatin treatment resulted in synergistic cell death. Cell cycle analyses further revealed that this combined treatment resulted in a G1 cell cycle arrest, as well as a sub-G1 population, indicative of apoptosis. Activation of apoptosis was confirmed by Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and an increase in the levels of active caspase 3 and cleaved poly (ADP-ribose) polymerase. Furthermore, it was demonstrated that apoptosis occurs through the intrinsic pathway, evident from the release of cytochrome c. Finally, combined DTIC and pitavastatin treatment was demonstrated to also activate autophagy as part of a cell death mechanism. The present study provides novel evidence to suggest that the combined treatment of DTIC and pitavastatin may be effective in the treatment of melanoma.

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

PubMed Central

Al-Qatati, Abeer; Aliwaini, Saeb

2017-01-01

Melanoma is an aggressive skin cancer and its incidence is increasing faster than any other type of cancer. Whilst dacarbazine (DTIC) is the standard chemotherapy for metastatic melanoma, it has limited success. Statins, including pitavastatin, have been demonstrated to have a range of anti-cancer effects in a number of human cancer cell lines. The present study therefore explored the anti-cancer activity of combined DTIC and pitavastatin in A375 and WM115 human melanoma cells. Cell survival assays demonstrated that combined DTIC and pitavastatin treatment resulted in synergistic cell death. Cell cycle analyses further revealed that this combined treatment resulted in a G1 cell cycle arrest, as well as a sub-G1 population, indicative of apoptosis. Activation of apoptosis was confirmed by Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and an increase in the levels of active caspase 3 and cleaved poly (ADP-ribose) polymerase. Furthermore, it was demonstrated that apoptosis occurs through the intrinsic pathway, evident from the release of cytochrome c. Finally, combined DTIC and pitavastatin treatment was demonstrated to also activate autophagy as part of a cell death mechanism. The present study provides novel evidence to suggest that the combined treatment of DTIC and pitavastatin may be effective in the treatment of melanoma. PMID:29344241

Pitavastatin attenuates AGEs-induced mitophagy via inhibition of ROS generation in the mitochondria of cardiomyocytes.

PubMed

Zha, Zhimin; Wang, Junhong; Li, Shiling; Guo, Yan

2017-11-01

This study aimed to investigate whether pitavastatin protected against injury induced by advanced glycation end products products (AGEs) in neonatal rat cardiomyocytes, and to examine the underlying mechanisms. Cardiomyocytes of neonatal rats were incubated for 48 hours with AGEs (100mg/mL), receptor for advanced glycation end products (RAGE), antibody (1 mg/mL) and pitavastatin (600 ng/mL). The levels of p62 and beclin1 were determined by Western blotting. Mitochondrial membrane potential (DYm) and the generation of reactive oxygen species (ROS) were measured through the JC-1 and DCFH-DA. In the AGEs group, the expression of beclin1 was remarkably increased compared to the control group, while the expression of p62 was significantly decreased. AGEs also markedly decreasedDYm and significantly increased ROS compared with the control group. After treatment with RAGE antibody or pitavastatin, the level of beclin1 was markedly decreased compared with the AGEs group, but the level of p62 was remarkably increased. In the AGEs+ RAGE antibody group and AGEs+ pitavastatin group,DYm was significantly increased and ROS was remarkably decreased compared with the AGEs group. In conclusion, AGEs-RAGE may induce autophagy of cardiomyocytes by generation of ROS and pitavastatin could protect against AGEs-induced injury against cardiomyocytes.

Impact of currently prescribed lipid-lowering drugs on plasma PCSK9 concentration: single or in combination study in rats

PubMed Central

2014-01-01

Background An emerging data suggested a significant impact of statins on PCSK9 concentration, while the rapid impacts of other lipid-lowering drugs such as ezetimibe and xuezhikang alone or in combination on PCSK9 and lipid profile have not been assessed. This study aims to investigate whether an enhanced PCSK9 concentration by single or combined therapy of lipid-lowering drugs currently used precedes the changes of lipid profile in rats. Methods Sixty-three rats were randomly divided into six groups and orally administrated with placebo (N = 13), ezetimibe 10 mg/kg daily, Xuezhikang 1200 mg/kg daily, ezetimibe 10 mg/kg plus Xuezhikang 1200 mg/kg daily, pitavastatin 10 mg/kg daily or pitavastatin 10 mg/kg plus ezetimibe 10 mg/kg daily for 3 days (N = 10 for each group respectively). Blood samples were obtained at day 3 after orally administration. Plasma PCSK9 levels were determined by ELISA and lipid profile were measured by enzymatic assay. Results Ezetimibe, Xuezhikang and pitavastatin alone and Xuezhikang plus ezetimibe as well as pitavastatin plus ezetimibe increased PCSK9 levels by 124%, 56%, 111%, 63% and 204% respectively (p < 0.05 compared with placebo). However, Xuezhikang plus ezetimibe did not enhance greater PCSK9 levels compared to monotherapy. Ezetimibe and pitavastatin in combination induced higher PCSK9 levels than pitavastatin monotherapy or co-therapy with ezetimibe plus Xuezhikang. There was no significant difference between any groups with regard to lipid profile levels at day 3 (P > 0.05). Conclusions Elevated PCSK9 concentration by ezetimibe, Xuezhikang and pitavastatin alone or in combination was found prior to the alterations of lipid profile in rats. Combination of Xuezhikang and ezetimibe significantly attenuated increase in PCSK9 compared to ezetimibe plus pitavastatin, suggesting that the former combination may be better than the latter in future clinical application. PMID:24533584

Pravastatin reduces radiation-induced damage in normal tissues.

PubMed

Doi, Hiroshi; Matsumoto, Seiji; Odawara, Soichi; Shikata, Toshiyuki; Kitajima, Kazuhiro; Tanooka, Masao; Takada, Yasuhiro; Tsujimura, Tohru; Kamikonya, Norihiko; Hirota, Shozo

2017-05-01

Pravastatin is an inhibitor of 3-hydroxy-3-methyl- glutaryl-coenzyme A reductase that has been reported to have therapeutic applications in a range of inflammatory conditions. The aim of the present study was to assess the radioprotective effects of pravastatin in an experimental animal model. Mice were divided into two groups: The control group received ionizing radiation with no prior medication, while the pravastatin group received pravastatin prior to ionizing radiation. Pravastatin was administered orally at 30 mg/kg body weight in drinking water at 24 and 4 h before irradiation. Intestinal crypt epithelial cell survival and the incidence of apoptosis in the intestine and lung were measured post-irradiation. The effect of pravastatin on intestinal DNA damage was determined by immunohistochemistry. Finally, the effect of pravastatin on tumor response to radiotherapy was examined in a mouse mesothelioma xenograft model. Pravastatin increased the number of viable intestinal crypts and this effect was statistically significant in the ileum (P<0.0001). The pravastatin group showed significantly lower apoptotic indices in all examined parts of the intestine (P<0.0001) and tended to show reduced apoptosis in the lung. Pravastatin reduced the intestinal expression of ataxia-telangiectasia mutated and gamma-H2AX after irradiation. No apparent pravastatin-related differences were observed in the response of xenograft tumors to irradiation. In conclusion, pravastatin had radioprotective effects on the intestine and lung and reduced radiation-induced DNA double-strand breaks. Pravastatin may increase the therapeutic index of radiotherapy.

Pitavastatin

MedlinePlus

... fatty substances such as low-density lipoprotein (LDL) cholesterol ('bad cholesterol') in the blood and to increase the amount of high-density lipoprotein (HDL) cholesterol ('good cholesterol'). Pitavastatin is in a class of ...

Pitavastatin is a potent anti-inflammatory agent in the rat paw model of acute inflammation.

PubMed

Qadir, Farida; Alam, Syed Mahboob; Siddiqi, Abeer Qamar; Kamran, Afshan

2014-11-01

Statins are used extensively as anti-hyperlipidemic agents. In addition to curtailing cholesterol synthesis they have been found to have multiple actions unrelated to cholesterol lowering "the pleiotropic effects," which includes inhibition of inflammation. We aimed at investigating the effect of pitavastatin a 3rd generation statin, in suppressing acute inflammation in rat paw edema model. Male Sprague-Dawley rats were randomly assigned to one of five groups (n=8): Control, indomethacin and pitavastatin (0.2mg/kg, 0.4mg/kg, 0.8mg/kg) treated. 1hour following treatment, inflammation was induced by sub-planter injection of egg albumin into the hind paw. Anti-inflammatory effect was evaluated by measurement of edema formation every half hour for three hours, assessment of polymorphonuclear leukocyte (PMNL) infiltration and measurement of tissue damage in skin biopsies. Ascending doses of pitavastatin were found to attenuate these parameters. The lowest dose of pitavastatin (0.2mg/kg) was found to significantly reduce edema volume, PMNL infiltration and tissue damage. The efficacy of the smallest dose was found comparable to indomethacin.

Pitavastatin: clinical effects from the LIVES Study.

PubMed

Teramoto, Tamio

2011-11-01

Although clinical trials provide useful information on drug safety and efficacy, results do not always reflect those observed in the real world. The Japanese long-term prospective post-marketing surveillance LIVALO Effectiveness and Safety (LIVES) Study was designed to assess the efficacy and safety of pitavastatin in clinical practice in ~20,000 patients. After 104 weeks, pitavastatin was associated with significant reductions in low-density lipoprotein-cholesterol (LDL-C) (29.1%) that largely occurred within 4 weeks of treatment initiation. In patients with abnormal triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-C) levels at baseline, pitavastatin reduced TG and increased HDL-C by 22.7% and 19.9%, respectively. Overall, 88.2% of the primary prevention low-risk patients attained their Japan Atherosclerosis Society LDL-C target, compared with 82.7% of intermediate-risk patients, 66.5% of high-risk patients and 50.3% of secondary prevention patients. Only 10.4% of pitavastatin-treated patients experienced adverse events (AEs), of which approximately 84% were mild and around 1% was severe. Increases in blood creatine phosphokinase (2.7%), alanine aminotransferase (1.8%), myalgia (1.1%), aspartate aminotransferase (1.5%) and gamma-glutamyltransferase (1.0%) were the most common AEs and only 7.4% of patients discontinued pitavastatin due to AEs. Regression analysis demonstrated that age was not a significant factor for the incidence of any AE or myopathy-associated events. A subanalysis of initial LIVES data focussing on the effects of pitavastatin on HDL-C levels showed that HDL-C was elevated by 5.9% in all patients and by 24.6% in those with low (

Low-density lipoprotein cholesterol targeting with pitavastatin + ezetimibe for patients with acute coronary syndrome and dyslipidaemia: the HIJ-PROPER study, a prospective, open-label, randomized trial.

PubMed

Hagiwara, Nobuhisa; Kawada-Watanabe, Erisa; Koyanagi, Ryo; Arashi, Hiroyuki; Yamaguchi, Junichi; Nakao, Koichi; Tobaru, Tetsuya; Tanaka, Hiroyuki; Oka, Toshiaki; Endoh, Yasuhiro; Saito, Katsumi; Uchida, Tatsuro; Matsui, Kunihiko; Ogawa, Hiroshi

2017-08-01

To elucidate the effects of intensive LDL-C lowering treatment with a standard dose of statin and ezetimibe in patients with dyslipidaemia and high risk of coronary events, targeting LDL-C less than 70 mg/dL (1.8 mmol/L), compared with standard LDL-C lowering lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L). The HIJ-PROPER study is a prospective, randomized, open-label trial to assess whether intensive LDL-C lowering with standard-dose pitavastatin plus ezetimibe reduces cardiovascular events more than standard LDL-C lowering with pitavastatin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidaemia. Patients were randomized to intensive lowering (target LDL-C < 70 mg/dL [1.8 mmol/L]; pitavastatin plus ezetimibe) or standard lowering (target LDL-C 90 mg/dL to 100 mg/dL [2.3-2.6 mmol/L]; pitavastatin monotherapy). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischaemia-driven revascularization. Between January 2010 and April 2013, 1734 patients were enroled at 19 hospitals in Japan. Patients were followed for at least 36 months. Median follow-up was 3.86 years. Mean follow-up LDL-C was 65.1 mg/dL (1.68 mmol/L) for pitavastatin plus ezetimibe and 84.6 mg/dL (2.19 mmol/L) for pitavastatin monotherapy. LDL-C lowering with statin plus ezetimibe did not reduce primary endpoint occurrence in comparison with standard statin monotherapy (283/864, 32.8% vs. 316/857, 36.9%; HR 0.89, 95% CI 0.76-1.04, P = 0.152). In, ACS patients with higher cholesterol absorption, represented by elevated pre-treatment sitosterol, was associated with significantly lower incidence of the primary endpoint in the statin plus ezetimibe group (HR 0.71, 95% CI 0.56-0.91). Although intensive lowering with standard pitavastatin plus ezetimibe showed no more cardiovascular benefit than standard pitavastatin monotherapy in ACS patients with dyslipidaemia, statin plus ezetimibe may be more effective than statin monotherapy in patients with higher cholesterol absorption; further confirmation is needed. UMIN000002742, registered as an International Standard Randomized Controlled Trial. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology

Pitavastatin treatment induces neuroprotection through the BDNF-TrkB signalling pathway in cultured cerebral neurons after oxygen-glucose deprivation.

PubMed

Cui, Xiaoyan; Fu, Zhenqiang; Wang, Menghan; Nan, Xiaofei; Zhang, Boai

2018-05-01

Along with their lipid-lowering effect, statins have been reported to have neuroprotective function in both in vivo and in vitro models of neurodegenerative diseases. We conducted this study in order to uncover the he neuroprotective effect of the lipophilic statin pitavastatin (PTV) and investigate the underlying molecular mechanisms using primary cultured cerebral neurons exposed to oxygen-glucose deprivation (OGD). The primary cultured cerebral neurons were randomly assigned into four groups: the control group, the pitavastatin treatment group, the OGD group and the OGD + pitavastatin treatment group. The pitavastatin's concentration were set as follows: 1μM, 15μM, 30μM. After 3 hours OGD treatment, we use MTT method to assessment cell viability, immunofluorescence to observe neuron morphology and western blot method analysis the BDNF, TrkB. PTV at concentrations of 1 μM and 15 μM elevated the survival rate of cortical neurons exposed to OGD, whereas 30 μM PTV did not show such an effect. Moreover, PTV promoted neuronal dendrite growth at concentrations of 1 μM and 15 μM. Increased expression levels of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) were observed in both of the following two scenarios: when neurons were treated with PTV for 48 hours and when PTV was added after the OGD procedure. Pitavastatin treatment induces neuroprotection in cultured cerebral neurons after oxygen-glucose deprivation this neuroprotection induced by PTV involves the BDNF-TrkB signalling pathway.

Role of Pitavastatin in Prevention of Osteopenic Changes in Ovariectomized Rats.

PubMed

Qadir, Farida; Alam, Syed Mahboob; Zehra, Tabassum; Mehmood, Ahmar; Siddiqi, Abeer Qamar

2016-01-01

To determine the effect of pitavastatin, a third generation statin, on development of osteopenia in ovariectomized rats. Experimental study. Department of Pharmacology, Basic Medical Sciences Institute, Jinnah Postgraduate Medical Center, Karachi, from January to July 2013. Forty female Sprague Dawley rats were divided into ovariectomized (OVX), Sham OVX and OVX given pitavastatin 0.4 mg/kg/day, 0.8 mg/kg/day, for 8 weeks. Bone density measurements using CT scan and Archimedes’ principle were made on femora and tibiae. Blood samples were analyzed for acid phosphatase (ACP) and alkaline phosphatase (ALP) levels. Ovariectomy-induced osteopenic changes were indicated by significant decrease in bone densities and Hounsfield (HU) index of distal femoral and proximal tibial metaphyses and elevation of ACP and ALP levels. 0.4 mg/kg pitavastatin did not significantly alter the evaluated parameters. 0.8 mg/kg produced a restoration of HU of lower femur and femoral density comparable to Sham. HU of upper tibia and tibial density following 0.8 mg/kg was significantly higher than OVX but was not approximate to Sham. ALP and ACP with 0.8 mg/kg were comparable to Sham. Supra-therapeutic dose of pitavastatin was effective in preventing estrogen deficiency-induced decrease in bone density of ovariectomized rates, over an 8-week period.

Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

PubMed Central

Kawata, S; Yamasaki, E; Nagase, T; Inui, Y; Ito, N; Matsuda, Y; Inada, M; Tamura, S; Noda, S; Imai, Y; Matsuzawa, Y

2001-01-01

Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg−1d for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin (n = 41) groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 ± 9.8 months (mean ± SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = 0.006). The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11286466

Effects of pitavastatin on walking capacity and CD34+/133+ cell number in patients with peripheral artery disease.

PubMed

Arao, Kenshiro; Yasu, Takanori; Endo, Yasuhiro; Funazaki, Toshikazu; Ota, Yoshimi; Shimada, Kazunori; Tokutake, Eiichi; Naito, Naoki; Takase, Bonpei; Wake, Minoru; Ikeda, Nahoko; Horie, Yasuto; Sugimura, Hiroyuki; Momomura, Shin-Ichi; Kawakami, Masanobu

2017-10-01

This multi-center prospective non-randomized comparative study investigated the effects of pitavastatin in patients with peripheral artery disease (PAD) in terms of exercise tolerance capacities and peripheral CD34 + /133 + cell numbers. At baseline, a peripheral blood test was administered to 75 patients with PAD, along with a treadmill exercise test using the Skinner-Gardner protocol to measure asymptomatic walking distance (AWD) and maximum walking distance (MWD). Each patient was assigned to a 6-month pitavastatin treatment group (n = 53) or a control group (n = 22), according to the patient's preference. The tests were repeated in both groups at 3 and 6 months. Baseline AWD and MWD correlated positively with the ankle-brachial pressure index (r = 0.342, p = 0.0032 and r = 0.324, p = 0.0054, respectively). Both AWD and MWD values improved at 3 and 6 months compared with baseline, and the degrees of their improvement were higher in the pitavastatin treatment group. CD34 + /133 + cell numbers did not change over time or between groups. Eighty-seven percent of patients in the treatment group attained low-density lipoprotein cholesterol levels below 100 mg/dL after 3 months. The study shows that pitavastatin may be effective in increasing exercise tolerance capacity in patients with PAD.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-12-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: 131I-chTNT; Abatacept, adalimumab, alemtuzumab, APC-8015, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, azimilide hydrochloride; Bevacizumab, bortezomib, bosentan, buserelin; Caspofungin acetate, CC-4047, ChAGCD3, ciclesonide, clopidogrel, curcumin, Cypher; Dabigatran etexilate, dapoxetine hydrochloride, darbepoetin alfa, darusentan, denosumab, DMXB-Anabaseine, drospirenone, drospirenone/estradiol, duloxetine hydrochloride, dutasteride; Edodekin alfa, efaproxiral sodium, elaidic acid-cytarabine, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, eszopiclone, etonogestrel/testosterone decanoate, exenatide; Fulvestrant; Gefitinib, glycine, GVS-111; Homoharringtonine; ICC-1132, imatinib mesylate, iodine (I131) tositumomab, i.v. gamma-globulin; Levetiracetam, levocetirizine, lintuzumab, liposomal nystatin, lumiracoxib, lurtotecan; Manitimus, mapatumumab, melatonin, micafungin sodium, mycophenolic acid sodium salt; Oblimersen sodium, OGX-011, olmesartan medoxomil, omalizumab, omapatrilat, oral insulin; Parathyroid hormone (human recombinant), pasireotide, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, phVEGF-A165, pimecrolimus, pitavastatin calcium, plerixafor hydrochloride, posaconazole, pramlintide acetate, prasterone, pregabalin, PT-141; Quercetin; Ranolazine, rosuvastatin calcium, rubitecan, rupatadine fumarate; Sardomozide, sunitinib malate; Tadalafil, talactoferrin alfa, tegaserod maleate, telithromycin, testosterone transdermal patch, TH-9507, tigecycline, tiotropium bromide, tipifarnib, tocilizumab, treprostinil sodium; Valdecoxib, vandetanib, vardenafil hydrochloride hydrate, voriconazole. Copyright 2005 Prous Science. All rights reserved.

Pravastatin and endothelium dependent vasomotion after coronary angioplasty: the PREFACE trial

PubMed Central

Mulder, H; Schalij, M; Kauer, B; Visser, R; van Dijkman, P R M; Jukema, J; Zwinderman, A; Bruschke, A

2001-01-01

OBJECTIVE—To test the hypothesis that the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor pravastatin ameliorates endothelium mediated responses of dilated coronary segments: the PREFACE (pravastatin related effects following angioplasty on coronary endothelium) trial.
DESIGN—A double blind, randomised, placebo controlled, multicentre study.
SETTING—Four hospitals in the Netherlands.
PATIENTS—63 non-smoking, non-hypercholesterolaemic patients scheduled for elective balloon angioplasty (pravastatin 34, placebo 29).
INTERVENTIONS—The effects of three months of pravastatin treatment (40 mg daily) on endothelium dependent vasomotor function were studied. Balloon angioplasty was undertaken one month after randomisation, and coronary vasomotor function tests using acetylcholine were performed two months after balloon angioplasty. The angiograms were analysed quantitatively.
MAIN OUTCOME MEASURES—The efficacy measure was the acetylcholine induced change in mean arterial diameter, determined in the dilated segment and in an angiographically normal segment of an adjacent non-manipulated coronary artery.
RESULTS—Increasing acetylcholine doses produced vasoconstriction in the dilated segments (p = 0.004) but not in the normal segments. Pravastatin did not affect the vascular response to acetylcholine in either the dilated segments (p = 0.09) or the non-dilated sites. Endothelium dependent vasomotion in normal segments was correlated with that in dilated segments (r = 0.47, p < 0.001). There were fewer procedure related events in the pravastatin group than in the placebo group (p < 0.05).
CONCLUSIONS—Endothelium dependent vasomotion in normal segments is correlated with that in dilated segments. A significant beneficial effect of pravastatin on endothelial function could not be shown, but in the dilated segments there was a trend towards a beneficial treatment effect in the pravastatin group.


Keywords: angioplasty; endothelium; acetylcholine; pravastatin PMID:11602546

Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe).

PubMed

Kim, Kyung-Jin; Kim, Sang-Hyun; Yoon, Young Won; Rha, Seung-Woon; Hong, Soon-Jun; Kwak, Choong-Hwan; Kim, Weon; Nam, Chang-Wook; Rhee, Moo-Yong; Park, Tae-Ho; Hong, Taek-Jong; Park, Sungha; Ahn, Youngkeun; Lee, Namho; Jeon, Hui-Kyung; Jeon, Dong-Woon; Han, Kyoo-Rok; Moon, Keon-Woong; Chae, In-Ho; Kim, Hyo-Soo

2016-10-01

We aimed to compare the effects of fixed-dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS). This multicenter eight-week randomized double-blind phase III study evaluated the safety and efficacy of fixed-dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid-lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed-dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily). Fixed-dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed-dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%-63%, 37%-43%, and 19%-24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non-DM or non-MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non-DM or MetS vs non-MetS patients. Fixed-dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS. © 2016 The Authors Cardiovascular Therapeutics Published by John Wiley & Sons Ltd.

[Simultaneous determination of repaglinide and pravastatin sodium in rat plasma by LC-ms/MS and its application on pharmacokinetic interactions study].

PubMed

Ma, Yan-Rong; Zhou, Yan; Zhang, Guo-Qiang; Rao, Zhi; Huang, Jing; Wei, Yu-hui; Wu, Xin-An

2014-01-01

The study aims to establish a method for simultaneous determination of repaglinide and pravastatin sodium in rat plasma by LC-MS/MS and to study its pharmacokinetic interactions. Eighteen male SD rats were divided into repaglinide group, pravastatin sodium group and co-administration group. Blood samples were collected at different times after oral administration. Repaglinide and pravastatin sodium in rat plasma were separated by Agilent HC-C18 with the mobile phase consisting of methanol-0.1% formic acid (80 : 20). Detection and quantification were performed by using ESI-MS. The detector was operated in selected Reaction-monitoring mode at m/z 453.3-->230.1 for repaglinide, m/z 447.2-->327.4 for pravastatin sodium and m/z 285.1-->192.9 for diazepam as the internal standard. The calibration curve obtained was linear (R2>0.99) over the concentration range of 9.77-10,000 ng.mL-1 for repaglinide and 4.88-625 ng.mL-1 for pravastatin sodium. Compared with the single administration group, Cmax and AUC0-6h of repaglinide increased significantly (P<0.05) and tmax of pravastatin sodium prolonged (P<0.05) in co-administration group. The method is found to be simple, sensitive and accurate for determining the concentration of repaglinide and pravastatin sodium in rat plasma. There exists pharmacokinetic interactions in the co-administration of repaglinide and pravastatin sodium.

Pravastatin inhibits farnesol production in Candida albicans and improves survival in a mouse model of systemic candidiasis.

PubMed

Tashiro, Masato; Kimura, Soichiro; Tateda, Kazuhiro; Saga, Tomoo; Ohno, Akira; Ishii, Yoshikazu; Izumikawa, Koichi; Tashiro, Takayoshi; Kohno, Shigeru; Yamaguchi, Keizo

2012-05-01

Candidemia remains a major cause of morbidity and mortality, especially in immunocompromised patients. A strategy of reducing virulence and virulence factors of Candida spp. is an attractive approach for the treatment of serious infections caused by these yeasts. Recently, farnesol has been reported to be a quorum-sensing autoinducer, as well as a virulence factor of C. albicans. In the present study, we examined the effects of pravastatin, a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor on the in vitro production of farnesol. In addition, the synergistic effects of pravastatin with fluconazole (FLC) were examined in a mouse model of systemic infections. In vitro experiments demonstrated that pravastatin had synergistic activity with FLC as judged by fractional inhibitory concentration index (FICI) and suppression of farnesol production at sub-minimum inhibitory concentrations. Furthermore, significant improvement of survival in systemic infection models was shown with pravastatin supplementation. The survival benefits of pravastatin were correlated with reductions of fungal burden. These data suggest the potential of pravastatin as a supportive therapy against C. albicans infections. Synergistic antifungal activity and suppression of HMG-CoA reductase-associated Candida virulence factors, including farnesol, may explain, at least in part, the in vivo efficacy of pravastatin.

Evidence for a pharmacokinetic interaction between eslicarbazepine and rosuvastatin: Potential effects on xenobiotic transporters.

PubMed

Gidal, Barry E; Mintzer, Scott; Schwab, Matthias; Schutz, Ralph; Kharidia, Jahnavi; Blum, David; Grinnell, Todd; Sunkaraneni, Soujanya

2017-09-01

Patients with partial-onset seizures and comorbid cardiovascular disease may concomitantly receive eslicarbazepine acetate (ESL), an antiepileptic drug, and rosuvastatin, an HMG-CoA reductase inhibitor. This study evaluated the effect of multiple-dose ESL on the pharmacokinetic (PK) parameters of a single dose of rosuvastatin in healthy subjects. This was a Phase I, single-center, fixed-sequence, open-label study. Healthy subjects received two treatments, in sequence. Treatment A: a single 40mg oral dose of rosuvastatin on Day 1, followed by a washout period (Days 1-4); treatment B: titration of ESL (400-800mg once daily) on Days 5-18, followed by ESL 1200mg once daily on Days 19-35, with a single dose of rosuvastatin (40mg) on Day 32. Subjects then entered a 2-week follow-up period. Plasma concentrations of rosuvastatin were quantified for PK analyses. Safety and tolerability were assessed throughout the study. Thirty-three healthy subjects were enrolled and 30 completed the study. Mean rosuvastatin (standard deviation) t 1/2 was similar when rosuvastatin was used concomitantly with ESL and when it was used alone (26.5 [16.3]h, and 22.4 [9.5]h, respectively). The geometric least squares mean ratios (90% confidence intervals) of rosuvastatin exposure levels between rosuvastatin used concomitantly with ESL and rosuvastatin used alone were as follows: C max , 64.0% (55.9-73.3%); AUC (0-∞) , 63.0% (57.1-69.4%); and AUC (0-last) , 60.9% (55.2-67.1%). Concomitant use of ESL and rosuvastatin was generally well tolerated. Rosuvastatin exposure was 36-39% lower with steady-state administration of ESL, potentially due to reduced oral bioavailability of rosuvastatin. Consequently, when rosuvastatin is used with ESL, a rosuvastatin dose adjustment may be necessary if a clinically significant change in lipids is noted. Copyright © 2017. Published by Elsevier B.V.

Pre-incubation with cyclosporine A potentiates its inhibitory effects on pitavastatin uptake mediated by recombinantly expressed cynomolgus monkey hepatic organic anion transporting polypeptide.

PubMed

Takahashi, Tsuyoshi; Ohtsuka, Tatsuyuki; Uno, Yasuhiro; Utoh, Masahiro; Yamazaki, Hiroshi; Kume, Toshiyuki

2016-11-01

Cyclosporine A, an inhibitor of hepatic organic anion transporting polypeptides (OATPs), reportedly increased plasma concentrations of probe substrates, although its maximum unbound blood concentrations were lower than the experimental half-maximal inhibitory (IC 50 ) concentrations. Pre-incubation with cyclosporine A in vitro before simultaneous incubation with probes has been reported to potentiate its inhibitory effects on recombinant human OATP-mediated probe uptake. In the present study, the effects of cyclosporine A and rifampicin on recombinant cynomolgus monkey OATP-mediated pitavastatin uptake were investigated in pre- and simultaneous incubation systems. Pre-incubation with cyclosporine A, but not with rifampicin, decreased the apparent IC 50 values on recombinant cynomolgus monkey OATP1B1- and OATP1B3-mediated pitavastatin uptake. Application of the co-incubated IC 50 values toward R values (1 + [unbound inhibitor] inlet to the liver, theoretically maximum /inhibition constant) in static models, 1.1 in monkeys and 1.3 in humans, for recombinant cynomolgus monkey and human OATP1B1-mediated pitavastatin uptake might result in the poor prediction of drug interaction magnitudes. In contrast, the lowered IC 50 values after pre-incubation with cyclosporine A provided better prediction with R values of 3.9 for monkeys and 2.7 for humans when the estimated maximum cyclosporine A concentrations at the inlet to the liver were used. These results suggest that the enhanced inhibitory potential of perpetrator medicines by pre-incubation on cynomolgus monkey OATP-mediated pitavastatin uptake in vitro could be of value for the precise estimation of drug interaction magnitudes in silico, in accordance with the findings from pre-administration of inhibitors on pitavastatin pharmacokinetics validated in monkeys. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Baseline serum sitosterol level as predictor of adverse clinical events in acute coronary syndrome patients with dyslipidaemia: A sub-analysis of HIJ-PROPER.

PubMed

Yamaguchi, Junichi; Kawada-Watanabe, Erisa; Koyanagi, Ryo; Arashi, Hiroyuki; Sekiguchi, Haruki; Nakao, Koichi; Tobaru, Tetsuya; Tanaka, Hiroyuki; Oka, Toshiaki; Endo, Yasuhiro; Saito, Katsumi; Uchida, Tatsuro; Matsui, Kunihiko; Ogawa, Hiroshi; Hagiwara, Nobuhisa

2018-05-05

We aimed to examine the effect of serum sitosterol, a cholesterol absorption marker, on clinical outcomes in acute coronary syndrome patients with dyslipidaemia. This is a sub-analysis of the HIJ-PROPER trial that assesses the effect of aggressive low-density lipoprotein cholesterol (LDL-C) lowering treatment with pitavastatin + ezetimibe in 1734 acute coronary syndrome (ACS) patients with dyslipidaemia. Patients were divided into two groups based on sitosterol level at enrolment (cut-off value was 2.2 μg/mL; a median of baseline sitosterol level), and clinical outcomes were examined. The mean LDL-C level after 3 years in the low sitosterol group was 84.8 ± 20.1 mg/dL with pitavastatin-monotherapy and 64.6 ± 20.3 mg/dL with pitavastatin + ezetimibe, while corresponding values in the high sitosterol group were 91.0 ± 22.9 mg/dL and 71.1 ± 23.3 mg/dL, respectively. In the high sitosterol group, the Kaplan-Meier event rate for the primary endpoint at 3 years was 26.0% in the pitavastatin + ezetimibe group, as compared with 34.3% in the pitavastatin-monotherapy group (hazard ratio, 0.71; 95% confidence interval, 0.56-0.91; p = 0.006, p-value for interaction = 0.010). However, in the low sitosterol group, there was no significant reduction of the primary endpoint by pitavastatin + ezetimibe therapy. Aggressive lipid-lowering treatment with ezetimibe had a positive effect on clinical outcomes in the high sitosterol subset of ACS patients with dyslipidaemia, but not in the low sitosterol subset. This effect was independent of LDL-C reduction and suggests that sitosterol measurement on admission in ACS patients might contribute to a "personalised" lipid-lowering approach. Copyright © 2018 Elsevier B.V. All rights reserved.

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

PubMed

Taguchi, Isao; Iimuro, Satoshi; Iwata, Hiroshi; Takashima, Hiroaki; Abe, Mitsuru; Amiya, Eisuke; Ogawa, Takanori; Ozaki, Yukio; Sakuma, Ichiro; Nakagawa, Yoshihisa; Hibi, Kiyoshi; Hiro, Takafumi; Fukumoto, Yoshihiro; Hokimoto, Seiji; Miyauchi, Katsumi; Yamazaki, Tsutomu; Ito, Hiroshi; Otsuji, Yutaka; Kimura, Kazuo; Takahashi, Jun; Hirayama, Atsushi; Yokoi, Hiroyoshi; Kitagawa, Kazuo; Urabe, Takao; Okada, Yasushi; Terayama, Yasuo; Toyoda, Kazunori; Nagao, Takehiko; Matsumoto, Masayasu; Ohashi, Yasuo; Kaneko, Tetsuji; Fujita, Retsu; Ohtsu, Hiroshi; Ogawa, Hisao; Daida, Hiroyuki; Shimokawa, Hiroaki; Saito, Yasushi; Kimura, Takeshi; Inoue, Teruo; Matsuzaki, Masunori; Nagai, Ryozo

2018-05-08

Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) <120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group ( P <0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; P =0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73-0.93; P =0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (<95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730. © 2018 The Authors.

Pravastatin and endothelium dependent vasomotion after coronary angioplasty: the PREFACE trial.

PubMed

Mulder, H J; Schalij, M J; Kauer, B; Visser, R F; van Dijkman, P R; Jukema, J W; Zwinderman, A H; Bruschke, A V

2001-11-01

To test the hypothesis that the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor pravastatin ameliorates endothelium mediated responses of dilated coronary segments: the PREFACE (pravastatin related effects following angioplasty on coronary endothelium) trial. A double blind, randomised, placebo controlled, multicentre study. Four hospitals in the Netherlands. 63 non-smoking, non-hypercholesterolaemic patients scheduled for elective balloon angioplasty (pravastatin 34, placebo 29). The effects of three months of pravastatin treatment (40 mg daily) on endothelium dependent vasomotor function were studied. Balloon angioplasty was undertaken one month after randomisation, and coronary vasomotor function tests using acetylcholine were performed two months after balloon angioplasty. The angiograms were analysed quantitatively. The efficacy measure was the acetylcholine induced change in mean arterial diameter, determined in the dilated segment and in an angiographically normal segment of an adjacent non-manipulated coronary artery. Increasing acetylcholine doses produced vasoconstriction in the dilated segments (p = 0.004) but not in the normal segments. Pravastatin did not affect the vascular response to acetylcholine in either the dilated segments (p = 0.09) or the non-dilated sites. Endothelium dependent vasomotion in normal segments was correlated with that in dilated segments (r = 0.47, p < 0.001). There were fewer procedure related events in the pravastatin group than in the placebo group (p < 0.05). Endothelium dependent vasomotion in normal segments is correlated with that in dilated segments. A significant beneficial effect of pravastatin on endothelial function could not be shown, but in the dilated segments there was a trend towards a beneficial treatment effect in the pravastatin group.

Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung-targeted approach to deliver statins

PubMed Central

Zeki, Amir A; Bratt, Jennifer M; Chang, Kevin Y; Franzi, Lisa M; Ott, Sean; Silveria, Mark; Fiehn, Oliver; Last, Jerold A; Kenyon, Nicholas J

2015-01-01

Systemic treatment with statins mitigates allergic airway inflammation, TH2 cytokine production, epithelial mucus production, and airway hyperreactivity (AHR) in murine models of asthma. We hypothesized that pravastatin delivered intratracheally would be quantifiable in lung tissues using mass spectrometry, achieve high drug concentrations in the lung with minimal systemic absorption, and mitigate airway inflammation and structural changes induced by ovalbumin. Male BALB/c mice were sensitized to ovalbumin (OVA) over 4 weeks, then exposed to 1% OVA aerosol or filtered air (FA) over 2 weeks. Mice received intratracheal instillations of pravastatin before and after each OVA exposure (30 mg/kg). Ultra performance liquid chromatography – mass spectrometry was used to quantify plasma, lung, and bronchoalveolar lavage fluid (BALF) pravastatin concentration. Pravastatin was quantifiable in mouse plasma, lung tissue, and BALF (BALF > lung > plasma for OVA and FA groups). At these concentrations pravastatin inhibited airway goblet cell hyperplasia/metaplasia, and reduced BALF levels of cytokines TNFα and KC, but did not reduce BALF total leukocyte or eosinophil cell counts. While pravastatin did not mitigate AHR, it did inhibit airway hypersensitivity (AHS). In this proof-of-principle study, using novel mass spectrometry methods we show that pravastatin is quantifiable in tissues, achieves high levels in mouse lungs with minimal systemic absorption, and mitigates some pathological features of allergic asthma. Inhaled pravastatin may be beneficial for the treatment of asthma by having direct airway effects independent of a potent anti-inflammatory effect. Statins with greater lipophilicity may achieve better anti-inflammatory effects warranting further research. PMID:25969462

Transepithelial transport of rosuvastatin and effect of ursolic acid on its transport in Caco-2 monolayers.

PubMed

Hua, Wen Jin; Fang, Hu Jin; Hua, Wei Xiao

2012-09-01

The aim of this study was to determine transepithelial transport characteristics of rosuvastatin and effect of ursolic acid (P-gp potential inhibitor) and ko143 (ABC transporters selective inhibitor) on its transport in Caco-2 monolayers. A reliable Caco-2 cell monolayers model was established. The TEER value was used to inspect integrity of cell model. Apparent permeability coefficients (Papp(BL-AP) and Papp(AP-BL)) were used to analyze transepithelial transport of rosuvastatin. Uptake of rosuvastatin was time- and concentration-dependent in Caco-2 cell. The ko143 but not ursolic acid had effect on the uptake of rosuvastatin in Caco-2 cell monolayer model and affected apparent permeability coefficient and apparent permeability of rosuvastatin. Active transport and passive diffusion absorption existed in transepithelial transport of rosuvastatin in Caco-2 cell model. Ursolic acid had no effect on transport of rosuvastatin in Caco-2 cell monolayer. The result indicated that ursolic acid may not cause effect on intestinal absorption of rosuvastatin.

Long-Term Effect of Pravastatin on Carotid Intima–Media Complex Thickness

PubMed Central

Toyoda, Kazunori; Minematsu, Kazuo; Yasaka, Masahiro; Nagai, Yoji; Aoki, Shiro; Nezu, Tomohisa; Hosomi, Naohisa; Kagimura, Tatsuo; Origasa, Hideki; Kamiyama, Kenji; Suzuki, Rieko; Ohtsuki, Toshiho; Maruyama, Hirofumi; Kitagawa, Kazuo; Uchiyama, Shinichiro; Matsumoto, Masayasu

2018-01-01

Background and Purpose— The effect of statins on progression of carotid intima–media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. This study aimed to determine the effect of low-dose pravastatin on carotid IMT in Japanese patients with noncardioembolic ischemic stroke. Methods— This is a substudy of the J-STARS trial (Japan Statin Treatment Against Recurrent Stroke), a multicenter, randomized, open-label, parallel-group trial to examine whether pravastatin reduces stroke recurrence. Patients were randomized to receive pravastatin (10 mg daily, usual dose in Japan; pravastatin group) or not to receive any statins (control group). The primary outcome was IMT change of the common carotid artery for a 5-year observation period. IMT change was compared using mixed-effects models for repeated measures. Results— Of 864 patients registered in this substudy, 71 without baseline ultrasonography were excluded, and 388 were randomly assigned to the pravastatin group and 405 to the control group. Baseline characteristics were not significantly different, except National Institutes of Health Stroke Scale scores (median, 0 [interquartile range, 0–2] versus 1 [interquartile range, 0–2]; P=0.019) between the 2 groups. Baseline IMT (mean±SD) was 0.887±0.155 mm in the pravastatin group and 0.887±0.152 mm in the control group (P=0.99). The annual change in the IMT at 5-year visit was significantly reduced in the pravastatin group as compared with that in the control group (0.021±0.116 versus 0.040±0.118 mm; P=0.010). Conclusions— The usual Japanese dose of pravastatin significantly reduced the progression of carotid IMT at 5 years in patients with noncardioembolic stroke. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00361530. PMID:29191850

Rosuvastatin Treatment Affects Both Basal and Glucose-Induced Insulin Secretion in INS-1 832/13 Cells

PubMed Central

Salunkhe, Vishal A.; Elvstam, Olof; Eliasson, Lena; Wendt, Anna

2016-01-01

Rosuvastatin is a member of the statin family. Like the other statins it is prescribed to lower cholesterol levels and thereby reduce the risk of cardiovascular events. Rosuvastatin lowers the cholesterol levels by inhibiting the key enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) in the cholesterol producing mevalonate pathway. It has been recognized that apart from their beneficial lipid lowering effects, statins also exhibit diabetogenic properties. The molecular mechanisms behind these remain unresolved. To investigate the effects of rosuvastatin on insulin secretion, we treated INS-1 832/13 cells with varying doses (20 nM to 20 μM) of rosuvastatin for 48 h. At concentrations of 2 μM and above basal insulin secretion was significantly increased. Using diazoxide we could determine that rosuvastatin did not increase basal insulin secretion by corrupting the KATP channels. Glucose-induced insulin secretion on the other hand seemed to be affected differently at different rosuvastatin concentrations. Rosuvastatin treatment (20 μM) for 24–48 h inhibited voltage-gated Ca2+ channels, which lead to reduced depolarization-induced exocytosis of insulin-containing granules. At lower concentrations of rosuvastatin (≤ 2 μM) the stimulus-secretion coupling pathway was intact downstream of the KATP channels as assessed by the patch clamp technique. However, a reduction in glucose-induced insulin secretion could be observed with rosuvastatin concentrations as low as 200 nM. The inhibitory effects of rosuvastatin on glucose-induced insulin secretion could be reversed with mevalonate, but not squalene, indicating that rosuvastatin affects insulin secretion through its effects on the mevalonate pathway, but not through the reduction of cholesterol biosynthesis. Taken together, these data suggest that rosuvastatin has the potential to increase basal insulin secretion and reduce glucose-induced insulin secretion. The latter is possibly an unavoidable side effect of rosuvastatin treatment as it occurs through the same mechanisms as the lipid-lowering effects of the drug. PMID:26986474

Amyotrophic Lateral Sclerosis Associated with Statin Use: A Disproportionality Analysis of the FDA's Adverse Event Reporting System.

PubMed

Golomb, Beatrice A; Verden, Abril; Messner, Alexis K; Koslik, Hayley J; Hoffman, Keith B

2018-04-01

Apparent elevations in reporting of amyotrophic lateral sclerosis (ALS)-like conditions associated with statin use have been previously described from data obtained via US and European databases. The aim of this study was to examine US FDA Adverse Event Reporting System (FAERS) data to compare reporting odds ratios (RORs) of ALS and ALS-like conditions between statins and other drugs, for each statin agent. We assessed for disproportional rates of reported ALS and ALS-related conditions for each statin agent separately by using the ROR formula. FAERS data were analyzed through September 2015. RORs for ALS were elevated for all statins, with elevations possibly stronger for lipophilic statins. RORs ranged from 9.09 (6.57-12.6) and 16.2 (9.56-27.5) for rosuvastatin and pravastatin (hydrophilic) to 17.0 (14.1-20.4), 23.0 (18.3-29.1), and 107 (68.5-167) for atorvastatin, simvastatin, and lovastatin (lipophilic), respectively. For simvastatin, an ROR of 57.1 (39.5-82.7) was separately present for motor neuron disease. These findings extend previous evidence showing that significantly elevated ALS reporting extends to individual statin agents, and add to concerns about potential elevated occurrence of ALS-like conditions in association with statin usage.

Structural identifiability analyses of candidate models for in vitro Pitavastatin hepatic uptake.

PubMed

Grandjean, Thomas R B; Chappell, Michael J; Yates, James W T; Evans, Neil D

2014-05-01

In this paper a review of the application of four different techniques (a version of the similarity transformation approach for autonomous uncontrolled systems, a non-differential input/output observable normal form approach, the characteristic set differential algebra and a recent algebraic input/output relationship approach) to determine the structural identifiability of certain in vitro nonlinear pharmacokinetic models is provided. The Organic Anion Transporting Polypeptide (OATP) substrate, Pitavastatin, is used as a probe on freshly isolated animal and human hepatocytes. Candidate pharmacokinetic non-linear compartmental models have been derived to characterise the uptake process of Pitavastatin. As a prerequisite to parameter estimation, structural identifiability analyses are performed to establish that all unknown parameters can be identified from the experimental observations available. Copyright © 2013. Published by Elsevier Ireland Ltd.

A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects

PubMed Central

Jung, Jin Ah; Lee, Soo-Yun; Kim, Jung-Ryul; Ko, Jae-Wook; Jang, Seong Bok; Nam, Su Youn; Huh, Wooseong

2015-01-01

Purpose Valsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects. Subjects and methods Thirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment. Results For rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873−0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632−0.9701) for area under the concentration–time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946−1.0884) and 1.0072 (0.8893−1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events. Conclusion The pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their individual pharmacokinetics were not affected by their coadministration. No dose adjustment was required and the results are supportive of a study in a larger patient population. PMID:25767372

A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects.

PubMed

Jung, Jin Ah; Lee, Soo-Yun; Kim, Jung-Ryul; Ko, Jae-Wook; Jang, Seong Bok; Nam, Su Youn; Huh, Wooseong

2015-01-01

Valsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects. Thirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment. For rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873-0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632-0.9701) for area under the concentration-time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946-1.0884) and 1.0072 (0.8893-1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events. The pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their individual pharmacokinetics were not affected by their coadministration. No dose adjustment was required and the results are supportive of a study in a larger patient population.

A randomized, controlled comparison of different intensive lipid-lowering therapies in Chinese patients with non-ST-elevation acute coronary syndrome (NSTE-ACS): Ezetimibe and rosuvastatin versus high-dose rosuvastatin.

PubMed

Ran, Dan; Nie, Hui-Juan; Gao, Yu-Lin; Deng, Song-Bai; Du, Jian-Lin; Liu, Ya-Jie; Jing, Xiao-Dong; She, Qiang

2017-05-15

Statin combined with ezetimibe demonstrates significant benefit in lowering low density lipid cholesterol (LDL-C) and cardiovascular events abroad, but whether intermediate intensity statins combined with ezetimibe is superior to high-intensity statin monotherapy in Chinese people is unknown. A total of 125 patients were randomly assigned to a intermediate intensity rosuvastatin group (rosuvastatin 10mg/d, n=42), high-dose rosuvastatin group (rosuvastatin 20mg/d, n=41) or combination therapy group (ezetimibe 10mg/d and rosuvastatin 10mg/d, n=42) with a 12-week follow-up. The primary end point was the proportion of patients who achieved the 2011 ESC/EAS LDL-C goal <70mg/dL (1.8mmol/L) at week 12. Secondary end points included changes from baseline in lipids, the occurrence of all cardiovascular events, high-sensitivity C-reactive protein and safety markers. The combination therapy group in the primary end point was significantly higher than rosuvastatin (20mg) and rosuvastatin (10mg) at week 12 (81.0% vs 68.3% vs 33.3%, P<0.001). And the similar change was observed in reducing LDL-C levels at week 12 (67.28% vs 52.80% vs 43.89%, P<0.001). The incidence of drug-related adverse events was much higher in the rosuvastatin 20mg group than the rosuvastatin 10mg group and the combination therapy group (17.0% vs 2.4% vs 4.8%, P<0.05). The combination of rosuvastatin 10mg/ezetimibe 10mg was an effectively alternative therapy superior to rosuvastatin 20mg or 10mg with a greater effect on lowering LDL-C and a lower incidence of drug-related adverse events in Chinese patients. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Managing hypercholesterolemia and preventing cardiovascular events in elderly and younger Chinese adults: focus on rosuvastatin.

PubMed

Wang, Zhen; Ge, Junbo

2014-01-01

Coronary heart disease (CHD) is the leading cause of death worldwide. The efficacy and safety of statins in primary and secondary prevention of CHD is confirmed in several large studies, and rosuvastatin is the latest statin on market. We review the published literature on rosuvastatin in Chinese people. The pharmacokinetics of rosuvastatin in Chinese is somewhat different from that in Caucasians, but this does not influence the linear relationship between dosage and efficacy and with no drug accumulation. Rosuvastatin 5-20 mg/day is effective and safe in decreasing low-density lipoprotein cholesterol in both younger and elderly patients with hypercholesterolemia, even in very elderly patients. Rosuvastatin also shows anti-inflammatory and anti-atherosclerosis features, such as reducing carotid intima-media thickness and plaque area. Rosuvastatin can also improve the prognosis of Chinese CHD patients, such as in the case of acute myocardial infarction. Its adverse-event rate is low and comparable to other statins. In conclusion, rosuvastatin is effective and safe for younger or elderly Chinese patients.

Rationale, design features, and baseline characteristics: The Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome (HIJ-PROPER).

PubMed

Kawada-Watanabe, Erisa; Ogawa, Hiroshi; Koyanagi, Ryo; Arashi, Hiroyuki; Yamaguchi, Junichi; Matsui, Kunihiko; Hagiwara, Nobuhisa

2017-03-01

In contrast to current guidelines in Western countries, moderate reduction of low-density lipoprotein cholesterol (LDL-C) is recommended for Japanese patients with atherosclerotic cardiovascular disease and dyslipidemia even in secondary prevention. HIJ-PROPER (Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome) is a prospective, randomized, open-label, blinded endpoint multicenter trial designed to assess whether closely controlled LDL-C lowering with a standard statin dose plus ezetimibe, targeting LDL-C of <70mg/dL, would reduce cardiovascular events more than standard statin monotherapy targeting LDL-C of <100mg/dL as per the Japan Atherosclerotic Society guideline in patients with acute coronary syndrome (ACS) and dyslipidemia. We recruited patients with ACS and dyslipidemia who had undergone coronary angiography. Participants are randomly allocated to either intensive LDL-C lowering treatment (target LDL-C of <70mg/dL; pitavastatin plus ezetimibe) or standard LDL-C lowering treatment (target LDL-C of 90-100mg/dL; pitavastatin monotherapy). The primary endpoint is a composite of total death, non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina, and any ischemia-driven revascularization. Patients will be followed for a minimum of 3 years. Between January 2010 and April 2013, 1734 patients were enrolled from 19 hospitals in Japan with a mean age of 65.6 years; 75.5% were men and 83.3% were statin-naïve. The qualifying ACS was an acute MI in 61.5%. This study is expected to report its findings in August 2016. HIJ-PROPER will determine whether targeting LDL-C of <70mg/dL with pitavastatin plus ezetimibe can improve cardiovascular outcomes in Japanese patients with ACS and dyslipidemia in comparison to targeting LDL-C of 90-100mg/dL with standard pitavastatin monotherapy. UMIN000002742. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Pravastatin Protects Against Avascular Necrosis of Femoral Head via Autophagy.

PubMed

Liao, Yun; Zhang, Ping; Yuan, Bo; Li, Ling; Bao, Shisan

2018-01-01

Autophagy serves as a stress response and may contribute to the pathogenesis of avascular necrosis of the femoral head induced by steroids. Statins promote angiogenesis and ameliorate endothelial functions through apoptosis inhibition and necrosis of endothelial progenitor cells, however the process used by statins to modulate autophagy in avascular necrosis of the femoral head remains unclear. This manuscript determines whether pravastatin protects against dexamethasone-induced avascular necrosis of the femoral head by activating endothelial progenitor cell autophagy. Pravastatin was observed to enhance the autophagy activity in endothelial progenitor cells, specifically by upregulating LC3-II/Beclin-1 (autophagy related proteins), and autophagosome formation in vivo and in vitro . An autophagy inhibitor, 3-MA, reduced pravastatin protection in endothelial progenitor cells exposed to dexamethasone by attenuating pravastatin-induced autophagy. Adenosine monophosphate-activated protein kinase (AMPK) is a key autophagy regulator by sensing cellular energy changes, and indirectly suppressing activation of the mammalian target of rapamycin (mTOR). We found that phosphorylation of AMPK was upregulated however phosphorylation of mTOR was downregulated in pravastatin-treated endothelial progenitor cells, which was attenuated by AMPK inhibitor compound C. Furthermore, liver kinase B1 (a phosphorylase of AMPK) knockdown eliminated pravastatin regulated autophagy protein LC3-II in endothelial progenitor cells in vitro . We therefore demonstrated pravastatin rescued endothelial progenitor cells from dexamethasone-induced autophagy dysfunction through the AMPK-mTOR signaling pathway in a liver kinase B1-dependent manner. Our results provide useful information for the development of novel therapeutics for management of glucocorticoids-induced avascular necrosis of the femoral head.

Pravastatin reduces steroid-induced osteonecrosis of the femoral head in SHRSP rats

PubMed Central

2012-01-01

Background and purpose Although the definite cause of steroid-induced osteonecrosis of the femoral head (ONFH) is unknown, peripheral circulatory failure, lipid metabolism disturbance, and increased oxidative stress are considered to be possible causes. We investigated whether pravastatin as a statin treatment reduces (1) the incidence of ONFH, (2) the adipocyte area, and (3) bone marrow changes in the femoral head. Methods We divided up 81 thirteen-week-old spontaneously hypertensive stroke-prone (SHRSP)/Izm male rats into 4 groups: a control group (group C), a group given pravastatin (group P), a group given steroid (group S), and a group given both pravastatin and steroid (Group PS). The steroid was administered at 15 weeks of age. Pravastatin, as a statin, was administered in the drinking water for 4 weeks. The rats were killed when 17 weeks old. Osteonecrosis was diagnosed based on histopathological examination. Oxidative stress was assessed from immunostaining. Results The incidence of histological osteonecrosis was lower in the groups given pravastatin. The percentage of adipocyte area in the bone marrow was lower in the PS group than in the S group. Immunohistochemical staining for oxidative stress showed that staining was less in the PS group than in the S group. Pravastatin had no effect on the blood-derived biochemical findings on lipid metabolism. However, it reduced the incidence of steroid-induced ONFH in these SHRSP rats. We presume that this occurred by reducing oxidative stress and by reducing the percentage of adipocyte area in the femoral heads. Interpretation Our data suggest that pravastatin may be effective in reducing steroid-induced ONFH. PMID:22313369

Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects

PubMed Central

Cooper, Kelvin J; Martin, Paul D; Dane, Aaron L; Warwick, Mike J; Raza, Ali; Schneck, Dennis W

2003-01-01

Aims To examine in vivo the effect of ketoconazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Methods This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 14) received ketoconazole 200 mg or placebo twice daily for 7 days, and rosuvastatin 80 mg was coadministered on day 4 of dosing. Plasma concentrations of rosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 h postdose. Results Following coadministration with ketoconazole, rosuvastatin geometric least square mean AUC(0,t) and Cmax were unchanged compared with placebo (treatment ratios (90% confidence intervals): 1.016 (0.839, 1.230), 0.954 (0.722, 1.260), respectively). Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (> 85%) of the total inhibitors. Ketoconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. Conclusions Ketoconazole did not produce any change in rosuvastatin pharmacokinetics in healthy subjects. The data suggest that neither cytochrome P450 3A4 nor P-gp-mediated transport contributes to the elimination of rosuvastatin. PMID:12534645

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

PubMed

Miyauchi, Katsumi; Kimura, Takeshi; Shimokawa, Hiroaki; Daida, Hiroyuki; Iimuro, Satoshi; Iwata, Hiroshi; Ozaki, Yukio; Sakuma, Ichiro; Nakagawa, Yoshihisa; Hibi, Kiyoshi; Hiro, Takafumi; Fukumoto, Yoshihiro; Hokimoto, Seiji; Ohashi, Yasuo; Ohtsu, Hiroshi; Saito, Yasushi; Matsuzaki, Masunori; Nagai, Ryozo

2018-03-30

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2007-12-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Intergrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 249553, 2-Methoxyestradiol; Abatacept, Adalimumab, Adefovir dipivoxil, Agalsidase beta, Albinterferon alfa-2b, Aliskiren fumarate, Alovudine, Amdoxovir, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, AQ-13, Aripiprazole, AS-1404, Asoprisnil, Atacicept, Atrasentan; Belimumab, Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brivaracetam; Catumaxomab, Cediranib, Cetuximab, cG250, Ciclesonide, Cinacalcet hydrochloride, Curcumin, Cypher; Darbepoetin alfa, Denosumab, Dihydrexidine; Eicosapentaenoic acid/docosahexaenoic acid, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Etoricoxib, Everolimus, Ezetimibe; Febuxostat, Fenspiride hydrochloride, Fondaparinux sodium; Gefitinib, Ghrelin (human), GSK-1562902A; HSV-tk/GCV; Iclaprim, Imatinib mesylate, Imexon, Indacaterol, Insulinotropin, ISIS-112989; L-Alanosine, Lapatinib ditosylate, Laropiprant; Methoxy polyethylene glycol-epoetin-beta, Mipomersen sodium, Motexafin gadolinium; Natalizumab, Nimotuzumab; OSC, Ozarelix; PACAP-38, Paclitaxel nanoparticles, Parathyroid Hormone-Related Protein-(1-36), Pasireotide, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Picoplatin, Pimecrolimus, Pitavastatin calcium, Plitidepsin; Ranelic acid distrontium salt, Ranolazine, Recombinant human relaxin H2, Regadenoson, RFB4(dsFv)-PE38, RO-3300074, Rosuvastatin calcium; SIR-Spheres, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talabostat, Taribavirin hydrochloride, Taxus, Temsirolimus, Teriparatide, Tiotropium bromide, Tipifarnib, Tirapazamine, Tocilizumab; UCN-01, Ularitide, Uracil, Ustekinumab; V-260, Vandetanib, Vatalanib succinate, Vernakalant hydrochloride, Vorinostat; YM-155; Zileuton, Zoledronic acid monohydrate.

Combination effect naringin and pravastatin in lipid profile and glucose in obese rats.

PubMed

Raffoul-Orozco, Abdel K; Ávila-González, Ana E; Rodríguez-Razón, Christian M; García-Cobian, Teresa A; Pérez-Guerrero, Edsaul E; García-Iglesias, Trinidad; Rubio-Arellano, Edy David

2018-01-15

The purpose of this study was to compare the effect of naringin 100mg/kg in combination with pravastatin 10mg/kg by gavage for 6weeks compared with monotherapy over lipid profiles, glucose levels and weight in murine model of obesity. The study design was planned with 5 groups of 6 male Wistar Albina rats: Group 1: control with balanced food and vehicle (C-); Group 2: control with Obesity and vehicle (C+); Group 3: Obesity+naringin (N); Group 4: Obesity+pravastatin (P); Group 5: Obesity+pravastatin+naringin (NP). Obesity was developed with a food model. The naringin groups showed a decrease in weight gain and low glucose values compared to the control group (weight NP:311.4 vs C+:348.6; glucose NP: 173.12 vs C+:235.56) (p<0.05); the group with naringin+pravastatin combination showed the total cholesterol (TC), LDL and triglycerides (TGs) to normal levels (TC NP:51.6 vs C+:83.4; LDL NP:9.32 vs C+:32.32; TGs NP:39.4 vs C+:89.4) (p<0.05); but was not statistically significant compared with monotherapy. The combination of naringin and pravastatin did not appear to be better than monotherapy on lipids, but its use could generate euglycemic and antiobesogenic effects, in addition to diminishing the adverse hepatic effects of pravastatin in rats. Copyright © 2017 Elsevier Inc. All rights reserved.

Short-term memory loss associated with rosuvastatin.

PubMed

Galatti, Laura; Polimeni, Giovanni; Salvo, Francesco; Romani, Marcello; Sessa, Aurelio; Spina, Edoardo

2006-08-01

Memory loss and cognitive impairment have been reported in the literature in association with several 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), but we found no published case reports associated with rosuvastatin. To our knowledge, this is the first reported case of rosuvastatin-related short-term memory loss. A 53-year-old Caucasian man with hypercholesterolemia experienced memory loss after being treated with rosuvastatin 10 mg/day. He had no other concomitant conditions or drug therapies. After discontinuation of rosuvastatin, the neuropsychiatric adverse reaction resolved gradually, suggesting a probable drug association. During the following year, the patient remained free from neuropsychiatric disturbances. Clinicians should be aware of possible adverse cognitive reactions during statin therapy, including rosuvastatin.

Managing hypercholesterolemia and preventing cardiovascular events in elderly and younger Chinese adults: focus on rosuvastatin

PubMed Central

Wang, Zhen; Ge, Junbo

2014-01-01

Coronary heart disease (CHD) is the leading cause of death worldwide. The efficacy and safety of statins in primary and secondary prevention of CHD is confirmed in several large studies, and rosuvastatin is the latest statin on market. We review the published literature on rosuvastatin in Chinese people. The pharmacokinetics of rosuvastatin in Chinese is somewhat different from that in Caucasians, but this does not influence the linear relationship between dosage and efficacy and with no drug accumulation. Rosuvastatin 5–20 mg/day is effective and safe in decreasing low-density lipoprotein cholesterol in both younger and elderly patients with hypercholesterolemia, even in very elderly patients. Rosuvastatin also shows anti-inflammatory and antiatherosclerosis features, such as reducing carotid intima-media thickness and plaque area. Rosuvastatin can also improve the prognosis of Chinese CHD patients, such as in the case of acute myocardial infarction. Its adverse-event rate is low and comparable to other statins. In conclusion, rosuvastatin is effective and safe for younger or elderly Chinese patients. PMID:24353409

Ascorbic acid supplementation partially prevents the delayed reproductive development in juvenile male rats exposed to rosuvastatin since prepuberty.

PubMed

Leite, Gabriel Adan Araújo; Figueiredo, Thamiris Moreira; Sanabria, Marciana; Dias, Ana Flávia Mota Gonçalves; Silva, Patrícia Villela E; Martins Junior, Airton da Cunha; Barbosa Junior, Fernando; Kempinas, Wilma De Grava

2017-10-01

Dyslipidemias are occurring earlier in the population due to the increase of obesity and bad eating habits. Rosuvastatin inhibits the enzyme HMG-CoA reductase, decreasing total cholesterol. Ascorbic acid is an important antioxidant compound for male reproductive system. This study aimed to evaluate whether ascorbic acid supplementation may prevent the reproductive damage provoked by rosuvastatin administration at prepuberty. Male pups were distributed into six experimental groups that received saline solution 0.9%, 3 or 10mg/kg/day of rosuvastatin, 150mg/day of ascorbic acid, or 150mg/day of ascorbic acid associated with 3 or 10mg/kg/day of rosuvastatin from post-natal day (PND) 23 until PND53. Rosuvastatin-treated groups showed delayed puberty installation, androgen depletion and impairment on testicular and epididymal morphology. Ascorbic acid partially prevented these reproductive damages. In conclusion, rosuvastatin exposure is a probable risk to reproductive development and ascorbic acid supplementation may be useful to prevent the reproductive impairment of rosuvastatin exposure. Copyright © 2017 Elsevier Inc. All rights reserved.

Rosuvastatin safety: An experimental study of myotoxic effects and mitochondrial alterations in rats.

PubMed

El-Ganainy, Samar O; El-Mallah, Ahmed; Abdallah, Dina; Khattab, Mahmoud M; Mohy El-Din, Mahmoud M; El-Khatib, Aiman S

2017-01-04

Myopathy is the most commonly reported adverse effect of statins. All statins are associated with myopathy, though with different rates. Rosuvastatin is a potent statin reported to induce myopathy comparable to earlier statins. However, in clinical practice most patients could tolerate rosuvastatin over other statins. This study aimed to evaluate the myopathic pattern of rosuvastatin in rats using biochemical, functional and histopathological examinations. The possible deleterious effects of rosuvastatin on muscle mitochondria were also examined. The obtained results were compared to myopathy induced by atorvastatin in equimolar dose. Results showed that rosuvastatin induced a rise in CK, a slight increase in myoglobin level together with mild muscle necrosis. Motor activity, assessed by rotarod, showed that rosuvastatin decreased rats' performance. All these manifestations were obviously mild compared to the prominent effects of atorvastatin. Parallel results were obtained in mitochondrial dysfunction parameters. Rosuvastatin only induced a slight increase in LDH and a minor decrease in ATP (∼14%) and pAkt (∼12%). On the other hand, atorvastatin induced an increase in LDH, lactate/pyruvate ratio and a pronounced decline in ATP (∼80%) and pAkt (∼65%). These findings showed that rosuvastatin was associated with mild myotoxic effects in rats, especially when compared to atorvastatin. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Computational NMR, IR/RAMAN calculations in sodium pravastatin: Investigation of the Self-Assembled Nanostructure of Pravastatin-LDH (Layered Double Hydroxides) Systems

NASA Astrophysics Data System (ADS)

Petersen, Philippe; Cunha, Vanessa; Gonçalves, Marcos; Petrilli, Helena; Constantino, Vera; Instituto de Física, Departamento de Física de Materiais e Mecânica Team; Instituto de Química, Departamento de Química Fundamental Team

2013-03-01

Layered double hydroxides (LDH) can be used as nanocontainers for immobilization of Pravastatin, in order to obtain suitable drug carriers. The material's structure and spectroscopic properties were analyzed by NMR, IR/RAMAN and supported by theoretical calculations. Density Functional Theory (DFT) calculations were performed using the Gaussian03 package. The geometry optimizations were performed considering the single crystal X-ray diffraction data of tert-octylamonium salt of Pravastatin. Tetramethylsilane (TMS), obtained with the same basis set, was used as reference for calculating the chemical shift of 13C. A scaling factor was used to compare theoretical and experimental harmonic vibrational frequencies. Through the NMR and IR/RAMAN spectra, we were able to make precise assignments of the NMR and IR/RAMAN of Sodium Pravastatin. We acknowledge support from CAPES, INEO and CNPQ.

Effect of rosuvastatin monotherapy and in combination with fenofibrate or omega-3 fatty acids on serum vitamin D levels.

PubMed

Makariou, Stefania E; Liberopoulos, Evangelos N; Agouridis, Aris P; Challa, Anna; Elisaf, Moses

2012-12-01

Low levels of 25(OH) vitamin D [25(OH)VitD] have been recognized as a new cardiovascular disease (CVD) risk factor. Statins seem to increase 25(OH)VitD concentration. To investigate whether combined treatment with the usual dose of rosuvastatin plus fenofibrate or omega-3 fatty acids would increase 25(OH)VitD levels compared with the high-dose rosuvastatin monotherapy in participants with mixed dislipidemia. We randomly allocated 60 patients with mixed dyslipidemia (low-density lipoprotein cholesterol: >160 mg/dL plus triglycerides: >200 mg/dL) to receive rosuvastatin 40 mg (n = 22), rosuvastatin 10 mg plus fenofibrate 200 mg (n = 21), or rosuvastatin 10 mg plus omega-3 fatty acids 2 g (n = 17) daily for 3 months. Our primary end point was changes in the levels of serum 25(OH)VitD. Rosuvastatin monotherapy was associated with a 53% increase in 25(OH)VitD (from 14.6 [1.0-38.0] to 17.8 [5.3-49.6] ng/mL; P = .000). Rosuvastatin plus micronized fenofibrate and rosuvastatin plus omega-3 fatty acids were associated with increases of 64% (from 14.1 [1.0-48.0] to 18.4 [6.7-52.4] ng/mL, P = .001) and 61% (from 10.4 [6.6-38.4] to 14.0 [9.6-37.6] ng/mL, P = .04), respectively. The changes in 25(OH)VitD after treatment were comparable in the 3 groups. High-dose rosuvastatin monotherapy and the usual dose of rosuvastatin plus fenofibrate or omega-3 fatty acids are associated with significant and similar increases in the 25(OH)VitD levels. This increase may be relevant in terms of CVD risk prevention.

Rosuvastatin protects against podocyte apoptosis in vitro

PubMed Central

Cormack-Aboud, Fionnuala C.; Brinkkoetter, Paul T.; Pippin, Jeffrey W.; Shankland, Stuart J.; Durvasula, Raghu V.

2009-01-01

Background. Clinical studies suggest that statins reduce proteinuria and slow the decline in kidney function in chronic kidney disease. Given a rich literature identifying podocyte apoptosis as an early step in the pathophysiological progression to proteinuria and glomerulosclerosis, we hypothesized that rosuvastatin protects podocytes from undergoing apoptosis. Regarding a potential mechanism, our lab has shown that the cell cycle protein, p21, has a prosurvial role in podocytes and there is literature showing statins upregulate p21 in other renal cells. Therefore, we queried whether rosuvastatin is prosurvival in podocytes through a p21-dependent pathway. Methods. Two independent apoptotic triggers, puromycin aminonucleoside (PA) and adriamycin (ADR), were used to induce apoptosis in p21 +/+ and p21 −/− conditionally immortalized mouse podocytes with or without pre-exposure to rosuvastatin. Apoptosis was measured by two methods: Hoechst 33342 staining and fluorescence-activated cell sorting (FACS). To establish a role for p21, p21 levels were measured by western blotting following rosuvastatin exposure and p21 was stably transduced into p21 −/− mouse podocytes. Results. Rosuvastatin protects against ADR- and PA-induced apoptosis in podocytes. Further, exposure to rosuvastatin increases p21 levels in podocytes in vitro. ADR induces apoptosis in p21 −/− mouse podocytes, but rosuvastatin's protective effect is not seen in the absence of p21. Reconstituting p21 in p21 −/− podocytes restores rosuvastatin's prosurvival effect. Conclusion. Rosuvastatin is prosurvival in injured podocytes. Rosuvastatin exerts its protective effect through a p21-dependent antiapoptotic pathway. These findings suggest that statins decrease proteinuria by protecting against podocyte apoptosis and subsequent podocyte depopulation. PMID:18820279

Rosuvastatin pharmacokinetics and pharmacogenetics in Caucasian and Asian subjects residing in the United States.

PubMed

Birmingham, Bruce K; Bujac, Sarah R; Elsby, Robert; Azumaya, Connie T; Zalikowski, Julie; Chen, Yusong; Kim, Kenneth; Ambrose, Helen J

2015-03-01

Systemic exposure to rosuvastatin in Asian subjects living in Japan or Singapore is approximately twice that observed in Caucasian subjects in Western countries or in Singapore. This study was conducted to determine whether pharmacokinetic differences exist among the most populous Asian subgroups and Caucasian subjects in the USA. Rosuvastatin pharmacokinetics was studied in Chinese, Filipino, Asian-Indian, Korean, Vietnamese, Japanese and Caucasian subjects residing in California. Plasma concentrations of rosuvastatin and metabolites after a single 20-mg dose were determined by mass spectrometric detection. The influence of polymorphisms in SLCO1B1 (T521>C [Val174Ala] and A388>G [Asn130Asp]) and in ABCG2 (C421>A [Gln141Lys]) on exposure to rosuvastatin was also assessed. The average rosuvastatin area under the curve from time zero to time of last quantifiable concentration was between 64 and 84 % higher, and maximum drug concentration was between 70 and 98 % higher in East Asian subgroups compared with Caucasians. Data for Asian-Indians was intermediate to these two ethnic groups at 26 and 29 %, respectively. Similar increases in exposure to N-desmethyl rosuvastatin and rosuvastatin lactone were observed. Rosuvastatin exposure was higher in subjects carrying the SLCO1B1 521C allele compared with that in non-carriers of this allele. Similarly, exposure was higher in subjects carrying the ABCG2 421A allele compared with that in non-carriers. Plasma exposure to rosuvastatin and its metabolites was significantly higher in Asian populations residing in the USA compared with Caucasian subjects living in the same environment. This study suggests that polymorphisms in the SLCO1B1 and ABCG2 genes contribute to the variability in rosuvastatin exposure.

The Synergistic Neuroprotective Effects of Combined Rosuvastatin and Resveratrol Pretreatment against Cerebral Ischemia/Reperfusion Injury.

PubMed

Liu, Ying; Yang, HongNa; Jia, GuoYong; Li, Lan; Chen, Hui; Bi, JianZhong; Wang, CuiLan

2018-06-01

It is well accepted that both rosuvastatin and resveratrol exert neuroprotective effects on cerebral ischemia/reperfusion injury through some common pathways. Resveratrol has also been demonstrated to protect against cerebral ischemia/reperfusion injury through enhancing autophagy. Thus, we hypothesized that combined rosuvastatin and resveratrol pretreatment had synergistic effects on cerebral ischemia/reperfusion injury. Adult male Sprague Dawley rats receiving middle cerebral artery occlusion surgery as animal model of cerebral ischemia/reperfusion injury were randomly assigned to 4 groups: control, resveratrol alone pretreatment, rosuvastatin alone pretreatment, and combined rosuvastatin and resveratrol pretreatment. Rosuvastatin (10 mg/kg) or resveratrol (50 mg/kg) was administrated once a day for 7 days before cerebral ischemia onset. We found that combined rosuvastatin and resveratrol pretreatment not only significantly decreased the neurologic defective score, cerebral infarct volume, the levels of caspase-3, and Interleukin-1β (IL-1β) but also significantly increased the ratios of Bcl-2/Bax and LC3II/LC3I, as well as the level of Becline-1, compared with resveratrol alone or rosuvastatin alone pretreatment group. Rosuvastatin alone pretreatment significantly increased the ratio of LC3II/LC3I and the level of Beclin-1. However, there were no significant differences in the neurologic defective score, cerebral infarct volume, the levels of caspase-3, IL-1β, and Beclin-1, and the ratios of Bcl-2/Bax and LC3II/LC3I between resveratrol pretreatment group and rosuvastatin pretreatment group. Synergistically enhanced antiapoptosis, anti-inflammation, and autophagy activation might be responsible for the synergistic neuroprotective effects of combining rosuvastatin with resveratrol on cerebral ischemia/reperfusion injury. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers

PubMed Central

Kim, Tae-Eun; Ha, Na; Kim, Yunjeong; Kim, Hyunsook; Lee, Jae Wook; Jeon, Ji-Young; Kim, Min-Gul

2017-01-01

Previous in vitro studies have demonstrated the inhibitory effect of green tea on drug transporters. Because rosuvastatin, a lipid-lowering drug widely used for the prevention of cardiovascular events, is a substrate for many drug transporters, there is a possibility that there is interaction between green tea and rosuvastatin. The aim of this study was to investigate the effect of green tea on the pharmacokinetics of rosuvastatin in healthy volunteers. An open-label, three-treatment, fixed-sequence study was conducted. On Day 1, 20 mg of rosuvastatin was given to all subjects. After a 3-day washout period, the subjects received 20 mg of rosuvastatin plus 300 mg of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea (Day 4). After a 10-day pretreatment of EGCG up to Day 14, they received rosuvastatin (20 mg) plus EGCG (300 mg) once again (Day 15). Blood samples for the pharmacokinetic assessments were collected up to 8 hours after each dose of rosuvastatin. A total of 13 healthy volunteers were enrolled. Compared with the administration of rosuvastatin alone, the concomitant use at Day 4 significantly reduced the area under the concentration–time curve from time 0 to the last measurable time (AUClast) by 19% (geometric mean ratio 0.81, 90% confidence interval [CI] 0.67–0.97) and the peak plasma concentration (Cmax) by 15% (geometric mean ratio 0.85, 90% CI 0.70–1.04). AUClast or Cmax of rosuvastatin on Day 15 was not significantly different from that on Day 1. This study demonstrated that co-administration of EGCG reduces the systemic exposure of rosuvastatin by 19%, and pretreatment of EGCG can eliminate that effect of co-administration of EGCG. PMID:28533679

Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial.

PubMed

Farnier, Michel; Jones, Peter; Severance, Randall; Averna, Maurizio; Steinhagen-Thiessen, Elisabeth; Colhoun, Helen M; Du, Yunling; Hanotin, Corinne; Donahue, Stephen

2016-01-01

To compare lipid-lowering efficacy of adding alirocumab to rosuvastatin versus other treatment strategies (NCT01730053). Patients receiving baseline rosuvastatin regimens (10 or 20 mg) were randomized to: add-on alirocumab 75 mg every-2-weeks (Q2W) (1-mL subcutaneous injection via pre-filled pen); add-on ezetimibe 10 mg/day; or double-dose rosuvastatin. Patients had cardiovascular disease (CVD) and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL (1.8 mmol/L) or CVD risk factors and LDL-C ≥100 mg/dL (2.6 mmol/L). In the alirocumab group, dose was blindly increased at Week 12 to 150 mg Q2W (also 1-mL volume) in patients not achieving their LDL-C target. Primary endpoint was percent change in calculated LDL-C from baseline to 24 weeks (intent-to-treat). 305 patients were randomized. In the baseline rosuvastatin 10 mg group, significantly greater LDL-C reductions were observed with add-on alirocumab (-50.6%) versus ezetimibe (-14.4%; p < 0.0001) and double-dose rosuvastatin (-16.3%; p < 0.0001). In the baseline rosuvastatin 20 mg group, LDL-C reduction with add-on alirocumab was -36.3% compared with -11.0% with ezetimibe and -15.9% with double-dose rosuvastatin (p = 0.0136 and 0.0453, respectively; pre-specified threshold for significance p < 0.0125). Overall, ∼80% alirocumab patients were maintained on 75 mg Q2W. Of alirocumab-treated patients, 84.9% and 66.7% in the baseline rosuvastatin 10 and 20 mg groups, respectively, achieved risk-based LDL-C targets. Treatment-emergent adverse events occurred in 56.3% of alirocumab patients versus 53.5% ezetimibe and 67.3% double-dose rosuvastatin (pooled data). The addition of alirocumab to rosuvastatin provided incremental LDL-C lowering versus adding ezetimibe or doubling the rosuvastatin dose. Copyright © 2015 Regeneron Pharmaceuticals, Inc. Published by Elsevier Ireland Ltd.. All rights reserved.

Lipid lowering efficacy and safety of Ezetimibe combined with rosuvastatin compared with titrating rosuvastatin monotherapy in HIV-positive patients.

PubMed

Saeedi, Ramesh; Johns, Kevin; Frohlich, Jiri; Bennett, Matthew T; Bondy, Gregory

2015-06-19

HIV-infected patients on antiretroviral therapy frequently develop dyslipidemias and, despite therapy with potent lipid-lowering agents, a high percentage does not achieve guideline recommended lipid targets. In this study, we examined the efficacy of combination treatment with a statin and the cholesterol transport blocker, ezetimibe, vs. monotherapy with a statin in HIV-infected patients not achieving lipid goals. This was a 12-week, prospective, randomized, open-label clinical trial. Patients were eligible if they had an apolipoprotein B (apoB) >0.80 g/L despite therapy with rosuvastatin 10 mg daily for a minimum of 12 weeks. Patients were randomized to take ezetimibe 10 mg/rosuvastatin 10 mg or rosuvastatin 20 mg for 12 weeks. Percentage and absolute change in apoB (primary outcome), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apoliporpotein A1 (apoA1), apoB/apoA1, TC/HDL-C, atherogenic index of plasma (API), and high-sensitivity C-reactive protein (hsCRP) were compared. Changes in safety parameters (such as AST, ALT, CK) and clinical symptoms were also assessed. Forty-three patients (23 on ezetimibe 10 mg/rosuvastatin 10 mg and 20 on rosuvastatin 20 mg) completed the trial. Baseline characteristics did not differ between the groups. Significant improvements in apoB were seen with both ezetimibe plus rosuvastatin (mean of -0.17 g/L, p < 0.001) and rosuvastatin 20 mg (mean of -0.13 g/L, p = 0.03) treatment groups, but did not differ between groups (p = 0.53). Significant between-group differences were observed for mean TC (-1.01 mmol/L vs. -0.50 mmol/L, p = 0.03), TG (-0.62 mmol/L vs -0.17 mmol/L, p = 0.03), and non-HDL-C (-0.97 mmol/L vs. -0.53 mmol/L, p = 0.03) all in favour of the ezetimibe plus rosuvastatin group. Two patients, both in the rosuvastatin 20 mg group, experienced mild myalgias; neither discontinued the study. The addition of ezetimibe to rosuvastatin appears to be safe in patients with HIV. Furthermore, the combination of ezetimibe and rosuvastatin improved TG, AIP and non-HDL cholesterol levels more than a dose increase in rosuvastatin in patients with HIV-associated dyslipidemia.

Effects of long-term pravastatin treatment on spermatogenesis and on adrenal and testicular steroidogenesis in male hypercholesterolemic patients.

PubMed

Bernini, G P; Brogi, G; Argenio, G F; Moretti, A; Salvetti, A

1998-05-01

To evaluate the influence of an hydrophilic statin, pravastatin, on adrenal and testicular steroidogenesis and spermatogenesis, eight male hypercholesterolemic patients were studied. All patients observed a hypocholesterolemic diet and received placebo for 4 weeks followed by pravastatin (20 mg/die) for 6 months. Before, during (4th-5th week) and at the end (23th-24th week) of active treatment, CRH (1 microgram i.v.), ACTH (Synacthen 250 micrograms i.v.) and human CG (HCG 3000 IU i.m.) tests were performed in addition to semen analysis. Pravastatin significantly reduced total cholesterol (20.3%), calculated LDL-cholesterol (24.6%) and apolipoprotein B (10.5%, increased apolipoprotein A1 (16.1%) and did not influence plasma HDL-cholesterol and triglycerides. Basal plasma cortisol, aldosterone, androstenedione, testosterone and oestradiol did not change under active treatment. Pravastatin administration affected neither adrenal hormone responses to CRH and ACTH or testicular response to HCG nor spermatogenesis in respect of motility, morphology and sperm count. In conclusion, long-term pravastatin treatment, at doses effective in improving lipid profile, did not influence testicular reproductive and endocrine function and did not interfere with basal and stimulated adrenal activity of male hypercholesterolemic patients.

Mixed effects of OATP1B1, BCRP and NTCP polymorphisms on the population pharmacokinetics of pravastatin in healthy volunteers.

PubMed

Lu, Xue-Feng; Zhou, Yang; Bi, Kai-Shun; Chen, Xiao-Hui

2016-09-01

1. Pravastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of hyperlipidaemia. This study aims to investigate the effects of genetic polymorphisms in OATP1B1, BCRP and NTCP on pravastatin population pharmacokinetics in healthy Chinese volunteers using a non-linear mixed-effect modelling (NONMEM) approach. A two-compartment model with a first-order absorption and elimination described plasma pravastatin concentrations well. 2. Genetic polymorphisms of rs4149056 (OATP1B1) and rs2306283 (OATP1B1) were found to be associated with a significant (p < 0.01) decrease in the apparent clearance from the central compartment (CL/F), while rs2296651 (NTCP) increased CL/F to a significant degree (p < 0.01). The combination of these three polymorphisms reduced the inter-individual variability of CL/F by 78.8%. 3. There was minimal effect of rs2231137 (BCRP) and rs2231142 (BCRP) on pravastatin pharmacokinetics (0.01 < p < 0.05), whereas rs11045819 (OATP1B1), rs1061018 (BCRP) and rs61745930 (NTCP) genotypes do not appear to be associated with pravastatin pharmacokinetics based on the population model (p > 0.05). 4. The current data suggest that the combination of rs4149056, rs2306283 and rs2296651 polymorphisms is an important determinant of pravastatin pharmacokinetics.

Effect of pravastatin on responsiveness to N-monomethyl-L-arginine in patients with hypercholesterolaemia.

PubMed

Bayerle-Eder, Michaela; Fuchsjäger-Mayrl, Gabriele; Sieder, Anna; Polska, Elzbieta; Roden, Michael; Stulnig, Thomas; Bischof, Martin G; Waldhäusl, Werner; Schmetterer, Leopold; Wolzt, Michael

2002-01-01

Improvement of endothelial function in hypercholesterolaemia is attributed to lipid lowering and to pleiotropic effects of statin therapy. We investigated whether responsiveness to inhibition of constitutive NO formation with N-monomethyl-L-arginine (L-NMMA) is improved after 7 and 28 days of pravastatin. Twelve female and four male subjects with mild or moderate primary hypercholesterolaemia were randomized to pravastatin (20 mg per oral (p.o.) n=8) or placebo (n=8) in a double blind parallel group design. Vascular responsiveness was studied by intravenous bolus infusions of L-NMMA (cumulative doses of 3 and 6 mg/kg). Mean arterial blood pressure (MAP) and pulse rate (PR) were measured noninvasively, pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation amplitudes (FPA) and renal plasma flow (RPF) was measured by the PAH clearance method. Pravastatin lowered plasma cholesterol levels by 16 and 24% after 7 and 28 days of treatment, respectively (P<0.01). L-NMMA caused comparable changes in MAP, PR and RPF between groups. L-NMMA reduced FPA to a similar extent in both groups before and after 7 days of treatment, but the response to L-NMMA was significantly enhanced after 28 days of pravastatin (21%; P<0.001 vs baseline) and greater than after placebo (15%; P<0.01 vs pravastatin). Pravastatin enhances responsiveness to L-NMMA in the ocular microvasculature. Improved responsiveness is associated with changes in total cholesterol levels.

Rosuvastatin Pharmacokinetics in Asian and White Subjects Wild Type for Both OATP1B1 and BCRP Under Control and Inhibited Conditions.

PubMed

Wu, Hsin-Fang; Hristeva, Nadya; Chang, Jae; Liang, Xiaorong; Li, Ruina; Frassetto, Lynda; Benet, Leslie Z

2017-09-01

The Food and Drug Administration recommends rosuvastatin dosage reductions in Asian patients because pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects compared with Caucasian controls. Yet, no explanation for this ethnic difference has been confirmed. Here we show that rosuvastatin exposure in Asians and Whites does not differ significantly when all subjects are wild-type carriers for both solute carrier organic anion transporter 1B1 *1a and ATP-binding cassette subfamily G member 2 c.421 transporters in a 2-arm, randomized, cross-over rosuvastatin pharmacokinetics study in healthy white and Asian volunteers. For single rosuvastatin doses, AUC 0-48 were 92.5 (±36.2) and 83.5 (±32.2) ng/mL × h and C max were 10.0 (±4.1) and 7.6 (±3.0) ng/mL for Asians and Whites, respectively. When transporters were inhibited by intravenous rifampin, rosuvastatin AUC 0-48 and C max also showed no ethnic differences. Our study suggests that both SLCO1B1 and ABCG2 polymorphisms are better predictors of rosuvastatin exposure than ethnicity alone and could be considered in precision medicine dosing of rosuvastatin. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Pravastatin and cardiovascular outcomes stratified by baseline eGFR in the lipid-lowering component of ALLHAT

PubMed Central

Rahman, Mahboob; Baimbridge, Charles; Davis, Barry R.; Barzilay, Joshua I.; Basile, Jan N.; Henriquez, Mario A.; Huml, Anne; Kopyt, Nelson; Louis, Gail T.; Pressel, Sara L.; Rosendorff, Clive; Sastrasinh, Sithiporn; Stanford, Carol

2013-01-01

Background/Aims: The role of statins in preventing cardiovascular outcomes in patients with chronic kidney disease (CKD) is unclear. This paper compares cardiovascular outcomes with pravastatin vs. usual care, stratified by baseline estimated glomerular filtration rate (eGFR). Methods: Post-hoc analyses of a prospective randomized open-label clinical trial; 10,151 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) were randomized to pravastatin 40 mg/day or usual care. Mean follow-up was 4.8 years. Results: Through Year 6, total cholesterol declined in pravastatin (–20.7%) and usual-care groups (–11.2%). Use of statin therapy in the pravastatin group was 89.8% (Year 2) and 87.0% (Year 6). Usual-care group statin use increased from 8.2% (Year 2) to 23.5% (Year 6). By primary intention-to-treat analyses, no significant differences were seen between groups for coronary heart disease (CHD), total mortality or combined cardiovascular disease; findings were consistent across eGFR strata. In exploratory “as-treated” analyses (patients actually using pravastatin vs. not using), pravastatin therapy was associated with lower mortality (HR = 0.76 (0.68 – 0.85), p < 0.001) and lower CHD (HR = 0.84 (0.73 – 0.97), p = 0.01), but not combined cardiovascular disease (HR = 0.95 (0.88 – 1.04), p = 0.30). Total cholesterol reduction of 10 mg/dl from baseline to Year 2 was associated with 5% lower CHD risk. Conclusions: In hypertensive patients with moderate dyslipidemia, pravastatin was not superior to usual care in preventing total mortality or CHD independent of baseline eGFR level. However, exploratory “as-treated” analyses suggest improved mortality and CHD risk in participants using pravastatin, and decreased CHD events associated with achieved reduction in total cholesterol. Potential benefit from statin therapy may depend on degree of reduction achieved in total and LDL-cholesterol and adherence to therapy. PMID:23816477

Rosuvastatin

MedlinePlus

Crestor® ... Rosuvastatin is used together with diet, weight-loss, and exercise to reduce the risk of heart attack ... who are at risk of developing heart disease. Rosuvastatin is also used to decrease the amount of ...

Ticagrelor and Rosuvastatin Have Additive Cardioprotective Effects via Adenosine.

PubMed

Birnbaum, Yochai; Birnbaum, Gilad D; Birnbaum, Itamar; Nylander, Sven; Ye, Yumei

2016-12-01

Ticagrelor inhibits the equilibrative-nucleoside-transporter-1 and thereby, adenosine cell re-uptake. Ticagrelor limits infarct size (IS) in non-diabetic rats and the effect is adenosine-dependent. Statins, via ecto-5'-nucleotidase activation, also increase adenosine levels and limit IS. Ticagrelor and rosuvastatin have additive effects on myocardial adenosine levels, and therefore, on IS and post-reperfusion activation of the NLRP3-inflammasome. Diabetic ZDF rats received via oral gavage; water (control), ticagrelor (150 mg/kg/d), prasugrel (7.5 mg/kg/d), rosuvastatin (5 mg/kg/d), ticagrelor + rosuvastatin and prasugrel + rosuvastatin for 3d. On day 4, rats underwent 30 min coronary artery occlusion and 24 h of reperfusion. Two additional groups received, ticagrelor + rosuvastatin or water in combination with CGS15943 (CGS, an adenosine receptor antagonist, 10 mg/kg i.p. 1 h before ischemia). Both ticagrelor and rosuvastatin increased myocardial adenosine levels with an additive effect of the combination whereas prasugrel had no effect. Similarly, both ticagrelor and rosuvastatin significantly reduced IS with an additive effect of the combination whereas prasugrel had no effect. The effect on IS was adenosine dependent as CGS15943 reversed the effect of ticagrelor + rosuvastatin. The ischemia-reperfusion injury increased myocardial mRNA levels of NLRP3, ASC, IL-1β and IL-6. Ticagrelor and rosuvastatin, but not prasugrel, significantly decreased these pro-inflammatory mediators with a trend to an additive effect of the combination. The combination also increased the levels of anti-inflammatory 15-epilipoxin A 4 . Ticagrelor and rosuvastatin when given in combination have an additive effect on local myocardial adenosine levels in the setting of ischemia reperfusion. This translates into an additive cardioprotective effect mediated by adenosine-induced effects including downregulation of pro- but upregulation of anti-inflammatory mediators.

A review of the efficacy of rosuvastatin in patients with type 2 diabetes.

PubMed

Tuomilehto, J; Leiter, L A; Kallend, D

2004-10-01

It has been estimated that 92% of individuals with type 2 diabetes, without cardiovascular disease (CVD), have a dyslipidaemic profile. Several guidelines on cardiovascular risk now recommend that patients with diabetes should be considered at high risk of CVD and should thus receive lipid-lowering therapy to reduce low-density lipoprotein cholesterol (LDL-C) to below 2.5 mmol/L. Since their introduction in 1987, statins have revolutionized the management of CVD. The most recent statin to be introduced, rosuvastatin, has been shown to be the most effective at lowering LDL-C, as well as consistently raising HDL-C across the 10-40 mg dose range. This has been confirmed by many studies, including the Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study in which rosuvastatin 10 mg was shown to be more effective than commonly used doses of other statins, both for LDL-C reduction and achieving treatment target goals. The effectiveness of rosuvastatin has also been studied in type 2 diabetes patients in three studies: the URANUS (Use of Rosuvastatin vs. Atorvastatin iN type 2 diabetes mellitUS), ANDROMEDA (A raNdomized, Double-blind study to compare Rosuvastatin [10 & 20 mg] and atOrvastatin [10 & 20 Mg] in patiEnts with type II DiAbetes) and CORALL (COmpare Rosuvastatin [10-40 mg] with Atorvastatin [20-80 mg] on apo B/apo A-1 ratio in patients with type 2 diabetes meLLitus and dyslipidaemia) studies. URANUS and ANDROMEDA showed rosuvastatin to be more effective than atorvastatin at reducing LDL-C and achieving treatment target goals. CORALL demonstrated rosuvastatin 10, 20 and 40 mg to be more effective at lowering LDL-C than 20, 40 and 80 mg of atorvastatin, respectively. Ongoing studies will evaluate whether these properties of rosuvastatin translate into beneficial effects on atherosclerosis and significant reductions in cardiovascular events.

Anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium-induced colitis model

PubMed Central

Shin, Seung Kak; Cho, Jae Hee; Kim, Eui Joo; Kim, Eun-Kyung; Park, Dong Kyun; Kwon, Kwang An; Chung, Jun-Won; Kim, Kyoung Oh; Kim, Yoon Jae

2017-01-01

AIM To evaluate the anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium (DSS)-induced colitis model. METHODS An acute colitis mouse model was induced by oral administration of 5% DSS in the drinking water for 7 d. In the treated group, rosuvastatin (0.3 mg/kg per day) was administered orally before and after DSS administration for 21 d. On day 21, mice were sacrificed and the colons were removed for macroscopic examination, histology, and Western blot analysis. In the in vitro study, IEC-6 cells were stimulated with 50 ng/mL tumor necrosis factor (TNF)-α and then treated with or without rosuvastatin (2 μmol/L). The levels of reactive oxygen species (ROS), inflammatory mediators, and apoptotic markers were measured. RESULTS In DSS-induced colitis mice, rosuvastatin treatment significantly reduced the disease activity index and histological damage score compared to untreated mice (P < 0.05). Rosuvastatin also attenuated the DSS-induced increase of 8-hydroxy-2’-deoxyguanosine and NADPH oxidase-1 expression in colon tissue. Multiplex ELISA analysis revealed that rosuvastatin treatment reduced the DSS-induced increase of serum IL-2, IL-4, IL-5, IL-6, IL-12 and IL-17, and G-CSF levels. The increased levels of cleaved caspase-3, caspase-7, and poly (ADP-ribose) polymerase in the DSS group were attenuated by rosuvastatin treatment. In vitro, rosuvastatin significantly reduced the production of ROS, inflammatory mediators and apoptotic markers in TNF-α-treated IEC-6 cells (P < 0.05). CONCLUSION Rosuvastatin had the antioxidant, anti-inflammatory and anti-apoptotic effects in DSS-induced colitis model. Therefore, it might be a candidate anti-inflammatory drug in patients with inflammatory bowel disease. PMID:28740344

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2002-05-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables can be retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abarelix, abciximab, acarbose, alefacept, alteplase, amisulpride, amoxicillin trihydrate, apomorphine hydrochloride, aprepitant, argatroban monohydrate, aspirin, atenolol; Betamethasone dipropionate, betamethasone valerate, bicalutamide, bleomycin sulfate; Calcium carbonate, candesartan cilexetil, celecoxib, cetirizine hydrochloride, cisplatin, clarithromycin, clavulanate potassium, clomethiazole edisilate, clopidogrel hydrogensulfate, cyclophosphamide, chorionic gonadotropin (human); Dalteparin sodium, desloratadine, dexamethasone, doxorubicin, DPC-083; Efalizumab, efavirenz, enoxaparin sodium, eprosartan mesilate, etanercept, etoposide, ezetimibe; Faropenem daloxate, fenofibrate, fluocinolone acetonide, flutamide, fluvastatin sodium, follitropin beta, fondaparinux sodium; Gabapentin, glibenclamide, goserelin, granisetron hydrochloride; Haloperidol, hydrochlorothiazide; Imiquimod, interferon beta-1a, irbesartan, iseganan hydrochloride; L-758298, lamivudine, lanoteplase, leflunomide, leuprorelin acetate, loratadine, losartan potassium; Melagatran, metformin hydrochloride, methotrexate, metronidazole, micafungin sodium, mitoxantrone hydrochloride; Nelfinavir mesilate, neutral insulin injection, nizatidine; Olopatadine hydrochloride, omeprazole, ondansetron hydrochloride; Pamidronate sodium, paracetamol, paroxetine hydrochloride, perindopril, pimecrolimus, pioglitazone hydrochloride, piroxicam, pleconaril, pralmorelin, pravastatin sodium, prednisolone, prednisone, propofol; Raloxifene hydrochloride, ranpirnase, remifentanil hydrochloride, risedronate sodium, risperidone, rofecoxib, ropinirole hydrochloride, rosuvastatin calcium; Sevoflurane, sildenafil citrate, simvastatin, somatropin; Tacrolimus, tamoxifen citrate, telmisartan, temozolomide, thiopental sodium, tinzaparin sodium, tirofiban hydrochloride, treosulfan, triamcinolone acetonide; Urokinase; Valsartan, vardenafil, vincristine; Warfarin sodium; Ximelagatran; Zidovudine.

Pharmacokinetic Interaction Between Rosuvastatin, Telmisartan, and Amlodipine in Healthy Male Korean Subjects: A Randomized, Open-label, Multiple-dose, 2-period Crossover Study.

PubMed

Son, Mijeong; Guk, Jinju; Kim, Yukyung; Woo Chae, Dong; Heo, Young-A; Soh, Dongjun; Park, Kyungsoo

2016-08-01

Rosuvastatin, a hydroxy methylglutaryl coenzyme A reductase inhibitor; telmisartan, an angiotensin receptor blocker; and amlodipine, a calcium channel inhibitor, are commonly prescribed together for the treatment of hypertension nonresponsive to monotherapy and accompanied by dyslipidemia. However, the pharmacokinetic interactions among these 3 substances are not well understood. The aim of this study was to investigate the pharmacokinetic drug-drug interactions among rosuvastatin, telmisartan, and amlodipine in a healthy Korean male population. In both parts of this randomized, open-label, multiple-dose, 2-part, 2-period crossover study, subjects aged 19 to 55 years were enrolled. In part 1, each subject received rosuvastatin 20 mg with and without 2 fixed-dose combination (FDC) tablets of telmisartan/amlodipine 40/5 mg, once daily for 9 consecutive days. In part 2, each subject received 2 FDC tablets of telmisartan/amlodipine 40/5 mg with and without rosuvastatin 20 mg, once daily for 9 consecutive days. In both parts, there was a 13-day washout period between treatments. Pharmacokinetic samples were collected up to 72 hours after the last dose in subjects who received rosuvastatin only, and up to 144 hours after the last dose in subjects who received telmisartan/amlodipine with or without rosuvastatin. Adverse events (AEs) were assessed via interviews and physical examinations. Forty-eight subjects were enrolled, of whom 19 in part 1 and 22 in part 2 completed the study. In Part 1, the 90% CIs of the geometric mean ratios (GMRs) (coadministration of rosuvastatin and telmisartan/amlodipine to monotherapy with rosuvastatin) of the primary pharmacokinetic parameters (AUCτ and Cmax,ss) were: rosuvastatin, 1.1436 to 1.3059 and 1.8970 to 2.3514, respectively; and N-desmethyl rosuvastatin, 0.8441 to 1.0200 and 1.1971 to 1.5457. In part 2, the 90% CIs of the GMRs (coadministration to monotherapy with telmisartan/amlodipine) were: telmisartan, 1.1204 to 1.4228 and 0.9940 to 1.5940; amlodipine, 0.9705 to 1.0636 and 0.9813 to 1.0779. There were no significant differences in the prevalences of AEs between the treatments, and all reported AEs were mild or moderate. These results demonstrate that when rosuvastatin, telmisartan, and amlodipine are coadministered to healthy male subjects, pharmacokinetic exposure increases with respect to rosuvastatin and telmisartan, whereas no change occurs with respect to amlodipine. However, based on previous analyses, the degree of increase in the exposure observed was not regarded as clinically significant. All treatments were well-tolerated. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Rosuvastatin for cardiovascular prevention: too many uncertainties.

PubMed

2009-08-01

A randomised trial showed that rosuvastatin had some efficacy in preventing a first cardiovascular event, but there was an increased risk of diabetes. The article describing this study is too imprecise to recommend the use of rosuvastatin in this setting.

Pravastatin reduces the risk for cardiovascular disease in Japanese hypercholesterolemic patients with impaired fasting glucose or diabetes: diabetes subanalysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study.

PubMed

Tajima, Naoko; Kurata, Hideaki; Nakaya, Noriaki; Mizuno, Kyoichi; Ohashi, Yasuo; Kushiro, Toshio; Teramoto, Tamio; Uchiyama, Shinichiro; Nakamura, Haruo

2008-08-01

Diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD) in patients with no history of CVD. Evidence for the effect of statins on CVD in the diabetic population in low-risk populations (e.g., Japanese) is limited. We evaluated the effect of pravastatin on risk reduction of CVD related to baseline glucose status in a primary prevention setting. The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, in patients with mild-to-moderate hypercholesterolemia (220-270 mg/dL), showed that low-dose pravastatin significantly reduced the risk for CVD by 26%. This exploratory subanalyses examined the efficacy of diet plus pravastatin on CVD in 2210 patients with abnormal fasting glucose (AFG, including 1746 patients with DM and 464 patients with impaired fasting glucose (IFG) at 5 years in the MEGA Study. CVD was threefold higher in AFG patients (threefold higher in DM, and twofold higher in IFG) compared with normal fasting glucose (NFG) patients in the diet group. Diet plus pravastatin treatment significantly reduced the risk of CVD by 32% (hazard ratio 0.68, 95% CI 0.48-0.96, number needed to treat, 42) in the AFG group compared with the diet alone group, and no significant interaction between AFG and NFG (interaction P=0.85) was found. Safety problems were not observed during long-term treatment with pravastatin. In conclusion, pravastatin reduces the risk of CVD in subjects with hypercholesterolemia and abnormal fasting glucose in the primary prevention setting in Japan.

Simvastatin-lnduced nocturnal leg pain disappears with pravastatin substitution.

PubMed

Stojaković, Natasa; Igić, Rajko

2013-01-01

Statins have similar side effects that do not always occur at the same rate among the various statins. We present a case of simvastatin-induced muscle toxicity that disappeared when pravastatin was substituted for the original drug. A 74-year-old male, a nonsmoker, complained of severe nocturnal leg cramps. The patient also complained that similar painful cramping occurred when he walked rapidly or jogged. Because some components of his lipid panel exceeded the'desirable' range, and as he had a history of myocardial infarction, his family physician prescribed simvastatin (40 mg/day). The patient had taken this medication for the past eight years. The painful nocturnal episodes started two years ago and affected either one or the other leg. Four months ago we discontinued his simvastatin and prescribed pravastatin (80 mg/day). At a follow-up visit six weeks later, the patient reported that his leg pains at night and the pain experienced after brisk walking had disappeared. Four months after the substitution of pravastatin for simvastatin, the patient reported that his complete lack of symptoms had continued. These painful muscle cramps were probably caused by an inadequate vascular supply to the calf and foot muscles. Perhaps a combination of advanced age and atherosclerotic changes created a predisposition for the simvastatin-induced leg cramps. Pravastatin differs from simvastatin in several ways.l It is not metabolized by cytochrome P450 (CYP) 3A4 oxidases, and thus is not influenced by CYP 3A4 inhibitors like simvastatin. Also, simvastatin is associated with single-nucleotide polymorphisms located within the SLCO1B1 gene on the chromosome 12 and established myopathy, while pravastatin lacks this association. These differences may contribute to increased tolerance to pravastatin in this particular case.

Reduced levels of TNF alpha in hypercholesterolemic individuals after treatment with pravastatin for 8 weeks.

PubMed

Solheim, S; Seljeflot, I; Arnesen, H; Eritsland, J; Eikvar, L

2001-08-01

cellular adhesion molecules (CAMs) expressed on the endothelial surface play a key role in the inflammatory process of atherosclerosis, and increased expression of CAMs has been shown in hypercholesterolemic individuals. The expression of CAMs is mediated by several cytokines including tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6). The aim of the present study was to assess the influence of pravastatin 40 mg per day on selected soluble CAMs; intercellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), E-selectin, P-selectin and some circulating markers of inflammation; C-reactive protein (CRP) and the cytokines TNF alpha and IL-6. 40 non-diabetic men, age below 70 years, with serum total cholesterol 6--10 mmol/l combined with HDL-cholesterol < or =1.2 mmol/l were included. The study was randomized, double blinded, placebo controlled, cross over designed with 8 weeks intervention periods. Fasting blood samples were drawn after 8 and 16 weeks. significant reduction of total cholesterol was achieved after treatment with pravastatin (7.8 on placebo vs. 5.7 mmol/l on pravastatin). TNF alpha was significantly reduced after treatment with pravastatin (1.33 on placebo vs. 1.10 pg/ml on pravastatin, P=0.032), whereas no differences in the levels of the measured sCAMs, CRP and IL-6 were found. Subgroup analysis among smokers versus non-smokers showed a significant reduction in the level of TNF alpha only among the smokers. hypercholesterolemic individuals treated with pravastatin 40 mg per day for 8 weeks showed a statistically significant reduction in the levels of TNF alpha as compared with placebo.

Anti-atherosclerotic effects of pravastatin in brachiocephalic artery in comparison with en face aorta and aortic roots in ApoE/LDLR-/- mice.

PubMed

Kostogrys, Renata B; Franczyk-Zarow, Magdalena; Gasior-Glogowska, Marlena; Kus, Edyta; Jasztal, Agnieszka; Wrobel, Tomasz P; Baranska, Malgorzata; Czyzynska-Cichon, Izabela; Drahun, Anna; Manterys, Angelika; Chlopicki, Stefan

2017-02-01

Cholesterol-dependent and independent mechanisms were proposed to explain anti-atherosclerotic action of statins in humans. However, their effects in murine models of atherosclerosis have not been consistently demonstrated. Here, we studied the effects of pravastatin on atherosclerosis in ApoE/LDLR -/- mice fed a control and atherogenic diet. ApoE/LDLR -/- mice were fed a control (CHOW) or an atherogenic (Low Carbohydrate High Protein, LCHP) diet. Two doses of pravastatin (40mg/kg and 100mg/kg) were used. The anti-atherosclerotic effects of pravastatin in en face aorta, cross-sections of aortic roots and brachiocephalic artery (BCA) were analysed. The lipid profile was determined. Fourier Transform Infrared Spectroscopy followed by Fuzzy C-Means (FCM) clustering was used for the quantitative assessment of plaque composition. Treatment with pravastatin (100mg/kg) decreased total and LDL cholesterol only in the LCHP group, but displayed a pronounced anti-atherosclerotic effect in BCA and abdominal aorta. The anti-atherosclerotic effect of pravastatin (100mg/kg) in BCA was associated with significant alterations of the chemical plaque composition, including a fall in cholesterol and cholesterol esters contents independently on total cholesterol and LDL concentration in plasma. Pravastatin at high (100mg/kg), but not low dose displayed a pronounced anti-atherosclerotic effect in ApoE/LDLR -/- mice fed a CHOW or LCHP diet that was remarkable in BCA, visible in en face aorta, whereas it was not observed in aortic roots, suggesting that previous inconsistencies might have been due to the various sites of atherosclerotic plaque analysis. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

In search for genetic determinants of clinically meaningful differential cardiovascular event reduction by pravastatin in the PHArmacogenetic study of Statins in the Elderly at risk (PHASE)/PROSPER study.

PubMed

Postmus, Iris; Johnson, Paul C D; Trompet, Stella; de Craen, Anton J M; Slagboom, P Eline; Devlin, James J; Shiffman, Dov; Sacks, Frank M; Kearney, Patricia M; Stott, David J; Buckley, Brendan M; Sattar, Naveed; Ford, Ian; Westendorp, Rudi G J; Jukema, J Wouter

2014-07-01

Statin therapy is widely used in the prevention and treatment of cardiovascular events and is associated with significant risk reductions. However, there is considerable variation in response to statin therapy both in terms of LDL cholesterol reduction and clinical outcomes. It has been hypothesized that genetic variation contributes importantly to this individual drug response. We investigated the interaction between genetic variants and pravastatin or placebo therapy on the incidence of cardiovascular events by performing a genome-wide association study in the participants of the PROspective Study of Pravastatin in the Elderly at Risk for vascular disease--PHArmacogenetic study of Statins in the Elderly at risk (PROSPER/PHASE) study (n = 5244). We did not observe genome-wide significant associations with a clinically meaningful differential cardiovascular event reduction by pravastatin therapy. In addition, SNPs with p-values lower than 1 × 10(-4) were assessed for replication in a case-only analysis within two randomized placebo controlled pravastatin trials, CARE (n = 711) and WOSCOPS (n = 522). rs7102569, on chromosome 11 near the ODZ4 gene, was replicated in the CARE study (p = 0.008), however the direction of effect was opposite. This SNP was not associated in WOSCOPS. In addition, none of the SNPs replicated significantly after correcting for multiple testing. We could not identify genetic variation that was significantly associated at genome-wide level with a clinically meaningful differential event reduction by pravastatin treatment in a large prospective study. We therefore assume that in daily practice the use of genetic characteristics to personalize pravastatin treatment to improve prevention of cardiovascular disease will be limited. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Treatment of altered body composition in HIV-associated lipodystrophy: comparison of rosiglitazone, pravastatin, and recombinant human growth hormone.

PubMed

Macallan, Derek C; Baldwin, Christine; Mandalia, Sundihya; Pandol-Kaljevic, Vjera; Higgins, Nadine; Grundy, Alan; Moyle, Graeme J

2008-01-01

Treatment options for HIV-associated lipodystrophy syndrome (HALS) remain limited. The objective of this randomized open-label study was to compare three emerging therapies, rosiglitazone, pravastatin, and growth hormone alone and together, in men and women with HALS. Sixty-four subjects received daily rosiglitazone (4 mg, n = 14), pravastatin (40 mg, n = 11), or rosiglitazone plus pravastatin (n = 13) for 48 weeks or recombinant human growth hormone (rhGH; Serostim 2 mg, 12 weeks, n = 13) alone or combined with rosiglitazone (n = 13). Primary endpoint was body composition change by dual X-ray absorptiometry (DXA) and computed tomography (CT). Rosiglitazone resulted in slow accrual of limb fat detected by DXA (+444 +/- 186 g; p < .05) but not CT. Pravastatin had no consistent significant effects on body composition, although it reduced total and LDL cholesterol. Negative interactions were observed between pravastatin and rosiglitazone. rhGH reduced abdominal fat by CT (-31 +/- 15 cm2, 26%; p < .05) and DXA (-1597 +/- 383 g, 27%; p < .05) and increased trunk and limb lean mass (+10% and +12%, respectively). However, effects largely disappeared within 12 weeks post treatment. rhGH alone impaired insulin sensitivity but not when combined with rosiglitazone. Prolonged rosiglitazone treatment slowly improves lipoatrophy. rhGH rapidly and selectively reduces visceral fat, although effects are short-lived; co-administered rosiglitazone abrogates rhGH-related insulin resistance.

Combination Therapy of Rosuvastatin and Ezetimibe in Patients with High Cardiovascular Risk.

PubMed

Yang, Young-June; Lee, Sang-Hak; Kim, Byung Soo; Cho, Yun-Kyeong; Cho, Hyun-Jai; Cho, Kyoung Im; Kim, Seok-Yeon; Ryu, Jae Kean; Cho, Jin-Man; Park, Joong-Il; Park, Jong-Seon; Park, Chang Gyu; Chun, Woo Jung; Kim, Myung-A; Jin, Dong-Kyu; Lee, Namho; Kim, Byung Jin; Koh, Kwang Kon; Suh, Jon; Lee, Seung-Hwan; Lee, Byoung-Kwon; Oh, Seung-Jin; Jin, Han-Young; Ahn, Youngkeun; Lee, Sang-Gon; Bae, Jang-Ho; Park, Woo Jung; Lee, Sang-Chol; Lee, Han Cheol; Lee, Jaewon; Park, Cheolwon; Lee, Backhwan; Jang, Yangsoo

2017-01-01

The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk. This was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 337 patients were screened. After a 4-week run-in period, 245 of these patients with high or moderately high risk as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines were randomly assigned. Patients received 1 of 6 regimens for 8 weeks as follows: (1) rosuvastatin 5 mg, (2) rosuvastatin 5 mg/ezetimibe 10 mg, (3) rosuvastatin 10 mg, (4) rosuvastatin 10 mg/ezetimibe 10 mg, (5) rosuvastatin 20 mg, or (6) rosuvastatin 20 mg/ezetimibe 10 mg. The primary outcome variable was percentage change in the level of LDL-C at week 8 of drug treatment. Secondary outcome variables included percentage changes of other lipid variables and achievement rates of LDL-C targets. Tolerability analyses were also performed. The percentage change of LDL-C ranged from -45% to -56% (mean, -51%) in the monotherapy groups and from -58% to -63% (mean, -60%) in the combination therapy groups. The percentage change was greater in the pooled combination therapy group than in the counterpart (P < 0.001 for the pooled groups); this difference was more obvious for regimens with a lower statin dose. The percentage reductions of total cholesterol and triglycerides were greater in the combination groups than in the monotherapy groups. The LDL-C target achievement rates were 64% to 87% (mean, 73%) in the monotherapy groups and 87% to 95% (mean, 91%) in the combination groups (P = 0.01 for the pooled groups). The rates were significantly greater in patients receiving the combination therapy than in the monotherapy at lower doses of rosuvastatin. The proportions of patients with various adverse events were not significantly different between the groups. Rosuvastatin/ezetimibe combination therapy has better efficacy and target achievement rates than rosuvastatin monotherapy in patients with high cardiovascular risk. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-04-01

(+)-Dapoxetine hydrochloride, [(123)I]-BZA, 9-Aminocamptothecin; Abacavir sulfate/lamivudine, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Alvocidib hydrochloride, Ambrisentan, Amsilarotene, Anacetrapib, Anakinra, Apricitabine, Aripiprazole, Arsenic trioxide, Atazanavir sulfate, Atazanavir/ritonavir, Atrasentan, Azacitidine; Banoxantrone, Bazedoxifene acetate, Bevacizumab, Bexarotene, Biphasic insulin aspart, Bortezomib, Bosentan, Bromfenac; Cachectin, Calcipotriol/betamethasone dipropionate, Canakinumab, Carfilzomib, CAT-354, CCX-282, Certolizumab pegol, Cetuximab, Choline fenofibrate, Clevudine, Clofarabine, CNTO-328, Corifollitropin alfa, Crofelemer; Daptomycin, Darbepoetin alfa, Darunavir, Dasatinib, Decitabine, Deferasirox, Denosumab, Duloxetine hydrochloride, Dutasteride; Emtricitabine, Enfuvirtide, Entecavir, Epoetin zeta, Erlotinib hydrochloride, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Farglitazar, Febuxostat, Fosamprenavir calcium, FX-06; Gabapentin enacarbil, Gefitinib; HIVIS DNA; Imatinib mesylate, INCB- 18424, Indacaterol, Inotuzumab ozogamicin, Insulin detemir; JNJ-26854165; Lacosamide, Landiolol, Laromustine, Lenalidomide, Liposomal doxorubicin, L-NAME, Lopinavir, Lopinavir/ritonavir, Lumiracoxib; Maraviroc, Mepolizumab, Methoxy polyethylene glycol- epoetin-beta, Miglustat, MK-0493, MVA-CMDR, Mycophenolic acid sodium salt; Natalizumab, Nepafenac, Neratinib, Neridronic acid, Nesiritide, Nilotinib hydrochloride monohydrate; Olmesartan medoxomil, Omacetaxine mepesuccinate, Omalizumab; Paclitaxel poliglumex, Palifermin, Patupilone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, PHA-848125, Pitavastatin calcium, Posaconazole, Povidone-iodine liposome complex, Prasugrel, Pregabalin, Prucalopride; Raltegravir potassium, Retigabine, Revaprazan hydrochloride, rhFSH, Rilpivirine, Rivaroxaban, Romidepsin, Rosuvastatin calcium, RWJ-676070; SAR-109659, Sitagliptin phosphate monohydrate, Sorafenib, Stavudine/Lamivudine/Nevirapine, Sunitinib malate; Tadalafil, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate/emtricitabine, Tenofovir disoproxil fumarate/emtricitabine/efavirenz, Teriparatide, Tigecycline, Tiotropium bromide, Tipifarnib, Tipranavir, Tocilizumab, Trifluridine/TPI; UP-780; Vandetanib, Vardenafil hydrochloride hydrate, Vatalanib succinate, Vitespen, Vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan; Zoledronic acid monohydrate. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Gateways to clinical trials. July-August 2008.

PubMed

Tomillero, A; Moral, M A

2008-01-01

(-)-Epigallocatechin gallate, 501516, 89-12; Abatacept, Adalimumab, Adefovir dipivoxil, AG-701, Agatolimod sodium, Alefacept, Aliskiren fumarate, Apixaban, Atazanavir sulfate, Atrasentan, Axitinib; BI-1744-CL, BIBF-1120, BIBW-2992, Bortezomib; Carboxyamidotriazole, Caspofungin acetate, CBP-501, Cediranib, Ceftobiprole, Certolizumab pegol, Cetuximab, Cholesteryl hydrophobized polysaccharide-Her2 protein complex, CHP-NY-ESO-1, Cypher; Dalbavancin, Dalcetrapib, Daptomycin, Darapladib, Deferasirox, Deforolimus, Denosumab, DNA-HIV-C, Dovitinib, DR-5001, Dronedarone hydrochloride, DT388IL3; E75, EC-17/EC-90, Ecogramostim, Efungumab, Entecavir, EP HIV-1090, EP-2101, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Faropenem daloxate, Fluticasone furoate, Fondaparinux sodium, Fospropofol disodium, Fulvestrant; Golimumab, GSK-089, GW-590735; HO/03/03, hTERT572, hTERT572Y; Iloperidone; Immunoglobulin intravenous (human), Ispinesib mesylate, Istradefylline, Ixabepilone; JR-031, JX-594; KLH; Laropiprant, Lecozotan hydrochloride, Lenalidomide, Lestaurtinib, Linezolid; MGCD-0103, MK-0646, MVA-BN Measles; NI-0401, Niacin/laropiprant, NSC-719239, NYVAC-C; Ospemifene; Paliperidone palmitate, PAN-811, PCV7, Pegfilgrastim, Peginterferon alfa-2a, PEGirinotecan, Perifosine, Pertuzumab, PF-00299804, Picoplatin, Pimavanserin tartrate, Pitavastatin calcium, Pomalidomide, Prasterone, Pratosartan, Prucalopride, PSMA27/pDOM, Pyridoxal phosphate; QS-21, Quercetin; Rebimastat, Rimonabant, Rolofylline, Romidepsin, Rosuvastatin calcium, RTS,S/SBAS2; SCH-530348, SN-29244, Soblidotin, Sodium dichloroacetate, Solifenacin succinate, Sorafenib, Spheramine, SU-6668, Succinobucol; Taranabant, Taxus, Telaprevir, Telavancin hydrochloride, Telbivudine, Tenofovir disoproxil fumarate, Tigecycline, Tiotropium bromide, Tocilizumab, Triphendiol; UC-781, Udenafil, UNIL-025; V-5 Immunitor, Valsartan/amlodipine besylate, Varenicline tartrate, Velafermin, Vernakalant hydrochloride, Vinflunine, Vitespen, Vorinostat, VX-001; Xience V, XRP-0038; Yttrium Y90 Epratuzumab; Z-360, Ziconotide, Ziprasidone hydrochloride, Zotarolimus, Zotarolimus-eluting stent. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

Comparison of Pharmacokinetics and Safety of a Fixed-dose Combination of Rosuvastatin and Ezetimibe Versus Separate Tablets in Healthy Subjects.

PubMed

Min, Kyoung Lok; Park, Min Soo; Jung, Jina; Chang, Min Jung; Kim, Choon Ok

2017-09-01

Rosuvastatin and ezetimibe are concomitantly used for dyslipidemia treatment. Compared with separate tablets, fixed-dose combination (FDC) tablets of rosuvastatin/ezetimibe could increase patient compliance. The aim of this study was to compare the pharmacokinetic (PK) profiles of an FDC tablet of rosuvastatin/ezetimibe and co-administration of rosuvastatin and ezetimibe as separate tablets in healthy Korean volunteers. This trial was a randomized, open-label, single-dose, 2-way crossover study. The healthy subjects received an FDC tablet of rosuvastatin 20 mg/ezetimibe 10 mg (test) or co-administration of rosuvastatin 20 mg and ezetimibe 10 mg (reference) in each period (periods 1 and 2), with a 14-day washout period. The blood samples for PK analysis were collected predose and up to 96 hours after administration, and safety was assessed throughout the study. Sixty-four healthy Korean subjects were enrolled, and 57 subjects completed the study. All subjects were men and mean age was 28.52 ± 5.93. The geometric least squares mean ratios (test/reference) and 90% CIs of C max and AUC 0-last were 101.54% (94.03-109.65) and 97.71% (91.86-103.93) for rosuvastatin, 108.93% (98.55-120.40) and 102.90% (96.72-109.47) for free ezetimibe, and 106.74% (98.18-116.05) and 104.24 % (99.53-109.17) for total ezetimibe. Twenty-four adverse events (AEs) were reported in 22 subjects. Three cases were related to the study drugs; 2 cases were mild, and 1 case was severe. However, all AEs were resolved without any sequelae. In addition, there were no serious AEs throughout the study. The FDC tablet of rosuvastatin/ezetimibe was well tolerated and resulted in comparable systemic exposure with co-administration of rosuvastatin and ezetimibe. ClinicalTrials.gov identifier: NCT02941848. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Pravastatin

MedlinePlus

... fatty substances such as low-density lipoprotein (LDL) cholesterol ('bad cholesterol') and triglycerides in the blood and to increase the amount of high-density lipoprotein (HDL) cholesterol ('good cholesterol') in the blood. Pravastatin is in ...

Investigating Transporter‐Mediated Drug‐Drug Interactions Using a Physiologically Based Pharmacokinetic Model of Rosuvastatin

PubMed Central

Wang, Q; Leil, T

2017-01-01

Rosuvastatin is a frequently used probe in transporter‐mediated drug‐drug interaction (DDI) studies. This report describes the development of a physiologically based pharmacokinetic (PBPK) model of rosuvastatin for prediction of pharmacokinetic (PK) DDIs. The rosuvastatin model predicted the observed single (i.v. and oral) and multiple dose PK profiles, as well as the impact of coadministration with transporter inhibitors. The predicted effects of rifampin and cyclosporine (6.58‐fold and 5.07‐fold increase in rosuvastatin area under the curve (AUC), respectively) were mediated primarily via inhibition of hepatic organic anion‐transporting polypeptide (OATP)1B1 (Inhibition constant (Ki) ∼1.1 and 0.014 µM, respectively) and OATP1B3 (Ki ∼0.3 and 0.007 µM, respectively), with cyclosporine also inhibiting intestinal breast cancer resistance protein (BCRP; Ki ∼0.07 µM). The predicted effects of gemfibrozil and its metabolite were moderate (1.88‐fold increase in rosuvastatin AUC) and mediated primarily via inhibition of hepatic OATP1B1 and renal organic cation transporter 3. This model of rosuvastatin will be useful in prospectively predicting transporter‐mediated DDIs with novel pharmaceutical agents in development. PMID:28296193

Differential Effects of Tipranavir plus Ritonavir on Atorvastatin or Rosuvastatin Pharmacokinetics in Healthy Volunteers▿

PubMed Central

Pham, P. A.; la Porte, C. J. L.; Lee, L. S.; van Heeswijk, R.; Sabo, J. P.; Elgadi, M. M.; Piliero, P. J.; Barditch-Crovo, P.; Fuchs, E.; Flexner, C.; Cameron, D. W.

2009-01-01

To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (Cmax) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the Cmax of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r. PMID:19667285

Non-lipid effects of rosuvastatin-fenofibrate combination therapy in high-risk Asian patients with mixed hyperlipidemia.

PubMed

Lee, Sang-Hak; Cho, Kyoung-Im; Kim, Jang-Young; Ahn, Young Keun; Rha, Seung-Woon; Kim, Yong-Jin; Choi, Yun-Seok; Choi, Si Wan; Jeon, Dong Woon; Min, Pil-Ki; Choi, Dong-Ju; Baek, Sang Hong; Kim, Kwon Sam; Byun, Young Sup; Jang, Yangsoo

2012-03-01

The aim of this study is to compare the non-lipid effects of rosuvastatin-fenofibrate combination therapy with rosuvastatin monotherapy in high-risk Asian patients with mixed hyperlipidemia. A total of 236 patients were initially screened. After six weeks of diet and life style changes, 180 of these patients were randomly assigned to receive one of two regimens: rosuvastatin 10 mg plus fenofibrate 160 mg or rosuvastatin 10 mg. The primary outcome variables were the incidences of muscle or liver enzyme elevation. The patients were followed for 24 weeks during drug treatment and for an additional four weeks after drug discontinuation. The rates of the primary outcome variables were similar between the two groups (2.8% and 3.9% in the combination and the rosuvastatin groups, respectively, p=1.00). The combination group had more, but not significantly, common treatment-related adverse events (AEs) (13.3% and 5.6%, respectively) and drug discontinuation due to AEs (10.0% and 3.3%, respectively) than the rosouvastatin group. Combination therapy was associated with higher elevations in homocysteine, blood urea nitrogen, and serum creatinine, whereas elevation in alanine aminotransferase was greater in the rosuvastatin group. Leukocyte count and hemoglobin level decreased to a greater extent in the combination group. The combination group showed greater reductions in TG and elevation in HDL-cholesterol. In our study population, the rosuvastatin-fenofibrate combination resulted in comparable incidences of myo- or hepatotoxicity as rosuvastatin monotherapy. However, this combination may need to be used with caution in individuals with underlying pathologies such as renal dysfunction (NCT01414803). Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chromatin remodeling by rosuvastatin normalizes TSC2-/meth cell phenotype through the expression of tuberin.

PubMed

Lesma, Elena; Ancona, Silvia; Orpianesi, Emanuela; Grande, Vera; Di Giulio, Anna Maria; Gorio, Alfredo

2013-05-01

Tuberous sclerosis complex (TSC) is a multi-systemic syndrome caused by mutations in TSC1 or TSC2 gene. In TSC2-null cells, Rheb, a member of the Ras family of GTPases, is constitutively activated. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase and block the synthesis of isoprenoid lipids with inhibition of Rheb farnesylation and RhoA geranylgeranylation. The effects of rosuvastatin on the function of human TSC2(-/-) and TSC2(-/meth) α-actin smooth muscle (ASM) cells have been investigated. The TSC2(-/-) and TSC2(-/meth) ASM cells, previously isolated in our laboratory from the renal angiomyolipoma of two TSC patients, do not express tuberin and bear loss of heterozigosity caused by a double hit on TSC2 and methylation of TSC2 promoter, respectively. Exposure to rosuvastatin affected TSC2(-/meth) ASM cell growth and promoted tuberin expression by acting as a demethylating agent. This occurred without changes in interleukin release. Rosuvastatin also reduced RhoA activation in TSC2(-/meth) ASM cells, and it required coadministration with the specific mTOR (mammalian target of rapamycin) inhibitor rapamycin to be effective in TSC2(-/-) ASM cells. Rapamycin enhanced rosuvastatin effect in inhibiting cell proliferation in TSC2(-/-) and TSC2(-/meth) ASM cells. Rosuvastatin alone did not alter phosphorylation of S6 and extracellular signal-regulated kinase (ERK), and at the higher concentration, rosuvastatin and rapamycin slightly decreased ERK phosphorylation. These results suggest that rosuvastatin may potentially represent a treatment adjunct to the therapy with mTOR inhibitors now in clinical development for TSC. In particular, rosuvastatin appears useful when the disease is originated by epigenetic defects.

Enterohepatic disposition of rosuvastatin in pigs and the impact of concomitant dosing with cyclosporine and gemfibrozil.

PubMed

Bergman, Ebba; Lundahl, Anna; Fridblom, Patrik; Hedeland, Mikael; Bondesson, Ulf; Knutson, Lars; Lennernäs, Hans

2009-12-01

The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n = 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a 2-h intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In treatment IV (TIV, n = 4) 5.9 mg of rosuvastatin was administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH), and femoral veins and bile from the common hepatic duct. The biliary recoveries of the administered rosuvastatin dose were 9.0 +/- 3.5 and 35.7 +/- 15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as shown by the median AUC(bile)/AUC(VH) ratio in TI of 1770 (1640-11,300). Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC(50) values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 +/- 0.06; TII, 0.46 +/- 0.13) and increased the AUC(VP) and AUC(VH) by 1.6- and 9.1-fold, respectively. In addition, the biliary exposure and f(e, bile) were reduced by approximately 50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the organic anion-transporting polypeptide family, rather than canalicular transporters.

Efficacy of short-term moderate or high-dose rosuvastatin in preventing contrast-induced nephropathy

PubMed Central

Liang, Min; Yang, Shicheng; Fu, Naikuan

2017-01-01

Abstract Background: The prophylactic efficacy of statin pretreatment for the prevention of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) remains controversial. The aim of the study was to perform a meta-analysis of randomized controlled trials (RCTs) to assess the effectiveness of short-term moderate or high-dose rosuvastatin pretreatment in preventing CIN. Methods: We included RCTs comparing short-term moderate or high-dose rosuvastatin treatment versus low-dose rosuvastatin treatment or placebo for preventing CIN. The primary endpoint was the incidence of CIN within 2 to 5 days after contrast administration, and related-parameters including serum creatinine (SCr), cystatin C (CysC), hypersensitive C-reactive protein (hs-CRP), urine microalbumin (mALB) were also extracted. Results: Fifteen RCTs with a total of 2673 patients were identified and analyzed. Patients who received moderate or high-dose rosuvastatin pretreatment had a 55% lower risk of CIN compared with low-dose rosuvastatin pretreatment or placebo group based on a fixed effect model (RR = 0.45, 95% CI 0.35–0.58, P < .0001). The benefit of moderate or high-dose rosuvastatin was consistent in both comparisons with low-dose rosuvastatin (RR = 0.40, 95% CI 0.27–0.59, P < .0001) or placebo (RR = 0.45, 95% CI 0.35–0.58, P < .0001). And moderate (20 mg) or high dose (≥40 mg) rosuvastatin significantly reduced the incidence of CIN compared with the control (RR = 0.39, 95% CI 0.29–0.54, P < .0001, RR = 0.56, 95% CI 0.37–0.85, P = .006, respectively). Subgroup analysis showed that moderate or high-dose rosuvastatin pretreatment could decrease the incidence of CIN in patients with chronic kidney disease (CKD) (RR = 0.53, 95% CI 0.30–0.93, P = .03) or diabetes mellitus (DM) (RR = 0.51, 95% CI 0.31–0.86, P = .01) or acute coronary syndrome (ACS) patients undergoing PCI (RR = 0.52, 95% CI 0.35–0.76, P = .0009) or in studies which received mean contrast volume ≥110 mL (RR = 0.43, 95% CI 0.32–0.58, P < .0001). The SCr, CysC, hs-CRP, and mALB after the operation in the moderate or high-dose rosuvastatin group were lower than those of low-dose rosuvastatin group. Conclusion: This meta-analysis demonstrated that moderate or high-dose rosuvastatin treatment could reduce the incidence of CIN in patients undergoing CAG or PCI. Moreover, moderate or high-dose rosuvastatin would be beneficial in high-risk patients with CKD or DM or undergoing PCI. PMID:28682890

Medication for Military Aircrew: Current Use, Issues, and Strategies for Expanded Options (les medicaments pour les equipaes militaires: Consommation actuelle, questions et strategies pour des options elargies)

DTIC Science & Technology

2001-06-01

HMG-CoA reductase inhibitors, commonly referred to as “statins” (lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin ) d. Others (nicotinic...cholesterol by 2 - 15%. Many statins (pravastatin, atorvastatin , fluvastatin, lovastatin, and simvastatin) have been developed for clinical use and are now...trail making test, or visual memory test.16 There are unpublished data about atorvastatin and pravastatin, in which both showed an increase in

Rosuvastatin reduced deep vein thrombosis in ApoE gene deleted mice with hyperlipidemia through non-lipid lowering effects

PubMed Central

Patterson, K.A.; Zhang, X.; Wrobleski, S.K.; Hawley, A.E.; Lawrence, D. A.; Wakefield, T.W.; Myers, D.D.; Diaz, J.A.

2013-01-01

Introduction Statins, particularly rosuvastatin, have recently become relevant in the setting of venous thrombosis. The objective of this study was to study the non-lipid lowering effects of rosuvastatin in venous thrombosis in mice with hyperlipidemia. Materials and Methods An inferior vena cava ligation model of venous thrombosis in mice was utilized. Saline or 5mg/kg of rosuvastatin was administered by gavage 48hs previous thrombosis. Blood, the inferior vena cava, thrombus, and liver were harvested 3, 6 hours, and 2 days post-thrombosis. Thrombus weight, inflammatory markers, and plasminogen activator inhibitor-1 expression and plasma levels were measured and neutrophil migration to the IVC was assessed. Results Rosuvastatin significantly decreased thrombus weight, plasminogen activator inhibitor-1 expression and plasma levels, expression of molecules related to the interleukin-6 pathway, and neutrophil migration into the vein wall. Conclusions This work supports the beneficial effects of rosuvastatin on venous thrombosis in mice with hyperlipidemia due to its non-lipid lowering effects. PMID:23276528

Quantification of pravastatin acid, lactone and isomers in human plasma by UHPLC-MS/MS and its application to a pediatric pharmacokinetic study.

PubMed

van Haandel, Leon; Gibson, Kim T; Leeder, J Steven; Wagner, Jonathan B

2016-02-15

An ultra high pressure liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for the simultaneous quantitation of pravastatin and major metabolites, 3'α-hydroxy-pravastatin, pravalactone and 3'α-hydroxy-pravalactone, in human plasma has been developed and validated. Aliquots of (100μL) plasma in EDTA were diluted in pH 4.5 (0.1M buffer) to stabilize the analytes and subjected to hydrophilic lipophilic balance (HLB) solid phase extraction on 96 well μelution plates. Extracted samples were evaporated to dryness and reconstituted in pH 4.5 buffer. Chromatographic separation was performed on a Cortecs™ C18 column (2.1×100mm, 1.8μm), using gradient elution with a blend of acetonitrile and 10mM methylammonium acetate buffer (pH 4.5) at a flow rate of 0.4mL/min. Mass spectrometric detection was performed using multiple reaction monitoring (MRM) switching between positive/negative electrospay ionization (ESI). Pravastatin, 3'α-hydroxy-pravastatin, and internal standards [(2)H3]-pravastatin, and [(2)H3]-3'α-hydroxy-pravastatin were monitored in negative ESI mode at ion transitions m/z 423.2→321.1 and 426.2→321.1, respectively. Positive ESI mode was used for the detection of pravalactone, 3'α-hydroxy-pravalactone, and internal standards [(2)H3]-pravalactone, and [(2)H3]-3'α-hydroxy-pravalactone at ion transitions m/z 438.2→183.1 and 441.2→269.1 respectively. The method was linear for all analytes in the concentration range 0.5-200nM with intra- and inter-day precisions (as relative standard deviation) of ≤5.2% and accuracy (as relative error) of ≤8.0% at all quality control levels. The method was successfully applied to the investigation of pharmacokinetic properties of pravastatin and its metabolites in children after an oral dose of 20-40mg. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of pravastatin on cardiovascular events and mortality in 1516 women with coronary heart disease: results from the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study.

PubMed

Hague, Wendy; Forder, Peta; Simes, John; Hunt, David; Tonkin, Andrew

2003-04-01

The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study showed that cholesterol-lowering therapy prevented further events in patients with coronary heart disease and average cholesterol levels. The aim of this subgroup analysis was to assess the effects of pravastatin in women. A total of 1516 women (756 assigned to take pravastatin) in a cohort of 9014 patients with previous myocardial infarction or unstable angina and a baseline plasma cholesterol level of 4.0 to 7.0 mmol/L (155-271 mg/dL) were assigned to receive pravastatin (40 mg/d) or placebo. Major cardiovascular disease events in 6 years were measured. Women were at a lesser risk than men for death from any cause (10.3% vs 14.8%, P <.01), death from coronary heart disease (6.6% vs 8.6%, P =.04), and coronary revascularization (13.6% vs 16.2%, P =.05) and at a similar risk of myocardial infarction (9.2% vs 10.5%, P =.26), stroke (3.6% vs 4.7%, P =.11), and hospitalization for unstable angina (25.1% vs 24.5%, P = 0.90). Pravastatin significantly reduced the risk of all prespecified cardiovascular events in all LIPID patients. Relative treatment effects in women did not differ significantly from those in men (P >.05) for any events except hospitalization for unstable angina. There were too few events to demonstrate separately significant effects in women; the estimated relative risk reduction with pravastatin was 11% (95% CI -18%-33%) for coronary heart disease death or nonfatal myocardial infarction, 18% (95% CI -25%-46%) for coronary heart disease death, 16% (95% CI -19%-41%) for myocardial infarction, and 17% (95% CI -2%-33%) for coronary heart disease death, myocardial infarction, or coronary revascularization. The study had the largest secondary-prevention female cohort studied thus far, but was not adequately powered to show separate effects in women. Nevertheless, the results were consistent with the main results of this and other trials in showing reduced risks with cholesterol-lowering treatment.

Rosuvastatin postconditioning protects isolated hearts against ischemia-reperfusion injury: The role of radical oxygen species, PI3K-Akt-GSK-3β pathway, and mitochondrial permeability transition pore.

PubMed

Liu, Chun-Wei; Yang, Fan; Cheng, Shi-Zhao; Liu, Yue; Wan, Liang-Hui; Cong, Hong-Liang

2017-02-01

Glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore (mPTP) play an important role in myocardial ischemia-reperfusion injury. The aim of this study was to investigate whether postconditioning with rosuvastatin is able to reduce myocardial ischemia-reperfusion injury and clarify the potential mechanisms. Isolated rat hearts underwent 30 minutes of ischemia and 60 minutes of reperfusion in the presence or absence of rosuvastatin (1-50 nmol/L). The activity of signaling pathway was determined by Western blot analysis, and Ca 2+ -induced mPTP opening was assessed by the use of a potentiometric method. Rosuvastatin significantly reduced myocardial infarct size and improved cardiac function at 5 and 10 nmol/L. Protection disappeared at higher concentration and reverted to increased damage at 50 nmol/L. At 5 nmol/L, rosuvastatin increased the phosphorylation of protein kinase B (Akt) and GSK-3β, concomitant with a higher Ca 2+ load required to open the mPTP. Rosuvastatin postconditioning also significantly increased superoxide dismutase activity and reduced malondialdehyde and radical oxygen species level. LY294002, phosphatidylinositol-3-kinase (PI3K) inhibitors, abolished these protective effects of rosuvastatin postconditioning. Rosuvastatin prevents myocardial ischemia-reperfusion injury by inducing phosphorylation of PI3K-Akt and GSK-3β, preventing oxidative stress and subsequent inhibition of mPTP opening. © 2016 John Wiley & Sons Ltd.

Dose-Dependent Effects of Statins for Patients with Aneurysmal Subarachnoid Hemorrhage: Meta-Regression Analysis.

PubMed

To, Minh-Son; Prakash, Shivesh; Poonnoose, Santosh I; Bihari, Shailesh

2018-05-01

The study uses meta-regression analysis to quantify the dose-dependent effects of statin pharmacotherapy on vasospasm, delayed ischemic neurologic deficits (DIND), and mortality in aneurysmal subarachnoid hemorrhage. Prospective, retrospective observational studies, and randomized controlled trials (RCTs) were retrieved by a systematic database search. Summary estimates were expressed as absolute risk (AR) for a given statin dose or control (placebo). Meta-regression using inverse variance weighting and robust variance estimation was performed to assess the effect of statin dose on transformed AR in a random effects model. Dose-dependence of predicted AR with 95% confidence interval (CI) was recovered by using Miller's Freeman-Tukey inverse. The database search and study selection criteria yielded 18 studies (2594 patients) for analysis. These included 12 RCTs, 4 retrospective observational studies, and 2 prospective observational studies. Twelve studies investigated simvastatin, whereas the remaining studies investigated atorvastatin, pravastatin, or pitavastatin, with simvastatin-equivalent doses ranging from 20 to 80 mg. Meta-regression revealed dose-dependent reductions in Freeman-Tukey-transformed AR of vasospasm (slope coefficient -0.00404, 95% CI -0.00720 to -0.00087; P = 0.0321), DIND (slope coefficient -0.00316, 95% CI -0.00586 to -0.00047; P = 0.0392), and mortality (slope coefficient -0.00345, 95% CI -0.00623 to -0.00067; P = 0.0352). The present meta-regression provides weak evidence for dose-dependent reductions in vasospasm, DIND and mortality associated with acute statin use after aneurysmal subarachnoid hemorrhage. However, the analysis was limited by substantial heterogeneity among individual studies. Greater dosing strategies are a potential consideration for future RCTs. Copyright © 2018 Elsevier Inc. All rights reserved.

A randomized placebo-controlled pilot study of pravastatin as an adjunctive therapy in schizophrenia patients: effect on inflammation, psychopathology, cognition and lipid metabolism

PubMed Central

Vincenzi, Brenda; Stock, Shannon; Borba, Christina P.C.; Cleary, Sarah M.; Oppenheim, Claire E.; Petruzzi, Liana J.; Fan, Xiaoduo; Copeland, Paul M.; Freudenreich, Oliver; Cather, Corinne; Henderson, David C.

2015-01-01

Objective The aim of this study was to investigate the role of pravastatin, as an adjunctive therapy, on inflammatory markers, lipid and glucose metabolism, psychopathology, and cognition in subjects with schizophrenia and schizoaffective disorder. Methods Schizophrenia or schizoaffective subjects (N=60) were randomized to receive either a 12-week supply of pravastatin 40 mg/day or placebo treatment. Anthropometric measures, lipids and glucose metabolism, inflammatory markers, psychopathology and cognitive performance were assessed at baseline, 6 weeks and 12 weeks. Results Pravastatin use was associated with a significant decrease in total cholesterol, low density lipoprotein (LDL) cholesterol and LDL particle number levels, but was not associated with any significant changes in cognition or psychopathology in the participants, except a significant decrease in the Positive and Negative Syndrome Scale (PANSS) positive symptoms score from baseline to week 6. However, this decrease failed to remain significant at 12 weeks. Interestingly, triglycerides, LDLCholesterol, Total cholesterol, LDL particle number, small LDL particle number, large very low density lipoprotein (VLDL) particle number and c-reactive protein (CRP) followed a similar pattern at 6 and 12 weeks as psychopathology. Conclusions These results suggest that a randomized trial with a larger sample size and a higher dosage of pravastatin, and would be helpful in further evaluating the anti-inflammatory properties of pravastatin, its association with improvements in cognitive symptoms, and its potential to reduce positive and negative symptoms associated with schizophrenia or schizoaffective disorders. PMID:25261882

Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels

USDA-ARS?s Scientific Manuscript database

Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipo...

Potentiating NK cell activity by combination of Rosuvastatin and Difluoromethylornithine for effective chemopreventive efficacy against Colon Cancer

PubMed Central

Janakiram, Naveena B.; Mohammed, Altaf; Bryant, Taylor; Zhang, Yuting; Brewer, Misty; Duff, Ashley; Biddick, Laura; Singh, Anil; Lightfoot, Stan; Steele, Vernon E; Rao, Chinthalapally V.

2016-01-01

Colorectal cancer (CRC) is the second highest cause of cancer-related deaths. A successful strategy to improve chemopreventive efficacies is by down-regulating tumor polyamines and enhancing NK cell activities. Colonic carcinogenesis was induced by azoxymethane (AOM) in male F344 rats. Eight weeks after AOM treatment, animals were fed diets containing Rosuvastatin and difluromethylornithine (DFMO) individually and in combination for 40 weeks. Both agents showed significant suppression of adenocarcinoma multiplicity and incidence with no toxicity compared to untreated rats. Low-dose Rosuvastatin plus DFMO suppressed colon adenocarcinoma multiplicity by 76% compared to low-dose Rosuvastatin (29%) and DFMO (46%), suggesting additive efficacy. Furthermore, low-dose combination caused a delay in colonic adenocarcinoma progression. DFMO, Rosuvastatin and/or combinations significantly decreased polyamine content and increased intra-tumoral NK cells expressing perforin plus IFN-γ compared to untreated colon tumors. Further ex-vivo analysis of splenic NK cells exposed to DFMO, Rosuvastatin or combination resulted in an increase of NKs with perforin expression. This is the first report on Rosuvastatin alone or combination strategy using clinically relevant statin plus DFMO doses which shows a significant suppression of colon adenocarcinomas, and their potential in increasing functional NK cells. This strategy has potential for further testing in high risk individuals for colon cancer. PMID:27841323

The relationship between the effect of pravastatin and risk factors for coronary heart disease in Japanese patients with hypercholesterolemia.

PubMed

Ishikawa, Toshitsugu; Mizuno, Kyoichi; Nakaya, Noriaki; Ohashi, Yasuo; Tajima, Naoko; Kushiro, Toshio; Teramoto, Tamio; Uchiyama, Shinichiro; Nakamura, Haruo

2008-10-01

Several epidemiologic studies in Japan have shown the risk factors for coronary heart disease (CHD) in the general population. The present analysis determined the risk factors for CHD in the MEGA Study, a large primary prevention trial with pravastatin in Japanese with hypercholesterolemia. The relationship between each baseline characteristic and the risk of CHD for the 5-year study period were evaluated using the Cox proportional hazard model. The multivariable predictors of CHD were sex, age, high-density lipoprotein-cholesterol (HDL-C), diabetes mellitus (DM), hypertension (HT), and history of smoking. Serum total and low-density lipoprotein-cholesterol were not independent risk factors for CHD in the current analysis. In addition, the effect of pravastatin was evaluated by subgroups in each risk factor using the interaction in a Cox model. Diet plus pravastatin treatment reduced CHD risk by 14-43% compared with diet alone, regardless of the presence or absence of risk factors. The risk factors for CHD were sex, age, DM, HT, smoking, and low HDL-C in the MEGA Study. The pravastatin treatment was effective for reducing the risk of CHD, regardless of the presence of risk factors.

Suppressive effect of pitavastatin on aortic arch dilatation in acute stanford type B aortic dissection: analysis of STANP trial.

PubMed

Masaki, Naoki; Kumagai, Kiichiro; Sasaki, Konosuke; Matsuo, Satoshi; Motoyoshi, Naotaka; Adachi, Osamu; Akiyama, Masatoshi; Kawamoto, Shunsuke; Tabayashi, Koichi; Saiki, Yoshikatsu

2018-04-06

Medical therapy for patients with uncomplicated acute type B aortic dissection (ABAD) is essentially accepted for its excellent early outcome; however, long-term outcomes have not been satisfactory due to aorta-related complications. This trial was performed to investigate the efficacy of a statin as an additive that may enhance the effectiveness of conventional medical treatment in patients with ABAD. This was a multi-center, prospective, and randomized comparative investigation of patients with uncomplicated ABAD. Fifty patients with ABAD compatible with inclusion criteria were randomly assigned to two groups and then received administration of pitavastatin (group P) or not (group C). We followed up the patients for 1 year from study onset. Two patients demised during the follow-up period (both were in group C). In addition, aorta-related interventions were performed in two patients (entry closure for aortic dissection by endovascular repair in one patient in each group). Aortic arch diameters at 1 year in group P tended to be smaller than in group C (P = 0.17), and the rate of change of the aortic arch diameters from onset to 1 year was significantly lower in group P (P = 0.046). Multivariate analysis identified patency of the false lumen was detected as a risk factor for aortic arch dilatation (P = 0.02), and pitavastatin intake was a negative risk factor (P = 0.03). Pitavastatin treatment, in addition to the standard antihypertensive therapy, may have a suppressive effect on aortic arch dilatation in patients with ABAD.

Homocysteine levels and treatment effect in the PROspective Study of Pravastatin in the Elderly at Risk.

PubMed

Drewes, Yvonne M; Poortvliet, Rosalinde K E; Blom, Jeanet W; de Ruijter, Wouter; Westendorp, Rudi G J; Stott, David J; Blom, Henk J; Ford, Ian; Sattar, Naveed; Wouter Jukema, J; Assendelft, Willem J J; de Craen, Anton J M; Gussekloo, Jacobijn

2014-02-01

To assess the effect of preventive pravastatin treatment on coronary heart disease (CHD) morbidity and mortality in older persons at risk for cardiovascular disease (CVD), stratified according to plasma levels of homocysteine. A post hoc subanalysis in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), started in 1997, which is a double-blind, randomized, placebo-controlled trial with a mean follow-up of 3.2 years. Primary care setting in two of the three PROSPER study sites (Netherlands and Scotland). Individuals (n = 3,522, aged 70-82, 1,765 male) with a history of or risk factors for CVD were ranked in three groups depending on baseline homocysteine level, sex, and study site. Pravastatin (40 mg) versus placebo. Fatal and nonfatal CHD and mortality. In the placebo group, participants with a high homocysteine level (n = 588) had a 1.8 higher risk (95% confidence interval (CI) = 1.2-2.5, P = .001) of fatal and nonfatal CHD than those with a low homocysteine level (n = 597). The absolute risk reduction in fatal and nonfatal CHD with pravastatin treatment was 1.6% (95% CI = -1.6 to 4.7%) in the low homocysteine group and 6.7% (95% CI = 2.7-10.7%) in the high homocysteine group (difference 5.2%, 95% CI = 0.11-10.3, P = .046). Therefore, the number needed to treat (NNT) with pravastatin for 3.2 years for benefit related to fatal and nonfatal CHD events was 14.8 (95% CI = 9.3-36.6) for high homocysteine and 64.5 (95% CI = 21.4-∞) for low homocysteine. In older persons at risk of CVD, those with high homocysteine are at highest risk for fatal and nonfatal CHD. With pravastatin treatment, this group has the highest absolute risk reduction and the lowest NNT to prevent fatal and nonfatal CHD. © 2014, Copyright the Authors. Journal compilation © 2014, The American Geriatrics Society.

Effects of intensive atorvastatin and rosuvastatin treatment on apolipoprotein B-48 and remnant lipoprotein cholesterol levels

USDA-ARS?s Scientific Manuscript database

Atorvastatin and rosuvastatin at maximal doses are both highly effective in lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Rosuvastatin has been shown to be more effective than atorvastatin in lowering LDL-C, small dense LDL-C and in raising high-density lipoprote...

Effects of rosuvastatin on platelet inhibition by clopidogrel in cardiovascular patients.

PubMed

Riondino, Silvia; Petrini, Natalia; Donato, Luciamaria; Torromeo, Concetta; Tanzilli, Gaetano; Pulcinelli, Fabio M; Barillà, Francesco

2009-08-01

Statin interference has been suggested among the mechanisms of reduction of the antiplatelet effect of clopidogrel. We thus sought to assess the influence of rosuvastatin on clopidogrel antiplatelet action in high-risk (HR) cardiovascular patients. To set the level of platelet inhibition by combined antithrombotic treatments we retrospectively studied two populations of HR patients, one under aspirin alone, the other under aspirin plus rosuvastatin, before and after addition of clopidogrel. The effects of rosuvastatin compared with atorvastatin were then prospectively investigated in patients who underwent percutaneous coronary intervention (PCI), under clopidogrel and aspirin treatment. Light transmission platelet aggregation (LTA) was studied in response to adenosine diphosphate (ADP) (5 microM) or arachidonic acid (0.5 mM). The inhibitory effect of clopidogrel in reducing ADP-induced LTA was similar in the two HR groups of patients. No difference in ADP-induced platelet aggregation was observed in the two PCI groups of patients with either atorvastatin or rosuvastatin. In conclusion, rosuvastatin does not interfere with the antiplatelet effect of clopidogrel in patients with cardiovascular disease.

Comparison of the efficacy of rosuvastatin versus atorvastatin in reducing apolipoprotein B/apolipoprotein A-1 ratio in patients with acute coronary syndrome: results of the CENTAURUS study.

PubMed

Lablanche, Jean-Marc; Leone, Attilio; Merkely, Bela; Morais, João; Alonso, Joaquim; Santini, Massimo; Eha, Jaan; Demil, Nacima; Licour, Muriel; Tardif, Jean-Claude

2010-03-01

The mechanism underlying statin-induced event reduction in patients with acute coronary syndrome remains unclear. To assess the efficacy of rosuvastatin 20mg versus atorvastatin 80 mg in reducing the apolipoprotein B/apolipoprotein A-1 (apoB/apoA-1) ratio at 3 months. Non-inferiority of rosuvastatin 20mg versus atorvastatin 80 mg in reducing low-density lipoprotein cholesterol at 1 and 3 months was also assessed. Patients with non-ST-elevation acute coronary syndrome were enrolled into this randomized, double blind, parallel-group trial. In total, 753 patients (369, rosuvastatin 20mg; 384, atorvastatin 80 mg) were included in the intention-to-treat analysis; 478 patients (226, rosuvastatin 20mg; 252, atorvastatin 80 mg) were included in the per-protocol analysis. Rosuvastatin 20mg was more effective than atorvastatin 80 mg in decreasing apoB/apoA-1 ratio at 1 month (-44.4% vs -42.9%, p=0.02) but not at 3 months (both -44.4%, p=0.87). Low-density lipoprotein cholesterol decreased by approximately 50% after 1 and 3 months in both groups. Non-inferiority of rosuvastatin 20mg versus atorvastatin 80 mg was demonstrated at 1 month (difference, -0.3% [95% confidence interval, -2.7; +2.1]), but not at 3 months (+1.0% [-1.6; 3.5]) (intention-to-treat analysis). In the per-protocol analysis, non-inferiority of rosuvastatin 20mg was demonstrated at both 1 (-0.7% [-3.5; 2.0]) and 3 (-0.5% [-3.5; 2.5]) months. In patients with non-ST-elevation acute coronary syndrome, rosuvastatin 20mg decreased apoB/apoA-1 ratio at 1 month more than atorvastatin 80 mg. No difference could be shown at 3 months; thus, the primary endpoint was not met.

Cost-effectiveness of rosuvastatin 20 mg for the prevention of cardiovascular morbidity and mortality: a Swedish economic evaluation of the JUPITER trial.

PubMed

Ohsfeldt, Robert L; Olsson, Anders G; Jensen, Marie M; Gandhi, Sanjay K; Paulsson, Thomas

2012-01-01

This study estimated the long-term health outcomes, healthcare costs, and cost-effectiveness of rosuvastatin 20 mg therapy in primary prevention of major cardiovascular disease (CVD) in a Swedish population. Based on data from the JUPITER trial, long-term CVD outcomes with rosuvastatin vs no active treatment were estimated for patients with an elevated baseline CVD risk (Framingham CVD score >20%, sub-population of JUPITER population) and for a population similar to the total JUPITER population. Using a decision-analytic model, trial CVD event rates were combined with epidemiological and cost data specific for Sweden. First and subsequent CVD events and death were estimated over a lifetime perspective. The observed relative risk reduction was extrapolated beyond the trial duration. Incremental effectiveness was measured as life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Treating 100,000 patients with rosuvastatin 20 mg was estimated to avoid 14,692 CVD events over the lifetime (8021 non-fatal MIs, 3228 non-fatal strokes, and 4924 CVD deaths) compared to placebo. This translated into an estimated gain of 42,122 QALYs and 36,865 total life years (LYG). Rosuvastatin was both more effective and less costly over a lifetime perspective, and rosuvastatin is subsequently a dominant alternative compared to no treatment in the assessed population. Using the overall JUPITER population, rosuvastatin was dominant for the lifetime horizon. In the sensitivity analysis, rosuvastatin was the dominant treatment strategy over a 20-year time horizon, and cost-effective with an incremental cost-effectiveness ratio (cost per QALY) of SEK 1783 over a 10-year time horizon. Some model inputs were derived from literature or other data sources, but uncertainty was controlled by sensitivity analyses. Results indicate that rosuvastatin 20 mg treatment is a cost-effective option vs no-treatment in patients with Framingham CVD risk >20% in Sweden and might even be cost saving if taking a long-term perspective.

Risk reductions for cardiovascular disease with pravastatin treatment by dyslipidemia phenotype: a post hoc analysis of the MEGA Study.

PubMed

Nishiwaki, Masato; Ikewaki, Katsunori; Ayaori, Makoto; Mizuno, Kyoichi; Ohashi, Yasuo; Ohsuzu, Fumitaka; Ishikawa, Toshitsugu; Nakamura, Haruo

2013-03-01

The beneficial effect of statins for cardiovascular disease (CVD) prevention has been well established. However, the effectiveness among different phenotypes of dyslipidemia has not been confirmed. We evaluated the effect of pravastatin on the incidence of CVD in relation to the phenotype of dyslipidemia. The MEGA Study evaluated the effect of low-dose pravastatin on primary prevention of CVD in 7832 Japanese patients, who were randomized to diet alone or diet plus pravastatin and followed for more than 5 years. These patients were classified into phenotype IIa (n=5589) and IIb (n=2041) based on the electrophoretic pattern for this post hoc analysis. In the diet group there was no significant difference in the incidence of coronary heart disease (CHD), stroke, CVD, and total mortality between the two phenotypes. Phenotype IIb patients, compared to phenotype IIa, had lower levels of high-density lipoprotein cholesterol (HDL-C) and a significantly higher incidence of CVD in relation to a low HDL-C level (<47.5mg/dL; p=0.02). Furthermore, pravastatin decreased the relative risk for each major endpoint in both type IIa and type IIb dyslipidemia. Significant risk reductions were observed for CHD by 38% (p=0.04) and CVD by 31% (p=0.02) in type IIa dyslipidemia but not in phenotype IIb. Pravastatin therapy provided significant risk reductions for CHD and CVD in patients with phenotype IIa dyslipidemia, but not in those with phenotype IIb dyslipidemia. Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Genotoxicity evaluation of HMG CoA reductase inhibitor rosuvastatin.

PubMed

Berber, Ahmet Ali; Celik, Mustafa; Aksoy, Hüseyin

2014-07-01

The genotoxic potential of rosuvastatin as one of the statin drugs was assessed by chromosomal aberrations (CAs), micronucleus (MN) and DNA damage by comet assay in the human peripheral blood lymphocytes. Rosuvastatin was used at concentrations of 0.0625, 0.125, 0.25, 0.5 and 1 µg/mL for these in vitro assays. In all assays, a negative and positive control were also included. CA frequencies were significantly increased in all concentrations at 24 hours and significantly increased in all concentrations except 0.0625 µg/mL at 48 hours, compared to the negative control. Rosuvastatin has a decreased mitotic index (MI) at 0.5- and 1-µg/mL concentrations at 24 hours and at 0.25, 0.5 and 1 µg/mL at 48 hours. A significant increase was observed for induction of MN in all treatments, compared to the negative control. Cytokinesis-block proliferation indices were not affected by treatments with rosuvastatin. In the comet assay, significant increases in comet tail length and tail moment were observed at 0.0625-, 0.5- and 1-µg/mL concentrations. Comet intensity was significantly increased in all concentrations except 0.0625 µg/mL. According to these results, rosuvastatin is cytotoxic and clastogenic/aneugenic in human peripheral lymphocytes. Further studies should be conducted in other test systems to evaluate the full genotoxic potential of rosuvastatin.

[Rosuvastatin improves insulin sensitivity in overweight rats induced by high fat diet. Role of SIRT1 in adipose tissue].

PubMed

Valero-Muñoz, María; Martín-Fernández, Beatriz; Ballesteros, Sandra; Cachofeiro, Victoria; Lahera, Vicente; de Las Heras, Natalia

2014-01-01

To study the effects of rosuvastatin on insulin resistance in overweight rats induced by high fat diet, as well as potential mediators. We used male Wistar rats fed with a standard diet (CT) or high fat diet (33.5% fat) (HFD); half of the animals HFD were treated with rosuvastatin (15mg/kg/day) (HFD+Rosu) for 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Treatment with Rosu did not modify body weight or the weight of the adipose packages in HFD rat. Plasma glucose and insulin levels and HOMA index were higher in HFD rats, and rosuvastatin treatment reduced them. Leptin/adiponectin ratio in plasma and lumbar adipose tissue were higher in HDF rats, and were reduced by rosuvastatin. SIRT-1, PPAR-γ and GLUT-4 protein expression in lumbar adipose tissue were lower in HFD rats and Rosu normalized expression of the three mediators. Rosuvastatin ameliorates insulin sensitivity induced by HFD in rats. This effect is mediated by several mechanisms including reduction of leptin and enhancement of SIRT-1, PPAR-γ and GLUT-4 expression in white adipose tissue. SIRT1 could be considered a major mediator of the beneficial effects of rosuvastatin on insulin sensitivity in overweight rats induced by diet. Copyright © 2013 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

Comparison of the effects of high-dose atorvastatin and high-dose rosuvastatin on oxidative stress in patients with acute myocardial infarction: A pilot study.

PubMed

Kilit, Celal; Koçak, Fatma Emel; Paşalı Kilit, Türkan

2017-04-01

Oxidative stress is increased in patients with acute myocardial infarction (AMI). Statins reduce oxidative stress independent of their effect in reducing low-density lipoprotein cholesterol (LDL-C). The aim of the present study was to compare the effects of atorvastatin and rosuvastatin on oxidative status by investigating serum paraoxonase, serum arylesterase, total oxidant status, total antioxidant status (TAS) and oxidative stress index (OSI) in patients with AMI. Seventy patients with AMI were randomized into 2 groups; total of 55 patients (19 females, 36 males) aged 32 to 86 years completed the study and were included in the analysis. Patients were treated with 80 mg atorvastatin or 40 mg rosuvastatin for 4 weeks. Lipid parameters and parameters of oxidative status were measured at admission and after 4-week statin treatment. After 4-week treatment, atorvastatin and rosuvastatin were associated with significant reduction in TAS, OSI, total cholesterol, and LDL-C levels. Serum paraoxonase level was significantly increased in both groups, while high-density lipoprotein cholesterol (HDL-C) level was significantly reduced in atorvastatin group. No statistically significant differences were found between atorvastatin and rosuvastatin in terms of actual difference in oxidative stress parameters. Atorvastatin and rosuvastatin have similar effects on oxidative status in patients with AMI. Rosuvastatin affected HDL-C level more favorably than atorvastatin.

Pravastatin and simvastatin inhibit the adhesion, replication and proliferation of Toxoplasma gondii (RH strain) in HeLa cells.

PubMed

Sanfelice, Raquel Arruda; da Silva, Suelen Santos; Bosqui, Larissa Rodrigues; Miranda-Sapla, Milena Menegazzo; Barbosa, Bellisa Freitas; Silva, Rafaela José; Ferro, Eloísa A Vieira; Panagio, Luciano Aparecido; Navarro, Italmar Teodorico; Bordignon, Juliano; Conchon-Costa, Ivete; Pavanelli, Wander Rogerio; Almeida, Ricardo Sergio; Costa, Idessania Nazareth

2017-03-01

The conventional treatment for toxoplasmosis with pyrimethamine and sulfadiazine shows toxic effects to the host, and it is therefore necessary to search for new drugs. Some studies suggest the use of statins, which inhibit cholesterol synthesis in humans and also the initial processes of isoprenoid biosynthesis in the parasite. Thus, the objective of this study was to evaluate the activity of the statins pravastatin and simvastatin in HeLa cells infected in vitro with the RH strain of T. gondii. HeLa cells (1×10 5 ) were infected with T. gondii tachyzoites (5×10 5 ) following two different treatment protocols. In the first protocol, T. gondii tachyzoites were pretreated with pravastatin (50 and 100μg/mL) and simvastatin (1.56 and 3.125μg/mL) for 30min prior to infection. In the second, HeLa cells were first infected (5×10 5 ) with tachyzoites and subsequently treated with pravastatin and simvastatin for 24h at the concentrations noted above. Initially, we evaluated the cytotoxicity of drugs by the MTT assay, number of tachyzoites adhered to cells, number of infected cells, and viability of tachyzoites by trypan blue exclusion. The supernatant of the cell cultures was collected post-treatment for determination of the pattern of Th1/Th2/Th17 cytokines by cytometric bead array. There was no cytotoxicity to HeLa cells with 50 and 100μg/mL pravastatin and 1.56 and 3.125μg/mL simvastatin. There was no change in the viability of tachyzoites that received pretreatment. Regarding the pre- and post-treatment of the cells with pravastatin and simvastatin alone, there was a reduction in adhesion, invasion and proliferation of cells to T. gondii. As for the production of cytokines, we found that IL-6 and IL-17 were significantly reduced in cells infected with T. gondii and treated with pravastatin and simvastatin, when compared to control. Based on these results, we can infer that pravastatin and simvastatin alone possess antiproliferative effects on tachyzoites forms of T. gondii, giving these drugs new therapeutic uses. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparison of the efficacy and safety of rosuvastatin 10 mg and atorvastatin 20 mg in high-risk patients with hypercholesterolemia – Prospective study to evaluate the Use of Low doses of the Statins Atorvastatin and Rosuvastatin (PULSAR)

PubMed Central

Clearfield, Michael B; Amerena, John; Bassand, Jean-Pierre; García, Hugo R Hernández; Miller, Sam S; Sosef, Froukje FM; Palmer, Michael K; Bryzinski, Brian S

2006-01-01

Background Many patients at high risk of cardiovascular disease do not achieve recommended low-density lipoprotein cholesterol (LDL-C) goals. This study compared the efficacy and safety of low doses of rosuvastatin (10 mg) and atorvastatin (20 mg) in high-risk patients with hypercholesterolemia. Methods A total of 996 patients with hypercholesterolemia (LDL-C ≥ 3.4 and < 5.7 mmol/L [130 and 220 mg/dL]) and coronary heart disease (CHD), atherosclerosis, or a CHD-risk equivalent were randomized to once-daily rosuvastatin 10 mg or atorvastatin 20 mg. The primary endpoint was the percentage change from baseline in LDL-C levels at 6 weeks. Secondary endpoints included LDL-C goal achievement (National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] goal < 100 mg/dL; 2003 European goal < 2.5 mmol/L for patients with atherosclerotic disease, type 2 diabetes, or at high risk of cardiovascular events, as assessed by a Systematic COronary Risk Evaluation (SCORE) risk ≥ 5% or 3.0 mmol/L for all other patients), changes in other lipids and lipoproteins, cost-effectiveness, and safety. Results Rosuvastatin 10 mg reduced LDL-C levels significantly more than atorvastatin 20 mg at week 6 (44.6% vs. 42.7%, p < 0.05). Significantly more patients achieved NCEP ATP III and 2003 European LDL-C goals with rosuvastatin 10 mg compared with atorvastatin 20 mg (68.8% vs. 62.5%, p < 0.05; 68.0% vs. 63.3%, p < 0.05, respectively). High-density lipoprotein cholesterol was increased significantly with rosuvastatin 10 mg versus atorvastatin 20 mg (6.4% vs. 3.1%, p < 0.001). Lipid ratios and levels of apolipoprotein A-I also improved more with rosuvastatin 10 mg than with atorvastatin 20 mg. The use of rosuvastatin 10 mg was also cost-effective compared with atorvastatin 20 mg in both a US and a UK setting. Both treatments were well tolerated, with a similar incidence of adverse events (rosuvastatin 10 mg, 27.5%; atorvastatin 20 mg, 26.1%). No cases of rhabdomyolysis, liver, or renal insufficiency were recorded. Conclusion In high-risk patients with hypercholesterolemia, rosuvastatin 10 mg was more efficacious than atorvastatin 20 mg at reducing LDL-C, enabling LDL-C goal achievement and improving other lipid parameters. Both treatments were well tolerated. PMID:17184550

Effects of 96 Weeks of Rosuvastatin on Bone, Muscle, and Fat in HIV-Infected Adults on Effective Antiretroviral Therapy.

PubMed

Erlandson, Kristine M; Jiang, Ying; Debanne, Sara M; McComsey, Grace A

2016-04-01

Heightened inflammation and immune activation are associated with lower bone mineral density (BMD) and lean body mass (LBM) among HIV-infected persons. We hypothesized that a reduction in inflammation with rosuvastatin would be associated with improvements in BMD and LBM. HIV-infected participants on stable antiretroviral therapy without statin indication and with heightened immune activation (≥19% CD8(+)CD38(+)HLA-DR(+) T cells) or inflammation (hsCRP ≥2 mg/liter) were randomized to rosuvastatin 10 mg daily or placebo for 96 weeks. Among 72 participants randomized to rosuvastatin and 75 to placebo, there were no significant differences in the relative changes in BMD (p > 0.29) or in fat (p ≥ 0.19). A trend toward increased LBM (p = 0.059) was seen in the rosuvastatin arm without differences in creatinine kinase or self-reported physical activity (p ≥ 0.10). In a multivariable regression model, rosuvastatin was associated with a significant positive effect on LBM after adjusting for age, sex, race, smoking status, and detectable HIV-1 viral load. Higher baseline sCD163 correlated with increases in LBM from weeks 0 to 96 (p = 0.023); greater changes in total and leg lean mass were seen among statin users with higher compared to lower baseline IP-10 levels (LBM 1.8 vs. -0.3%; p = 0.028 and leg lean mass 2.9 vs. -1.7%; p = 0.012). Rosuvastatin is associated with an absence of toxicity on BMD and a potential benefit on LBM over 96 weeks of therapy. The preservation of LBM in the rosuvastatin arm over the 2 years of the study is of major clinical relevance in delaying loss of muscle mass with aging.

Effects of Combination of Ezetimibe and Rosuvastatin on Coronary Artery Plaque in Patients with Coronary Heart Disease.

PubMed

Wang, Xiaofang; Zhao, Xiaoyan; Li, Ling; Yao, Haimu; Jiang, Yan; Zhang, Jinying

2016-05-01

In approximately 80% of cardiovascular disease-related deaths, patients suffer from coronary atherosclerotic heart disease. Ezetimibe is the first intestinal cholesterol absorption inhibitor. Its combination with statins for treating coronary atherosclerotic heart disease has attracted attention worldwide. The study group comprised 106 patients with coronary atherosclerotic heart disease and hyperlipidaemia. Each was randomly assigned to one of two groups: (1) Ezetimibe (10mg, once a night) plus rosuvastatin (10mg, once a night) (n=55) or (2) Rosuvastatin alone (10mg, once a night) (n=51). The primary endpoint was new or recurrent myocardial infarction, unstable angina pectoris, cardiac death, and stroke. Blood lipid, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9) levels were measured before treatment and at one, six and 12 months after treatment. Coronary plaque size and compositional changes were determined using intravascular ultrasonography. The combination of ezetimibe plus rosuvastatin decreased total cholesterol, low-density lipoprotein cholesterol, hsCRP, IL-6, and MMP-9 levels at six and 12 months after treatment. Statistical significance was detected between two groups. At 12 months, the plaque burden, plaque cross-sectional area, and percentage of necrotic plaque composition were significantly lower in the combination group than in rosuvastatin alone group (P<0.05). And compared with rosuvastatin alone group, the primary endpoint decreased more effectively in combination group. The combination of ezetimibe and rosuvastatin apparently diminishes lipid levels and plaque burden and improves plaque stability, which may be associated with the potent inhibitory effects of ezetimibe and rosuvastatin on inflammatory cytokines. Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Impact of the JUPITER trial on statin prescribing for primary prevention.

PubMed

Teng, Jennifer F T; Gomes, Tara; Camacho, Ximena; Grundy, Scott; Juurlink, David N; Mamdani, Muhammad M

2014-01-01

As the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial identified a new population of individuals with cholesterol levels below traditional treatment thresholds but with elevated high-sensitivity C-reactive protein (hs-CRP) levels who may benefit from primary prevention with statin therapy, we sought to evaluate the impact of this trial on the incident prescription rates of rosuvastatin alone as well as all statins in a primary prevention population. Population-based, cross-sectional time-series analysis. Administrative health care databases in Ontario, Canada. A total of 299,809 incident statin users 66 years or older were identified during the study period, from January 1, 2003, to March 31, 2011, who were prescribed statin therapy for primary prevention. We evaluated the incident rate of rosuvastatin and all statin use during each quarter of the study period. Overall, no significant trends in all incident statin use were observed (p=0.99). Furthermore, no significant differences were observed in incident rates of rosuvastatin (p=0.21) or all statin (p=0.41) use after the publication of the JUPITER trial. Despite the lack of impact of the JUPITER trial on rosuvastatin or all statin utilization, the relative market share of rosuvastatin increased from 9% to 65% over the study period. The publication of the JUPITER trial did not significantly affect trends in overall statin and rosuvastatin prescribing patterns for primary prevention in this study. Increases in the relative market share of rosuvastatin may be attributed to the impact of the pharmaceutical industry on prescribing patterns. Our results highlight the need to further improve the integration of evidence-based prescribing into cost-effective clinical practice. © 2013 Pharmacotherapy Publications, Inc.

Comparison of effectiveness of rosuvastatin versus atorvastatin on the achievement of combined C-reactive protein (<2 mg/L) and low-density lipoprotein cholesterol (< 70 mg/dl) targets in patients with type 2 diabetes mellitus (from the ANDROMEDA study).

PubMed

Betteridge, D John; Gibson, J Martin; Sager, Philip T

2007-10-15

Decreasing C-reactive protein (CRP) in addition to decreasing low-density lipoprotein (LDL) cholesterol may further decrease coronary heart disease risk. The effects of rosuvastatin compared with atorvastatin in achieving a combined target of LDL cholesterol <70 mg/dl and CRP <2 mg/L in 509 patients with type 2 diabetes mellitus was evaluated. CRP decreased significantly versus baseline in both treatment groups. Significantly more patients treated with rosuvastatin achieved the combined end point of LDL cholesterol <70 mg/dl and CRP <2 mg/L compared with atorvastatin by the end of the study period (58% vs 37%; p <0.001 vs atorvastatin). In conclusion, CRP was effectively decreased in patients with type 2 diabetes receiving rosuvastatin or atorvastatin, whereas rosuvastatin decreased LDL cholesterol significantly more than atorvastatin.

Rosuvastatin: A Review of the Pharmacology and Clinical Effectiveness in Cardiovascular Disease

PubMed Central

Luvai, Ahai; Mbagaya, Wycliffe; Hall, Alistair S.; Barth, Julian H.

2012-01-01

Rosuvastatin is a new generation HMG-CoA reductase inhibitor which exhibits some unique pharmacologic and pharmacokinetic properties. It has low extrahepatic tissue penetration, low potential for CYP3A4 interactions and substantial LDL-C lowering capacity and therefore has distinct advantages. We conducted a Medline literature search to identify rosuvastatin papers published in English. In this review, we outline the pharmacology of rosuvastatin, highlighting its efficacy and safety. We also review the major clinical trials with reference to primary and secondary prevention, familial hypercholesterolaemia and comparison with other statins. Finally we address its place in clinical practice. PMID:22442638

Adverse drug reaction: rosuvastatin as a cause for ischaemic colitis in a 64-year-old woman

PubMed Central

Tan, Jackie; Pretorius, Casper Francois; Flanagan, Paul Vincent; Pais, Antonio

2012-01-01

Rosuvastatin (Crestor, AstraZeneca) is a commonly used drug for managing hypercholesterolaemia. It is a very safe medication with mostly acceptable side effects. Rare but serious side effects are not well known. A 64-year-old woman presented with bloody diarrhoea after starting rosuvastatin for hypercholesterolaemia. Stool microscopy and culture ruled out infective causes. Abdominal CT scan revealed normal calibre celiac axis and superior mesenteric artery. Colonoscopic biopsy revealed ischaemic colitis as the final histological diagnosis. The patient is in complete remission after ceasing the medication. Rosuvastatin causing ischaemic colitis should be considered a rare but serious adverse drug reaction. PMID:22744258

Enhanced effect of losartan and rosuvastatin on neointima hyperplasia.

PubMed

Yi, Inseon; Lee, Jung-Jin; Park, Jeong-Sook; Zhang, Wei Yun; Kim, In-Su; Kim, Yohan; Shin, Chang-Yong; Kim, Hyung Sik; Myung, Chang-Seon

2010-04-01

The beneficial effects of losartan and rosuvastatin on neointimal formation have been well characterized, but little is known about the combined treatment benefit of these two drugs. This study was designed to investigate the synergistic effect of losartan combined with rosuvastatin on the magnitude of protective action in vascular injury mediated by cuff-induced neointimal formation model in vivo. Losartan at 20 mg/kg or rosuvastatin at 40 mg/kg significantly decreased both the neointimal formation and BrdU-positive cells in neointima, indicating the inhibition of cell proliferation including a progress of DNA synthesis. The combination treatment used lower doses of losartan with rosuvastatin (10 + 20 & 5 + 10 mg/kg, respectively) that proved to be significant in decreasing the neointimal formation and BrdU incorporation. These results were comparable to the diminution attained with monotherapy of either drug in higher doses. Interaction index measured by isobolar method indicated drug synergism in these two combinations of both drugs at lower doses. Therefore, the administration of losartan and rosuvastatin in combination with low doses synergistically decreased in cuff-induced neointimal formation by reducing cell proliferation, suggesting that this drug synergism may be fully effective with, lower adverse effects, for the treatment of vascular remodeling such as restenosis.

Quantitative and qualitative effects of rosuvastatin on LDL-cholesterol: what is the clinical significance?

PubMed

Rizzo, M; Berneis, K; Spinas, G A; Rini, G B; Kapur, N K

2009-03-01

Statins have emerged as the global leader in pharmacologic therapy for dyslipidaemia, and rosuvastatin has demonstrated clinical efficacy as well as safety in several clinical trials and postmarketing analyses. The present article reviewed the effects of rosuvastatin on the quantity and the quality of low-density lipoproteins (LDL). We searched for and reviewed all the available evidence in a systematic way. A literature search (by Medline and Scopus) was performed using the following headings: 'LDL-cholesterol', 'LDL size', 'LDL subclasses', 'small dense LDL', 'apolipoprotein B, apo B' and 'rosuvastatin' up to 11 November 2008. The authors also manually reviewed the references of selected articles for any pertinent material. Rosuvastatin reduces LDL-cholesterol levels to a greater extent than other statins and is able to modulate significantly LDL size and subclasses towards less atherogenic particles as well as the LDL particle number, as indirectly measured by the levels of apo B. The recent Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin study provides more evidence about the effectiveness of rosuvastatin therapy in reducing cardiovascular risk, even among persons who would not currently be considered for pharmacotherapy. Further insights on cardiovascular outcomes will be available by the on-going trials included in the GALAXY program that includes subjects with type-2 diabetes, haemodialysis recipients, patients with congestive heart failure and specific ethnic groups, such as African American, Hispanic and South Asian populations.

Antinociception induced by rosuvastatin in murine neuropathic pain.

PubMed

Miranda, Hugo F; Sierralta, Fernando; Aranda, Nicolas; Poblete, Paula; Castillo, Rodrigo L; Noriega, Viviana; Prieto, Juan Carlos

2018-06-01

Neuropathic pain, and subsequent hypernociception, can be induced in mice by paclitaxel (PTX) administration and partial sciatic nerve ligation (PSNL). Its pharmacotherapy has been a clinical challenge, due to a lack of effective treatment. In two models of mouse neuropathic pain (PTX and PSNL) the antinociception induced by rosuvastatin and the participation of proinflammatory biomarkers, interleukin (IL)- 1β, TBARS and glutathione were evaluated. A dose-response curve for rosuvastatin ip was obtained on cold plate, hot plate and Von Frey assays. Changes on spinal cord levels of IL-1β, glutathione and lipid peroxidation were measured at 7 and 14days in PTX and PSNL murine models. PTX or PSNL were able to induce in mice peripheral neuropathy with hypernociception, either to 7 and 14days. Rosuvastatin induced a dose dependent antinociception in hot plate, cold plate and Von Frey assays. The increased levels of IL-1β or TBARS induced by pretreatment with PTX or PSNL were reduced by rosuvastatin. The reduction of spinal cord glutathione, by PTX or PSNL, expressed as the ratio GSH/GSSG, were increased significantly in animals pretreated with rosuvastatin. The anti-inflammatory properties of statins could underlie their beneficial effects on neuropathic pain by reduction of proinflammatory biomarkers and activation of glia. The findings of this study suggest a potential usefulness of rosuvastatin in the treatment of neuropathic pain. Copyright © 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Rosuvastatin protects against angiotensin II-induced renal injury in a dose-dependent fashion.

PubMed

Park, Joon-Keun; Mervaala, Eero Ma; Muller, Dominik N; Menne, Jan; Fiebeler, Anette; Luft, Friedrich C; Haller, Hermann

2009-03-01

We showed earlier that statin treatment ameliorates target-organ injury in a transgenic model of angiotensin (Ang) II-induced hypertension. We now test the hypothesis that rosuvastatin (1, 10, and 50 mg/kg/day) influences leukocyte adhesion and infiltration, prevents induction of inducible nitric oxide synthase (iNOS), and ameliorates target-organ damage in a dose-dependent fashion. We treated rats harboring the human renin and human angiotensinogen genes (dTGR) from week 4 to 8 (n = 20 per group). Untreated dTGR developed severe hypertension, cardiac hypertrophy, and renal damage, with a 100-fold increased albuminuria and focal cortical necrosis. Mortality of untreated dTGR at age 8 weeks was 59%. Rosuvastatin treatment decreased mortality dose-dependently. Blood pressure was not affected. Albuminuria was reduced dose-dependently. Interstitial adhesion molecule (ICAM)-1 expression was markedly reduced by rosuvastatin, as were neutrophil and monocyte infiltration. Immunohistochemistry showed an increased endothelial and medial iNOS expression in small vessels, infiltrating cells, afferent arterioles, and glomeruli of dTGR. Immunoreactivity was stronger in cortex than medulla. Rosuvastatin markedly reduced the iNOS expression in both cortex and medulla. Finally, matrix protein (type IV collagen, fibronectin) expression was also dose- dependently reduced by rosuvastatin. Our findings indicate that rosuvastatin dose- dependently ameliorates angiotensin II-induced-organ damage and almost completely prevents inflammation at the highest dose. The data implicate 3-hydroxy-3-methylglutaryl coenzyme A function in signaling events leading to target-organ damage.

Effect of inhalation exposure to toluene on the activity of organic anion transporting polypeptide (Oatp) using pravastatin as a probe drug in rats.

PubMed

Mauro, Mariana; Lepera, Jose Salvador; Borsari, Bruno; Capela, Jorge Manuel Vieira; de Moraes, Natália Valadares

2018-07-01

1. Toluene, used as a pure substance or in solvent mixtures, is the cause of occupational exposures of large numbers of workers in the world. The organic anion transporting polypeptides (OATP: human; Oatp: rodents) are drug carriers which have been frequently associated to drug-drug interactions. The objective of this study was to evaluate the influence of inhalation exposure to toluene in Oatp in vivo activity using pravastatin as a probe drug in rats. 2. Male Wistar rats ((n = 6 per sampling time) were exposed to 85 mg/m 3 toluene by inhalation or air in a nose only exposure system for 6 h/d, 5 d/week during 4 weeks, in order to simulate the occupational exposure to toluene at level slightly above the occupational exposure limit proposed by the American Conference of Governmental Industrial Hygienists (ACGIH). After 4 weeks of exposure, animals received a single dose of 20 mg/kg pravastatin orally. 3. Areas under concentration × time curves extrapolated to infinite (AUC 0-∞ ) were calculated by Gauss Laguerre quadrature. Non-exposed animals showed AUC 0-∞ of 726.0 (261.8) ng h/mL for pravastatin and rats exposed to toluene 85 mg/m3 showed AUC 0-∞ of 681.8 (80.1) ng h/mL [data presented as mean (standard error of the mean)]. No significant difference was observed in pravastatin kinetic disposition between groups in terms of 95% confidence interval for the difference between means. 4. Toluene exposure by inhalation did not change the in vivo activity of Oatp evaluated by pravastatin kinetic disposition in rats.

13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis.

PubMed

Walker, Mary E; Souza, Patricia R; Colas, Romain A; Dalli, Jesmond

2017-08-01

Rheumatoid arthritis is an inflammatory condition characterized by overzealous inflammation that leads to joint damage and is associated with an increased incidence of cardiovascular disease. Statins are frontline therapeutics for patients with cardiovascular disease and exert beneficial actions in rheumatoid arthritis. The mechanism that mediates the beneficial actions of statins in rheumatoid arthritis remains of interest. In the present study, we found that the administration of 2 clinically relevant statins-atorvastatin (0.2 mg/kg) or pravastatin (0.2 mg/kg)-to mice during inflammatory arthritis up-regulated systemic and tissue amounts of a novel family of proresolving mediators, termed 13-series resolvins (RvTs), and significantly reduced joint disease. Of note, administration of simvastatin (0.2 mg/kg) did not significantly up-regulate RvTs or reduce joint inflammation. We also found that atorvastatin and pravastatin each reduced systemic leukocyte activation, including platelet-monocyte aggregates (∼25-60%). These statins decreased neutrophil trafficking to the joint as well as joint monocyte and macrophage numbers. Atorvastatin and pravastatin produced significant reductions (∼30-50%) in expression of CD11b and major histocompatibility complex class II on both monocytes and monocyte-derived macrophages in joints. Administration of an inhibitor to cyclooxygenase-2, the initiating enzyme in the RvT pathway, reversed the protective actions of these statins on both joint and systemic inflammation. Together, these findings provide evidence for the role of RvTs in mediating the protective actions of atorvastatin and pravastatin in reducing local and vascular inflammation, and suggest that RvTs may be useful in measuring the anti-inflammatory actions of statins.-Walker, M. E., Souza, P. R., Colas, R. A., Dalli, J. 13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis. © The Author(s).

Pravastatin reverses the membrane cholesterol reorganization induced by myocardial infarction within lipid rafts in CD14(+)/CD16(-) circulating monocytes.

PubMed

Salvary, Thomas; Gambert-Nicot, Ségolène; Brindisi, Marie-Claude; Meneveau, Nicolas; Schiele, François; Séronde, Marie-France; Lorgis, Luc; Zeller, Marianne; Cottin, Yves; Kantelip, Jean-Pierre; Gambert, Philippe; Davani, Siamak

2012-09-01

Large numbers of monocytes are recruited in the infarcted myocardium. Their cell membranes contain cholesterol-rich microdomains called lipids rafts, which participate in numerous signaling cascades. In addition to its cholesterol-lowering effect, pravastatin has several pleiotropic effects and is widely used as secondary prevention treatment after myocardial infarction (MI). The aim of this study was to investigate the effects of pravastatin on the organization of cholesterol within monocyte membrane rafts from patients who had suffered myocardial infarction. Monocytes from healthy donors and acute MI patients were cultured with or without 4μM pravastatin. Lipid rafts were extracted by Lubrol WX, caveolae and flat rafts were separated using a modified sucrose gradient. Cholesterol level and caveolin-1 expression in lipid rafts were determined. In healthy donors, cholesterol was concentrated in flat rafts (63±3 vs 13±1%, p<0.001). While monocytes from MI patients presented similar cholesterol distribution in both caveolae and flat rafts. Cholesterol distribution was higher in flat rafts in healthy donors, compared to MI patients (63±3 vs 41±2%, p<0.001), with less distribution in caveolae (13±1 vs 34±2%, p<0.001). Pravastatin reversed the cholesterol distribution in MI patients cells between flat rafts (41±2 vs 66±3%, p<0.001) and caveolae (34±2 vs 18±1%, p<0.001). In conclusion, MI redistributes cholesterol from flat rafts to caveolae indicating monocyte membrane reorganization. In vitro pravastatin treatment restored basal conditions in MI monocytes, suggesting another effect of statins. Copyright © 2012 Elsevier B.V. All rights reserved.

Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes

PubMed Central

Rondini, Elizabeth A.; Duniec-Dmuchowski, Zofia; Cukovic, Daniela; Dombkowski, Alan A.

2016-01-01

Squalene synthase inhibitors (SSIs), such as squalestatin 1 (SQ1), reduce cholesterol biosynthesis but cause the accumulation of isoprenoids derived from farnesyl pyrophosphate (FPP), which can modulate the activity of nuclear receptors, including the constitutive androstane receptor (CAR), farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs). In comparison, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (e.g., pravastatin) inhibit production of both cholesterol and nonsterol isoprenoids. To characterize the effects of isoprenoids on hepatocellular physiology, microarrays were used to compare orthologous gene expression from primary cultured mouse and rat hepatocytes that were treated with either SQ1 or pravastatin. Compared with controls, 47 orthologs were affected by both inhibitors, 90 were affected only by SQ1, and 51 were unique to pravastatin treatment (P < 0.05, ≥1.5-fold change). When the effects of SQ1 and pravastatin were compared directly, 162 orthologs were found to be differentially coregulated between the two treatments. Genes involved in cholesterol and unsaturated fatty acid biosynthesis were up-regulated by both inhibitors, consistent with cholesterol depletion; however, the extent of induction was greater in rat than in mouse hepatocytes. SQ1 induced several orthologs associated with microsomal, peroxisomal, and mitochondrial fatty acid oxidation and repressed orthologs involved in cell cycle regulation. By comparison, pravastatin repressed the expression of orthologs involved in retinol and xenobiotic metabolism. Several of the metabolic genes altered by isoprenoids were inducible by a PPARα agonist, whereas cytochrome P450 isoform 2B was inducible by activators of CAR. Our findings indicate that SSIs uniquely influence cellular lipid metabolism and cell cycle regulation, probably due to FPP catabolism through the farnesol pathway. PMID:27225895

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2006-01-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs:(R)-Flurbiprofen, 90Yttrium-DOTA-huJ591; ABT-510, ACP-103, Ad5-FGF4, adalimumab, ademetionine, AG-7352, alemtuzumab, Amb a 1 ISS-DNA, anakinra, apaziquone, aprepitant, aripiprazole, atazanavir sulfate; BAL-8557, bevacizumab, BMS-188797, bortezomib, bosentan, brivudine; Calcipotriol/betamethasone dipropionate, cannabidiol, caspofungin acetate, catumaxomab, CERE-120, cetuximab, ciclesonide, cilomilast, cizolirtine citrate, Cypher, cystemustine; Dalbavancin, darifenacin hydrobromide, dasatinib, deferasirox, denosumab, desmoteplase, dihydrexidine, dimethyl fumarate, dutasteride, DW-166HC; Eculizumab, enfuvirtide, entecavir, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, eszopiclone, etoricoxib, everolimus; Fallypride, febuxostat, fenretinide, fesoterodine, fingolimod hydrochloride; Gabapentin enacarbil, gefitinib; hMaxi-K, human papillomavirus vaccine, HYAL-CT1101; Imatinib mesylate, indiplon, inolimomab, ISAtx-247; J591; Lacosamide, landiolol, lasofoxifene tartrate, lestaurtinib, lidocaine/prilocaine, linezolid, lixivaptan, lonafarnib, lopinavir, lopinavir/ritonavir, lumiracoxib; Natalizumab, nesiritide; OC-108, omalizumab, onercept, OSC; Palifermin, palonosetron hydrochloride, parathyroid hormone (human recombinant), parecoxib sodium, PD-MAGE-3 vaccine, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegsunercept, pelitinib, pitavastatin calcium, plerixafor hydrochloride, posaconazole, prasterone sulfate, pregabalin; Ramelteon, ranelic acid distrontium salt, rasburicase, rosuvastatin calcium, rotigotine, RSD-1235, rufinamide, rupatadine fumarate; Sarizotan hydrochloride, SHL-749, sirolimus-eluting stent, solifenacin succinate, sunitinib malate; Tadalafil, talampanel, tasidotin hydrochloride, Taxus, tegaserod maleate, telavancin hydrochloride, tenofovir disoproxil fumarate, tiotropium bromide, tocilizumab, tositumomab, treprostinil sodium, tridolgosir hydrochloride, TTS-CD3; Ularitide; Valdecoxib, Val-Tyr sardine peptidase, vardenafil hydrochloride hydrate, voriconazole; Yttrium (90Y) edotreotide, Yttrium 90 (90Y) ibritumomab tiuxetan; Zileuton, zucapsaicin.

Achieving low-density lipoprotein cholesterol goals in high-risk patients in managed care: comparison of rosuvastatin, atorvastatin, and simvastatin in the SOLAR trial.

PubMed

Insull, William; Ghali, Jalal K; Hassman, David R; Y As, Joseph W; Gandhi, Sanjay K; Miller, Elinor

2007-05-01

To evaluate attainment of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III low-density lipoprotein cholesterol (LDL-C) goal of less than 100 mg/dL with statin treatments in managed care patients at high risk for coronary heart disease. In a randomized, open-label, multicenter trial (SOLAR [Satisfying Optimal LDL-C ATP III goals with Rosuvastatin]) performed at 145 US clinical centers from June 5, 2002 to July 12, 2004, high-risk men and women in a managed care population received typical starting doses of rosuvastatin (10 mg/d), atorvastatin (10 mg/d), or simvastatin (20 mg/d) for 6 weeks. Those who did not meet the LDL-C target of less than 100 mg/dL at 6 weeks had their dose titrated (doubled), and all patients were followed up for another 6 weeks. A total of 1632 patients were randomized to 1 of the 3 treatment regimens. After 6 weeks, 65% of patients taking rosuvastatin reached the LDL-C target of less than 100 mg/dL vs 41% with atorvastatin and 39% with simvastatin (P<.001 vs rosuvastatin for both). After 12 weeks, 76% of patients taking rosuvastatin reached the LDL-C target of less than 100 mg/dL vs 58% with atorvastatin and 53% with simvastatin (P<.001 vs rosuvastatin for both). Reductions in the LDL-C level, total cholesterol level, non-high-density lipoprotein cholesterol (non-HDL-C) level, and non-HDL-C/HDL-C ratio were significantly greater with rosuvastatin at both 6 and 12 weeks compared with the other statins. Adverse events were similar in type and frequency in all treatment groups, and only 3% of all patients discontinued treatment because of adverse events. No myopathy was observed, no clinically important impact on renal function was attributed to study medications, and clinically important increases in serum transaminases were rare. In a managed care population, 10 mg of rosuvastatin treatment resulted in more patients reaching the NCEP ATP III LDL-C goal compared with 10 mg of atorvastatin and 20 mg of simvastatin, potentially reducing the need for titration visits.

Pharmacokinetics and bioequivalence of a rosuvastatin/ezetimibe fixed-dose combination tablet versus single agents in healthy male subjects
.

PubMed

Kang, Woo Youl; Seong, Sook Jin; Ohk, Boram; Gwon, Mi-Ri; Kim, Bo Kyung; Na, Sookie; Kim, Hyun-Ju; Yoon, Young-Ran; Lee, Hae Won

2018-01-01

The pharmacokinetic profiles and bioequivalence of a new rosuvastatin/ezetimibe fixed-dose combination (FDC; NVP-1205) vs. rosuvastatin and ezetimibe concomitantly administered as single agents were evaluated. In this open-label, single-dose, crossover study (NCT02029625), eligible subjects were randomly assigned in a 1 : 1 ratio to receive a single dose of rosuvastatin (10 mg) with ezetimibe (10 mg) as either a FDC or as single agents concomitantly administered under fasted conditions, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected predose and up to 96 hours postdose in each period for determination of plasma rosuvastatin and ezetimibe concentrations by liquid-chromatography tandem mass spectroscopy and calculation of pharmacokinetic parameters. The mean C_max and AUC_0-t values of rosuvastatin were 12.5 ng/mL and 115.6 ng×h/mL for the FDC, and 12.2 ng/mL and 115.1 ng×h/mL for the single agents concomitantly administered, respectively. The mean C_max and AUC_0-t values of ezetimibe were 4.7 ng/mL and 67.3 ng×h/mL for the FDC, and 4.5 ng/mL and 68.2 ng×h/mL for the single agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the rosuvastatin C_max and AUC_0-t were 106.20 (96.62 - 116.74) and 102.88 (96.32 - 109.90), respectively. The GMR and 90% CI for the ezetimibe C_max and AUC_0-t were 108.96 (98.56 - 120.51) and 98.13 (92.01 - 104.66), respectively. All treatments were well tolerated during this study, with no serious adverse events reported. The rosuvastatin/ezetimibe (10/10 mg) FDC was bioequivalent to single agents concomitantly administered. A single dose of rosuvastatin/ezetimibe as the FDC or as single agents was well tolerated.
.

Pravastatin Effects on Placental Prosurvival Molecular Pathways in a Mouse Model of Preeclampsia.

PubMed

Saad, Antonio F; Diken, Zaid M; Kechichian, Talar B; Clark, Shannon M; Olson, Gayle L; Saade, George R; Costantine, Maged M

2016-11-01

Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta. Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group). Mice from the sFlt group were randomly assigned to receive pravastatin (5 mg/kg/d) in their drinking water from day 9 until killing (sFlt-1 + Pravastatin) or water (sFlt-1). The mFc control received water only. Mice were killed on day 18, and the placentas were collected. Protein mitogen-activated protein kinase (MAPK) pathway substrates were assayed using Bioplex Multiplex Immunoassay (Bio-Rad, Hercules, California). Data are reported as mean  ±  standard error of the mean or median (interquartile range) when appropriate. One-way analysis of variance followed by post hoc analysis was performed. Two-sided P value < .05 was considered statistically significant. The sFlt-1 + Pravastatin mice had significantly higher placental protein concentrations of prosurvival/ antiapoptotic factors (activating transcription factor 2, pp38, phosphorylated c-jun N-terminal kinase, and phosphorylated extracellular signal-regulated kinase) and of heat-shock protein 27 and signal transducer and activator of transcription 3, 2 factors crucial for embryonic and placental development during oxidative stress, compared to sFlt-1 mice (P  <  .05) and similar to the mFc control group. No differences were noted in substrates of the proapoptotic pp53 pathway. Pravastatin ability to prevent preeclampsia phenotype may be mediated through pleiotropic mechanisms involving a prosurvival/ antiapoptotic MAPK pathway in the placenta. Our results further support continued research in the role for statins in the prevention of preeclampsia. © The Author(s) 2016.

Efficacy of alternate day versus daily dosing of rosuvastatin

PubMed Central

Dulay, Daisy; LaHaye, Stephen A; Lahey, Karen A; Day, Andrew G

2009-01-01

BACKGROUND: Compared with other statins, rosuvastatin has a relatively long half-life, which may allow for the administration of this medication on an alternate day basis. OBJECTIVE: To compare the efficacy of administering rosuvastatin on a daily basis versus on an alternate day basis for the treatment of dyslipidemia. METHODS: In the present crossover study, 45 patients with documented hypercholesterolemia requiring pharmacotherapy were administered either 20 mg of rosuvastatin on alternate days or 10 mg of rosuvastatin daily for six weeks. After a four-week washout period, patients were then switched to the other regimen for another six weeks. The primary end point was the percentage reduction of low-density lipoprotein cholesterol (LDL-C). RESULTS: LDL-C decreased by 48.5% versus 40.9% with daily and alternate day dosing, respectively. This represented an additional absolute reduction of LDL-C of 7.6% (95% CI 1.8% to 13.4%, P=0.012) with the daily dosing regimen. Both dosing regimens provided similar improvements in high-density lipoprotein cholesterol and triglycerides. CONCLUSIONS: Compared with alternate day dosing, daily dosing of rosuvastatin provides a statistically significant advantage in LDL-C reduction. However, the alternate day regimen may be a viable option for those patients in whom cost is a limitation to compliance. PMID:19214297

Rationale and design of the EPISTEME trial: efficacy of post-stroke intensive rosuvastatin treatment for aortogenic embolic stroke.

PubMed

Ueno, Yuji; Yamashiro, Kazuo; Tanaka, Yasutaka; Watanabe, Masao; Shimada, Yoshiaki; Kuroki, Takuma; Miyamoto, Nobukazu; Daimon, Masao; Tanaka, Ryota; Miyauchi, Katsumi; Daida, Hiroyuki; Hattori, Nobutaka; Urabe, Takao

2014-02-01

Large atheromatous aortic plaques (AAPs) are associated with stroke recurrence. Rosuvastatin is a potent lipid-lowering agent and suppresses carotid and coronary artery atherosclerosis. It is unclear whether rosuvastatin has anti-atherogenic effects against AAPs in stroke patients. We designed a clinical trial in stroke patients to analyze changes in AAPs after rosuvastatin treatment using repeated transesophageal echocardiography (TEE). This trial is a prospective randomized open label study. Inclusion criteria were patients were ischemic stroke with hypercholesterolemia and AAPs ≥ 4 mm in thickness. The patients are randomly assigned to either a group treated with 5 mg/day rosuvastatin or a control group. Primary endpoint is the changes in volume and composition of AAPs after 6 months using transesophageal echocardiography (TEE). Biochemical findings are analyzed. By using repeated TEE and binary image analysis, we will be able to compare the dynamic changes in plaque composition of AAPs before and after therapy in the two groups. The EPISTEME trial will provide information on the changes in plaque volume and composition achieved by improvement of lipid profiles with rosuvastatin therapy in stroke patients with aortic atherosclerosis. The results of the study may provide evidence for a therapeutic strategy for aortogenic brain embolism. This study is registered with UMIN-CTR (UMIN000010548).

Effect of rosuvastatin on coronary atheroma in stable coronary artery disease: multicenter coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS).

PubMed

Takayama, Tadateru; Hiro, Takafumi; Yamagishi, Masakazu; Daida, Hiroyuki; Hirayama, Atsushi; Saito, Satoshi; Yamaguchi, Tetsu; Matsuzaki, Masunori

2009-11-01

It has been suggested that intensive lipid-lowering therapy using statins significantly decreases atheromatous plaque volume. The effect of rosuvastatin on plaque volume in patients with stable coronary artery disease (CAD), including those receiving prior lipid-lowering therapy, was examined in the present study. A 76-week open-label trial was performed at 37 centers in Japan. Eligible patients began treatment with rosuvastatin 2.5 mg/day, which could be increased at 4-week intervals to

Bergamot polyphenolic fraction enhances rosuvastatin-induced effect on LDL-cholesterol, LOX-1 expression and protein kinase B phosphorylation in patients with hyperlipidemia.

PubMed

Gliozzi, Micaela; Walker, Ross; Muscoli, Saverio; Vitale, Cristiana; Gratteri, Santo; Carresi, Cristina; Musolino, Vincenzo; Russo, Vanessa; Janda, Elzbieta; Ragusa, Salvatore; Aloe, Antonio; Palma, Ernesto; Muscoli, Carolina; Romeo, Franco; Mollace, Vincenzo

2013-12-10

Statins are the most commonly prescribed drugs to reduce cardiometabolic risk. Besides the well-known efficacy of such compounds in both preventing and treating cardiometabolic disorders, some patients experience statin-induced side effects. We hypothesize that the use of natural bergamot-derived polyphenols may allow patients undergoing statin treatment to reduce effective doses while achieving target lipid values. The aim of the present study is to investigate the occurrence of an enhanced effect of bergamot-derived polyphenolic fraction (BPF) on rosuvastatin-induced hypolipidemic and vasoprotective response in patients with mixed hyperlipidemia. A prospective, open-label, parallel group, placebo-controlled study on 77 patients with elevated serum LDL-C and triglycerides was designed. Patients were randomly assigned to a control group receiving placebo (n=15), two groups receiving orally administered rosuvastatin (10 and 20mg/daily for 30 days; n=16 for each group), a group receiving BPF alone orally (1000 mg/daily for 30 days; n=15) and a group receiving BPF (1000 mg/daily given orally) plus rosuvastatin (10mg/daily for 30 days; n=15). Both doses of rosuvastatin and BPF reduced total cholesterol, LDL-C, the LDL-C/HDL-C ratio and urinary mevalonate in hyperlipidemic patients, compared to control group. The cholesterol lowering effect was accompanied by reductions of malondialdehyde, oxyLDL receptor LOX-1 and phosphoPKB, which are all biomarkers of oxidative vascular damage, in peripheral polymorphonuclear cells. Addition of BPF to rosuvastatin significantly enhanced rosuvastatin-induced effect on serum lipemic profile compared to rosuvastatin alone. This lipid-lowering effect was associated with significant reductions of biomarkers used for detecting oxidative vascular damage, suggesting a multi-action enhanced potential for BPF in patients on statin therapy. © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

Rosuvastatin prevents angiotensin II-induced vascular changes by inhibition of NAD(P)H oxidase and COX-1

PubMed Central

Colucci, Rocchina; Fornai, Matteo; Duranti, Emiliano; Antonioli, Luca; Rugani, Ilaria; Aydinoglu, Fatma; Ippolito, Chiara; Segnani, Cristina; Bernardini, Nunzia; Taddei, Stefano; Blandizzi, Corrado; Virdis, Agostino

2013-01-01

Background and Purpose NAD(P)H oxidase and COX-1 participate in vascular damage induced by angiotensin II. We investigated the effect of rosuvastatin on endothelial dysfunction, vascular remodelling, changes in extracellular matrix components and mechanical properties of small mesenteric arteries from angiotensin II-infused rats. Experimental Approach Male rats received angiotensin II (120 ng·kg−1·min−1, subcutaneously) for 14 days with or without rosuvastatin (10 mg·kg−1·day−1, oral gavage) or vehicle. Vascular functions and morphological parameters were assessed by pressurized myography. Key Results In angiotensin II-infused rats, ACh-induced relaxation was attenuated compared with controls, less sensitive to L-NAME, enhanced by SC-560 (COX-1 inhibitor) or SQ-29548 (prostanoid TP receptor antagonist), and normalized by the antioxidant ascorbic acid or NAD(P)H oxidase inhibitors. After rosuvastatin, relaxations to ACh were normalized, fully sensitive to L-NAME, and no longer affected by SC-560, SQ-29548 or NAD(P)H oxidase inhibitors. Angiotensin II enhanced intravascular superoxide generation, eutrophic remodelling, collagen and fibronectin depositions, and decreased elastin content, resulting in increased vessel stiffness. All these changes were prevented by rosuvastatin. Angiotensin II increased phosphorylation of NAD(P)H oxidase subunit p47phox and its binding to subunit p67phox, effects inhibited by rosuvastatin. Rosuvastatin down-regulated vascular Nox4/NAD(P)H isoform and COX-1 expression, attenuated the vascular release of 6-keto-PGF1α, and enhanced copper/zinc-superoxide dismutase expression. Conclusion and Implications Rosuvastatin prevents angiotensin II-induced alterations in resistance arteries in terms of function, structure, mechanics and composition. These effects depend on restoration of NO availability, prevention of NAD(P)H oxidase-derived oxidant excess, reversal of COX-1 induction and its prostanoid production, and stimulation of endogenous vascular antioxidant defences. PMID:22817606

Effect of rosuvastatin on the echolucency of the common carotid intima-media in low-risk individuals: the METEOR trial.

PubMed

Lind, Lars; Peters, Sanne A E; den Ruijter, Hester M; Palmer, Mike K; Grobbee, Diederick E; Crouse, John R; O'Leary, Daniel H; Evans, Gregory W; Raichlen, Joel S; Bots, Michiel L

2012-10-01

The echolucency of the carotid intima-media is related to increased cardiovascular risk factor levels, morbidity, and mortality. The aim of this study was to assess the effect of statins on the echolucency of the common carotid intima-media in a low-risk population. Data from the Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin study were used. Ultrasound images from the far walls of the left and right common carotid arteries were used for evaluation of the echolucency of the carotid intima-media, measured by grayscale median (GSM). Low GSM values reflect echolucent structures, whereas high values reflect echogenic structures. The primary end point was the difference in the annual rate of change in GSM between rosuvastatin and placebo. Two-year change in GSM did not significantly differ between rosuvastatin and placebo in the total population, with a mean difference in the rate of change in GSM of 1.13 (95% confidence interval, -1.00 to 3.25). The effect of rosuvastatin differed across quintiles of baseline GSM values (P for interaction = .01). In the lowest quintile (n = 175) (i.e., in those with the most echolucent intima-media), the difference in the rate of change in GSM between rosuvastatin and placebo was 4.18 (95% confidence interval, -0.23 to 8.58). Increases in GSM were significantly related to decreasing low-density lipoprotein cholesterol levels in the lowest quintile (β = 0.76; 95% confidence interval, 0.26 to 1.25). Treatment with rosuvastatin did not affect the echolucency of the arterial wall in all low-risk individuals. However, a potential effect of rosuvastatin on the echolucency of the common carotid intima-media is most likely to be found in individuals with echolucent arterial walls at baseline. Copyright © 2012 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

Impact of intensive lipid lowering on lipid profiles over time and tolerability in stable coronary artery disease: insights from a subanalysis of the coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS).

PubMed

Kawashiri, Masa-Aki; Yamagishi, Masakazu; Sakamoto, Tomohiro; Takayama, Tadateru; Hiro, Takafumi; Daida, Hiroyuki; Hirayama, Atsushi; Saito, Satoshi; Yamaguchi, Tetsu; Matsuzaki, Masunori

2013-12-01

Previous studies have demonstrated that intensive lipid lowering using rosuvastatin results in regression of coronary plaques. However, few data exist regarding lipid profiles over time, drug tolerability, and the effects of prior use of lipid lowering agents in patients on rosuvastatin treatment. Therefore, we studied these matters in a subanalysis of the Coronary Atherosclerosis Study Measuring Effects of Rosuvastatin Using Intravascular Ultrasound in Japanese Subjects (COSMOS). Rosuvastatin was titrated for 76 weeks to attain LDL-C < 80 mg/dL in 213 Japanese dyslipidemic patients with CAD. Clinic visits were scheduled for every 4 weeks during the 76-week study period. Changes over time in lipid parameters, changes in those according to prior lipid-lowering therapy, and changes in those according to baseline lipid levels were evaluated in this subanalysis. Overall, 126 patients completed the study. The mean rosuvastatin dose at the last observation carried forward was 16.9 mg (range, 2.5-20 mg). Rosuvastatin significantly increased HDL-C, lowered LDL-C, and improved the LDL-C/HDL-C ratio (all, P < 0.0001). Increases in serum HDL-C levels were significantly greater in patients with HDL-C < 40 mg/dL than in those with HDL-C ≥ 40 mg/dL at baseline (P = 0.0005). The estimated glomerular filtration rate increased significantly by 2.84 ± 9.01 mL/min/1.73 m(2) (P < 0.0001). Of 166 adverse events in 74 patients, 113 events in 54 patients were laboratory values beyond the normal range. Rosuvastatin significantly improved lipid profiles, with an acceptable safety profile, contributing to plaque regression in Japanese patients with CAD. © 2013 John Wiley & Sons Ltd.

Influences of age, sex, and LDL-C change on cardiovascular risk reduction with pravastatin treatment in elderly Japanese patients: A post hoc analysis of data from the Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE)

PubMed Central

Ouchi, Yasuyoshi; Ohashi, Yasuo; Ito, Hideki; Saito, Yasushi; Ishikawa, Toshitsugu; Akishita, Masahiro; Shibata, Taro; Nakamura, Haruo; Orimo, Hajime

2006-01-01

Background: The Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE) found that the prevalence of cardiovascular events (CVEs) was significantly lower with standard-dose (10–20 mg/d) pravastatin treatment compared with low-dose (5 mg/d) pravastatin treatment in elderly (aged ⩾ 60 years) Japanese patients with hypercholesterolemia. Small differences in on-treatment total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels between the 2 dose groups in the PATE study were associated with significant differences in CVE prevalence. However, the reasons for these differences have not been determined. How sex and age differences influence the effectiveness of pravastatin also remains unclear. Objectives: The aims of this study were to determine the relationship between reduction in LDL-C level and CVE risk reduction in the PATE study and to assess the effects of sex and age on the effectiveness of pravastatin treatment (assessed using CVE risk reduction). Methods: In this post hoc analysis, Cox regression analysis was performed to study the relationship between on-treatment (pravastatin 5–20 mg/d) LDL-C level and CVE risk reduction using age, sex, smoking status, presence of diabetes mellitus and/or hypertension, history of cardiovascular disease (CVD), and high-density lipoprotein cholesterol level as adjustment factors. To explore risk reduction due to unspecified mechanisms other than LDLrC reduction, an estimated Kaplan-Meier curve from the Cox regression analysis was calculated and compared with the empirical (observed) Kaplan-Meier curve. Results: A total of 665 patients (527 women, 138 men; mean [SD] age, 72.8 [5.7] years) were enrolled in PATE and were followed up for a mean of 3.9 years (range, 3–5 years). Of those patients, 50 men and 173 women were ⩾75 years of age. Data from 619 patients were included in the present analysis. In the calculation of model-based Kaplan-Meier curves, data from an additional 32 patients were excluded from the LDL-C analysis because there were no data on pretreatment LDL levels; hence, the data from 587 patients were analyzed. A reduction in LDL-C level of 20 mg/dL was associated with an estimated CVE risk reduction of 24.7% (hazard ratio [HR] = 0.753; 95% CI, 0.625-0.907; P = 0.003). Risk was reduced by 22.2% in patients aged <75 years (HR = 0.778; 95% CI, 0.598–1.013; P = NS) and 29.9% in patients aged ⩾75 years (HR = 0.701; 95% CI, 0.526–0.934; P = 0.015). The risk reductions were 19.8% in women (HR = 0.802; 95% CI, 0.645–0.996; P = 0.046) and 35.8% in men (HR = 0.642; 95% CI, 0.453–0.911; P = 0.013). The risk reduction was 32.4% in patients without a history of CVD at enrollment (HR = 0.676; 95% CI, 0.525–0.870; P = 0.002) and 15.1% in those with a history of CVD (HR = 0.849; 95% CI, 0.630–1.143; P= NS). The estimated Kaplan-Meier curve strongly suggested that the effects of pravastatin were only partially associated with changes in LDLrC level. Conclusions: The results from this post hoc analysis suggest that pravastatin 5 to 20 mg/d might elicit CVE risk reduction by mechanisms other than cholesterol-lowering effects alone. They also suggest that pravastatin treatment might be effective in reducing the risk for CVEs in both female and male patients aged ⩾75 years. PMID:24678100

Influences of age, sex, and LDL-C change on cardiovascular risk reduction with pravastatin treatment in elderly Japanese patients: A post hoc analysis of data from the Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE).

PubMed

Ouchi, Yasuyoshi; Ohashi, Yasuo; Ito, Hideki; Saito, Yasushi; Ishikawa, Toshitsugu; Akishita, Masahiro; Shibata, Taro; Nakamura, Haruo; Orimo, Hajime

2006-07-01

The Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE) found that the prevalence of cardiovascular events (CVEs) was significantly lower with standard-dose (10-20 mg/d) pravastatin treatment compared with low-dose (5 mg/d) pravastatin treatment in elderly (aged ⩾ 60 years) Japanese patients with hypercholesterolemia. Small differences in on-treatment total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels between the 2 dose groups in the PATE study were associated with significant differences in CVE prevalence. However, the reasons for these differences have not been determined. How sex and age differences influence the effectiveness of pravastatin also remains unclear. The aims of this study were to determine the relationship between reduction in LDL-C level and CVE risk reduction in the PATE study and to assess the effects of sex and age on the effectiveness of pravastatin treatment (assessed using CVE risk reduction). In this post hoc analysis, Cox regression analysis was performed to study the relationship between on-treatment (pravastatin 5-20 mg/d) LDL-C level and CVE risk reduction using age, sex, smoking status, presence of diabetes mellitus and/or hypertension, history of cardiovascular disease (CVD), and high-density lipoprotein cholesterol level as adjustment factors. To explore risk reduction due to unspecified mechanisms other than LDLrC reduction, an estimated Kaplan-Meier curve from the Cox regression analysis was calculated and compared with the empirical (observed) Kaplan-Meier curve. A total of 665 patients (527 women, 138 men; mean [SD] age, 72.8 [5.7] years) were enrolled in PATE and were followed up for a mean of 3.9 years (range, 3-5 years). Of those patients, 50 men and 173 women were ⩾75 years of age. Data from 619 patients were included in the present analysis. In the calculation of model-based Kaplan-Meier curves, data from an additional 32 patients were excluded from the LDL-C analysis because there were no data on pretreatment LDL levels; hence, the data from 587 patients were analyzed. A reduction in LDL-C level of 20 mg/dL was associated with an estimated CVE risk reduction of 24.7% (hazard ratio [HR] = 0.753; 95% CI, 0.625-0.907; P = 0.003). Risk was reduced by 22.2% in patients aged <75 years (HR = 0.778; 95% CI, 0.598-1.013; P = NS) and 29.9% in patients aged ⩾75 years (HR = 0.701; 95% CI, 0.526-0.934; P = 0.015). The risk reductions were 19.8% in women (HR = 0.802; 95% CI, 0.645-0.996; P = 0.046) and 35.8% in men (HR = 0.642; 95% CI, 0.453-0.911; P = 0.013). The risk reduction was 32.4% in patients without a history of CVD at enrollment (HR = 0.676; 95% CI, 0.525-0.870; P = 0.002) and 15.1% in those with a history of CVD (HR = 0.849; 95% CI, 0.630-1.143; P= NS). The estimated Kaplan-Meier curve strongly suggested that the effects of pravastatin were only partially associated with changes in LDLrC level. The results from this post hoc analysis suggest that pravastatin 5 to 20 mg/d might elicit CVE risk reduction by mechanisms other than cholesterol-lowering effects alone. They also suggest that pravastatin treatment might be effective in reducing the risk for CVEs in both female and male patients aged ⩾75 years.

Simultaneous determination of rosuvastatin and propranolol in their binary mixture by synchronous spectrofluorimetry

NASA Astrophysics Data System (ADS)

El-Abasawi, Nasr M.; Attia, Khalid A. M.; Abo-serie, Ahmad A. M.; Morshedy, Samir; Abdel-Fattah, Ashraf

2018-06-01

Simultaneous determination of rosuvastatin calcium and propranolol hydrochloride using the first derivative synchronous spectrofluorimetry was described. This method involves measuring the synchronous fluorescence of both drugs in ethanol using, Δ λ = 60 nm then the first derivative was recorded and the peak amplitudes were measured at 350 and 374 nm for rosuvastatin calcium and propranolol hydrochloride, respectively. Under the optimum conditions, the linear ranges of rosuvastatin calcium and propranolol hydrochloride were 0.2-2 μg/mL and 0.1-1 μg/mL, respectively. The method was used for quantitative analysis of the drugs in raw materials and pharmaceutical dosage form. The validity of the proposed method was assessed according to an international conference on harmonization (ICH) guidelines.

Cost-effectiveness of rosuvastatin for primary prevention of cardiovascular events according to Framingham Risk Score in patients with elevated C-reactive protein.

PubMed

MacDonald, Gary P

2010-08-01

The Food and Drug Administration (FDA) recently approved rosuvastatin calcium for prevention of cardiovascular events in patients who have elevated levels of high-sensitivity C-reactive protein (hs-CRP) but not overt hyperlipidemia. The FDA's decision was based primarily on research reported by the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) Study Group. The cost-effectiveness of such treatment is unknown. To compare the cost-effectiveness of treatment with rosuvastatin vs standard management, according to Framingham Risk Score (FRS), for the primary prevention of cardiovascular events in patients who have hs-CRP levels of 2.0 mg/L or higher and low-density lipoprotein cholesterol (LDL-C) levels of less than 130 mg/dL. A Markov-type model was used to calculate the incremental cost-effectiveness ratio of rosuvastatin (20 mg daily) vs standard management for the primary prevention of cardiovascular events in patients over a 10-year period. Cost data were obtained from the Centers for Medicare & Medicaid Services and the Red Book drug reference. Health utility measures were obtained from the literature. Cardiovascular event data were obtained directly from the JUPITER Study Group. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted. Treating patients with rosuvastatin to prevent cardiovascular events based on a hs-CRP level greater than 2.0 mg/L and an LDL-C level of 130 mg/dL or lower would result in estimated incremental cost-effectiveness ratios of $35,455 per quality-adjusted life year (QALY) in patients with an FRS greater than 10% and $90,714 per QALY in patients with an FRS less than or equal to 10%. Results of probabilistic sensitivity analysis suggested that in patients with an FRS greater than 10%, the probability that rosuvastatin is considered cost-effective at $50,000 per QALY is approximately 98%. In patients with an FRS less than or equal to 10%, the probability that rosuvastatin is considered cost-effective at $50,000 per QALY is 0%. Compared with standard management, treatment with rosuvastatin is a cost-effective strategy over a 10-year period for preventing cardiovascular events in patients with FRS greater than 10%, elevated hs-CRP levels, and normal LDL-C levels.

Cost-Effectiveness Analysis of Atorvastatin versus Rosuvastatin in Primary and Secondary Cardiovascular Prevention Populations in Brazil and Columbia.

PubMed

Mould-Quevedo, Joaquín F; Gutiérrez-Ardila, Magda Vianey; Ordóñez Molina, Jaime Eduardo; Pinsky, Brett; Vargas Zea, Nicolás

2014-12-01

Latin America has witnessed a marked increase in cardiovascular (CV) disease, the leading cause of death in many countries. The benefits of lipid-lowering therapy to reduce CV-related events are widely accepted. Clinical evidence suggests that rosuvastatin is associated with slightly greater reductions in low-density lipoprotein cholesterol levels than is atorvastatin at comparable doses. Rosuvastatin, however, is often priced at a premium. Our objective was to examine the cost-effectiveness of using atorvastatin versus rosuvastatin in reducing CV events in Brazil and Colombia using real-world prices. A global Markov cohort model of primary and secondary CV prevention was developed and adapted to Brazilian and Colombian settings. The risks and costs of major CV events and efficacy, adherence, and costs of statins were considered. Total gains in life-years, quality-adjusted life-years, major CV events avoided, and costs over the lifetime horizon were estimated. Several dose comparisons were considered. In the Colombian analyses, differences in drug costs between therapies were considerable while outcomes were similar. The incremental cost per quality-adjusted life-year gained for rosuvastatin versus atorvastatin was more than $700,000 and $200,000 in primary and secondary prevention, respectively. Brazilian analyses found lower incremental cost-effectiveness ratios for rosuvastatin at some dose comparisons due to similar pricing between statins. Sensitivity analyses revealed that changes in treatment efficacy and adherence had the largest impact on results. In primary and secondary CV prevention, the efficacy advantage of rosuvastatin was minimal, while its acquisition cost was higher, particularly in Colombia. The incremental cost-effectiveness ratios were, therefore, generally in favor of atorvastatin being the cost-effective option. Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor.

PubMed

Kulmatycki, Kenneth; Hanna, Imad; Meyers, Dan; Salunke, Atish; Movva, Aishwarya; Majumdar, Tapan; Natrillo, Adrienne; Vapurcuyan, Arpine; Rebello, Sam; Sunkara, Gangadhar; Chen, Jin

2015-05-01

An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.

Baseline triglyceride levels and insulin sensitivity are major determinants of the increase of LDL particle size and buoyancy induced by rosuvastatin treatment in patients with primary hyperlipidemia.

PubMed

Kostapanos, Michael S; Milionis, Haralampos J; Lagos, Konstantinos G; Rizos, Christos B; Tselepis, Alexandros D; Elisaf, Moses S

2008-08-20

The influence of various statins on low-density-lipoprotein (LDL)-particle phenotype has been reportedly trivial or moderate. We assessed the effect of rosuvastatin (the newest statin available) on the LDL subfraction profile in patients with primary hyperlipidemia. One hundred and twenty patients with primary hyperlipidemia without evidence of cardiovascular disease were randomized to therapeutic lifestyle modification ('control' group, N=60) or therapeutic lifestyle modification plus rosuvastatin 20 mg/day (N=60). Laboratory evaluation was performed at baseline and 12 weeks post-treatment. LDL subfraction analysis was carried out electrophoretically using of high-resolution 3% polyacrylamide gel tubes and the Lipoprint LDL System. Rosuvastatin induced a redistribution of LDL-cholesterol from small-dense LDL particles to large-buoyant ones and increased the mean LDL particle size. This beneficial effect was observed only in patients with baseline triglyceride levels >or=150 mg/dl (mean LDL particle size 255+/-7 A vs 260+/-5 A, P<0.01), whereas the LDL subfraction profile was not altered in those with triglyceride levels <150 mg/dl. Stepwise multivariate linear regression analysis revealed that baseline triglyceride levels (R(2)=0.29, P=0.001) followed by baseline insulin resistance as assessed by the HOmeostasis Model Assessment (HOMA) (R(2)=0.25, P=0.001) were independently associated with the rosuvastatin-induced increase in the mean LDL particle size. In conclusion, rosuvastatin at 20 mg/day favorably modified the relative distribution of LDL-cholesterol distribution on LDL subfractions as well as on the mean LDL particle size in patients treated for primary dyslipidemia. Baseline triglyceride levels as well as baseline HOMA-index were found to be the major predictors of this beneficial action of rosuvastatin.

Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice: a clue to the disputed effect of statins on HDL.

PubMed

Marchesi, Marta; Parolini, Cinzia; Caligari, Silvia; Gilio, Donatella; Manzini, Stefano; Busnelli, Marco; Cinquanta, Paola; Camera, Marina; Brambilla, Marta; Sirtori, Cesare R; Chiesa, Giulia

2011-11-01

Besides a significant reduction of low-density lipoprotein (LDL) cholesterol, statins moderately increase high-density lipoprotein (HDL) levels. In vitro studies have indicated that this effect may be the result of an increased expression of apolipoprotein (apo)A-I, the main protein component of HDL. The aim of the present study was to investigate in vivo the effect of rosuvastatin on apoA-I expression and secretion in a transgenic mouse model for human apoA-I. Human apoA-I transgenic mice were treated for 28 days with 5, 10 or 20 mg·kg(-1) ·day(-1) of rosuvastatin, the most effective statin in raising HDL levels. Possible changes of apoA-I expression by treatment were investigated by quantitative real-time RT-PCR on RNA extracted from mouse livers. The human apoA-I secretion rate was determined in primary hepatocytes isolated from transgenic mice from each group after treatment. Rosuvastatin treatment with 5 and 10 mg·kg(-1) ·day(-1) did not affect apoA-I plasma levels, whereas a significant decrease was observed in mice treated with 20 mg·kg(-1) ·day(-1) of rosuvastatin (-16%, P < 0.01). Neither relative hepatic mRNA concentrations of apoA-I nor apoA-I secretion rates from primary hepatocytes were influenced by rosuvastatin treatment at each tested dose. In human apoA-I transgenic mice, rosuvastatin treatment does not increase either apoA-I transcription and hepatic secretion, or apoA-I plasma levels. These results support the hypothesis that other mechanisms may account for the observed HDL increase induced by statin therapy in humans. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9[S

PubMed Central

Ason, Brandon; Tep, Samnang; Davis, Harry R.; Xu, Yiming; Tetzloff, Glen; Galinski, Beverly; Soriano, Ferdie; Dubinina, Natalya; Zhu, Lei; Stefanni, Alice; Wong, Kenny K.; Tadin-Strapps, Marija; Bartz, Steven R.; Hubbard, Brian; Ranalletta, Mollie; Sachs, Alan B.; Flanagan, W. Michael; Strack, Alison; Kuklin, Nelly A.

2011-01-01

Reducing circulating LDL-cholesterol (LDL-c) reduces the risk of cardiovascular disease in people with hypercholesterolemia. Current approaches to reduce circulating LDL-c include statins, which inhibit cholesterol synthesis, and ezetimibe, which blocks cholesterol absorption. Both elevate serum PCSK9 protein levels in patients, which could attenuate their efficacy by reducing the amount of cholesterol cleared from circulation. To determine whether PCSK9 inhibition could enhance LDL-c lowering of both statins and ezetimibe, we utilized small interfer­ing RNAs (siRNAs) to knock down Pcsk9, together with ezetimibe, rosuvastatin, and an ezetimibe/rosuvastatin combination in a mouse model with a human-like lipid profile. We found that ezetimibe, rosuvastatin, and ezetimibe/rosuvastatin combined lower serum cholesterol but induce the expression of Pcsk9 as well as the Srebp-2 hepatic cholesterol biosynthesis pathway. Pcsk9 knockdown in combination with either treatment led to greater reductions in serum non-HDL with a near-uniform reduction of all LDL-c subfractions. In addition to reducing serum cholesterol, the combined rosuvastatin/ezetimibe/Pcsk9 siRNA treatment exhibited a significant reduction in serum APOB protein and triglyceride levels. Taken together, these data provide evidence that PCSK9 inhibitors, in combination with current therapies, have the potential to achieve greater reductions in both serum cholesterol and triglycerides. PMID:21262787

The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study.

PubMed

Hosomi, Naohisa; Nagai, Yoji; Kohriyama, Tatsuo; Ohtsuki, Toshiho; Aoki, Shiro; Nezu, Tomohisa; Maruyama, Hirofumi; Sunami, Norio; Yokota, Chiaki; Kitagawa, Kazuo; Terayama, Yasuo; Takagi, Makoto; Ibayashi, Setsuro; Nakamura, Masakazu; Origasa, Hideki; Fukushima, Masanori; Mori, Etsuro; Minematsu, Kazuo; Uchiyama, Shinichiro; Shinohara, Yukito; Yamaguchi, Takenori; Matsumoto, Masayasu

2015-09-01

Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 ± 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. Although whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. This study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.

Effects of a statin group drug, pravastatin, on the insulin resistance in patients with metabolic syndrome.

PubMed

Güçlü, Feyzullah; Ozmen, Bilgin; Hekimsoy, Zeliha; Kirmaz, Cengiz

2004-12-01

In West of Scotland Coronary Prevention Study (WOSCOPS), development of type 2 diabetes mellitus (DM) was found to decrease by 30% in pravastatin-treated patients. In the study, it is suggested that pleiotropic effects of pravastatin may be responsible too as well as its lipid lowering effect. The aim of this study was to assess the effects of pravastatin treatment on the insulin resistance in patients with metabolic syndrome with impaired glucose tolerance (IGT), by Homeostasis Model Assessment (HOMA) test, insulin sensitivity indices and glucose half activation time (glucose t1/2). Study population consisted of 25 women who were diagnosed with metabolic syndrome. At baseline and 10 weeks after the 20 mg/daily tablet pravastatin treatment, waist/hip circumference, body weight and arterial blood pressure measurements, plasma glucose, total cholesterol, triglyceride, high density lipoprotein (HDL)-cholesterol, transaminases, glycosylated haemoglobin (A1C) and insulin level measurements were obtained along with HOMA test and insulin tolerance test after 12 h of fasting. Insulin sensitivity indices and glucose t1/2 were assessed. After the treatment, a statistically significant decrease was observed in arterial blood pressure values (P < 0.0001). While plasma total cholesterol, low density lipoprotein (LDL)-cholesterol, and triglyceride levels were found to decrease significantly and HDL-cholesterol levels increased significantly, a decrease in baseline insulin levels, an increase in insulin sensitivity levels were observed along with an decrease in glucose t1/2. Related to the improvement in aforementioned parameters, statistically significant decreases were noted in HOMA, postprandial and fasting glucose levels and A1C values (P < 0.0001). Our study suggests that using pravastatin in the dyslipidemia treatment of metabolic syndrome with IGT may be an effective approach by its advantageous effects on insulin resistance. Based on this result, it is possible to say that this can be a risk lowering treatment approach for the development of type 2 DM.

13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis

PubMed Central

Walker, Mary E.; Souza, Patricia R.; Colas, Romain A.; Dalli, Jesmond

2017-01-01

Rheumatoid arthritis is an inflammatory condition characterized by overzealous inflammation that leads to joint damage and is associated with an increased incidence of cardiovascular disease. Statins are frontline therapeutics for patients with cardiovascular disease and exert beneficial actions in rheumatoid arthritis. The mechanism that mediates the beneficial actions of statins in rheumatoid arthritis remains of interest. In the present study, we found that the administration of 2 clinically relevant statins—atorvastatin (0.2 mg/kg) or pravastatin (0.2 mg/kg)—to mice during inflammatory arthritis up-regulated systemic and tissue amounts of a novel family of proresolving mediators, termed 13-series resolvins (RvTs), and significantly reduced joint disease. Of note, administration of simvastatin (0.2 mg/kg) did not significantly up-regulate RvTs or reduce joint inflammation. We also found that atorvastatin and pravastatin each reduced systemic leukocyte activation, including platelet-monocyte aggregates (∼25–60%). These statins decreased neutrophil trafficking to the joint as well as joint monocyte and macrophage numbers. Atorvastatin and pravastatin produced significant reductions (∼30–50%) in expression of CD11b and major histocompatibility complex class II on both monocytes and monocyte-derived macrophages in joints. Administration of an inhibitor to cyclooxygenase-2, the initiating enzyme in the RvT pathway, reversed the protective actions of these statins on both joint and systemic inflammation. Together, these findings provide evidence for the role of RvTs in mediating the protective actions of atorvastatin and pravastatin in reducing local and vascular inflammation, and suggest that RvTs may be useful in measuring the anti-inflammatory actions of statins.—Walker, M. E., Souza, P. R., Colas, R. A., Dalli, J. 13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis. PMID:28465323

Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations.

PubMed

Stein, Evan A; Dann, Eldad J; Wiegman, Albert; Skovby, Flemming; Gaudet, Daniel; Sokal, Etienne; Charng, Min-Ji; Mohamed, Mafauzy; Luirink, Ilse; Raichlen, Joel S; Sundén, Mattias; Carlsson, Stefan C; Raal, Frederick J; Kastelein, John J P

2017-08-29

Homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder, is characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerotic cardiovascular disease. Statin treatment starts at diagnosis, but no statin has been formally evaluated in, or approved for, HoFH children. The authors sought to assess the LDL-C efficacy of rosuvastatin versus placebo in HoFH children, and the relationship with underlying genetic mutations. This was a randomized, double-blind, 12-week, crossover study of rosuvastatin 20 mg versus placebo, followed by 12 weeks of open-label rosuvastatin. Patients discontinued all lipid-lowering treatment except ezetimibe and/or apheresis. Clinical and laboratory assessments were performed every 6 weeks. The relationship between LDL-C response and genetic mutations was assessed by adding children and adults from a prior HoFH rosuvastatin trial. Twenty patients were screened, 14 randomized, and 13 completed the study. The mean age was 10.9 years; 8 patients were on ezetimibe and 7 on apheresis. Mean LDL-C was 481 mg/dl (range: 229 to 742 mg/dl) on placebo and 396 mg/dl (range: 130 to 700 mg/dl) on rosuvastatin, producing a mean 85.4 mg/dl (22.3%) difference (p = 0.005). Efficacy was similar regardless of age or use of ezetimibe or apheresis, and was maintained for 12 weeks. Adverse events were few and not serious. Patients with 2 defective versus 2 negative LDL receptor mutations had mean LDL-C reductions of 23.5% (p = 0.0044) and 14% (p = 0.038), respectively. This first-ever pediatric HoFH statin trial demonstrated safe and effective LDL-C reduction with rosuvastatin 20 mg alone or added to ezetimibe and/or apheresis. The LDL-C response in children and adults was related to underlying genetic mutations. (A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia [HYDRA]; NCT02226198). Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Efficacy and safety of fixed-dose combination therapy with olmesartan medoxomil and rosuvastatin in Korean patients with mild to moderate hypertension and dyslipidemia: an 8-week, multicenter, randomized, double-blind, factorial-design study (OLSTA-D RCT: OLmesartan rosuvaSTAtin from Daewoong)

PubMed Central

Park, Jin-Sun; Shin, Joon-Han; Hong, Taek-Jong; Seo, Hong-Seog; Shim, Wan-Joo; Baek, Sang-Hong; Jeong, Jin-Ok; Ahn, Youngkeun; Kang, Woong-Chol; Kim, Young-Hak; Kim, Sang-Hyun; Hyon, Min-Su; Choi, Dong-Hoon; Nam, Chang-Wook; Park, Tae-Ho; Lee, Sang-Chol; Kim, Hyo-Soo

2016-01-01

The pill burden of patients with hypertension and dyslipidemia can result in poor medication compliance. This study aimed to evaluate the efficacy and safety of fixed-dose combination (FDC) therapy with olmesartan medoxomil (40 mg) and rosuvastatin (20 mg) in Korean patients with mild to moderate hypertension and dyslipidemia. This multicenter, randomized, double-blind, factorial-design study included patients aged ≥20 years with mild to moderate essential hypertension and dyslipidemia. Patients were randomly assigned to receive FDC therapy (40 mg olmesartan medoxomil, 20 mg rosuvastatin), 40 mg olmesartan medoxomil, 20 mg rosuvastatin, or a placebo. The percentage change from baseline in low-density lipoprotein cholesterol levels was compared between FDC therapy and olmesartan medoxomil, and the change from baseline in diastolic blood pressure was compared between FDC therapy and rosuvastatin 8 weeks after treatment. A total of 162 patients were included. The least square mean percentage change (standard error) from baseline in low-density lipoprotein cholesterol levels 8 weeks after treatment was significantly greater in the FDC than in the olmesartan medoxomil group (−52.3% [2.8%] vs −0.6% [3.5%], P<0.0001), and the difference was −51.7% (4.1%) (95% confidence interval: −59.8% to −43.6%). The least square mean change (standard error) from baseline in diastolic blood pressure 8 weeks after treatment was significantly greater in the FDC group than in the rosuvastatin group (−10.4 [1.2] mmHg vs 0.1 [1.6] mmHg, P<0.0001), and the difference was −10.5 (1.8) mmHg (95% confidence interval: −14.1 to −6.9 mmHg). There were 50 adverse events in 41 patients (22.7%) and eight adverse drug reactions in five patients (2.8%). The study found that FDC therapy with olmesartan medoxomil and rosuvastatin is an effective, safe treatment for patients with hypertension and dyslipidemia. This combination may improve medication compliance in patients with a large pill burden. PMID:27574399

Effect of rosuvastatin on risk markers for venous thromboembolism in cancer.

PubMed

Ades, S; Douce, D; Holmes, C E; Cory, S; Prior, S; Butenas, S; Callas, P; Cushman, M

2018-06-01

Essentials Statins lower venous thromboembolism risk in general but have not been studied in cancer patients. We completed a randomized trial of rosuvastatin vs. placebo among cancer patients on chemotherapy. Rosuvastatin did not significantly lower prothrombotic biomarkers including D-dimer. The role of statins in venous thrombosis prevention in cancer patients remains unknown. Background Statin therapy is associated with lower risk of venous thromboembolism (VTE) but has not been prospectively evaluated in patients with advanced cancer. Objectives We determined if statin administration in this high-risk population reduces the risk of VTE, based on established and emerging biomarkers. Patients/Methods This double-blind, crossover, randomized controlled trial among patients with advanced cancer receiving systemic therapy allocated participants to rosuvastatin 20 mg daily or placebo for 3-4 weeks prior to crossover to the alternative therapy, with a 3-5-week washout. D-dimer, C-reactive protein (CRP), soluble (s)P-selectin, factor VIII (FVIII), thrombin generation and exploratory biomarkers focusing on endogenous thrombin potential, including tissue factor (TF), activated factor IX (FIXa) and activated factor XI (FXIa), were measured at the start and end of both treatment periods. The primary outcome was change in D-dimer with rosuvastatin compared with placebo. Results Of 38 enrolled participants, 24 (63%) completed the study. Rosuvastatin did not cause statistically significant changes in D-dimer levels or any other biomarker. CRP levels decreased by 40%; 4.3 mg L -1 (95% confidence interval, -11.0 to +2.5 mg L -1 ) compared with placebo. In post-hoc analysis, participants who received rosuvastatin initially during their first line of treatment had a 13% decrease in D-dimer. Circulating TF, FIXa and FXIa were detected in 26%, 68% and 71% of cancer patients despite not being found in healthy individuals. Conclusions Rosuvastatin did not cause favorable changes in biomarkers of VTE risk in advanced cancer patients receiving chemotherapy. The role of statin therapy as thromboprophylaxis in the cancer population remains uncertain. © 2018 International Society on Thrombosis and Haemostasis.

Direct to consumer Internet advertising of statins: an assessment of safety.

PubMed

Williams, Bethan; Brown, David

2012-04-01

To evaluate a sample of Internet sites advertising statins for sale to the general public. A simulated customer search and evaluation of retrieved sites using evaluation tools focussing on quality (Q) and safe medicine use (SMU). Sites retrieved on 17 November 2010 were systematically analysed from 19 November to 23 December 2010. One hundred eighty-four sites met the inclusion criteria: 40 each for atorvastatin, pravastatin, rosuvastatin, and simvastatin and 24 for fluvastatin. Sites originated from 17 different countries. Most sites scored less than half the maximum Q score (26; range 5-17). Mean total SMU scores for each statin group were lower than 50% of the maximum (45; range of 0-28). There were no statistically significant differences between statins. General contraindications were absent in 92.4% of sites and contraindicated medicines in 47.3%. Key warnings on the appearance of symptoms associated with myopathy, liver disease, hypersensitivity, and pancreatitis were absent in 37, 48.4, 91.3, and 96.2% of sites, respectively. Most websites presented a chaotic and incomplete list of known side effects; just 13 (7.1%) presented a list compatible with current prescribing information. Only two-thirds (65.8%) attempted to describe any in lay language. A potential purchaser of statins is likely to encounter websites from a wide geographical base and of generally poor quality. This has potentially serious implications for the safety of purchasers who may not be aware of the problems associated with ordering medicines online or the actual medication, which they receive. Direct to consumer advertising websites need tighter controls. Copyright © 2012 John Wiley & Sons, Ltd.

A Modified Procedure for Estimating the Impact of the Uptake on the Overall Biliary Clearance in Sandwich Culture of Rat Hepatocytes.

PubMed

Jemnitz, Katalin; Szabo, Monika; Batai-Konczos, Attila; Szabo, Pal; Magda, Balazs; Veres, Zsuzsa

2015-01-01

Sandwich culture of hepatocytes is commonly applied for the prediction of in vivo biliary clearance (CLbil). In this paper, we present a modified procedure for the determination of in vitro CLbil in sandwich culture of rat hepatocytes, which allows the estimation of the impact of uptake processes on the overall CLbil. The main point of this modification is the separation of uptake and efflux processes. Ten drugs from four biopharmaceutics drug disposition classification system classes were chosen in order to demonstrate the advantages of this method: 1) the uptake is performed identically before the canaliculi are opened, thus the efflux starts at the same intracellular concentration of the drugs and the effect of Ca2+/Mg2+ depletion on the uptake is excluded; 2) exact intracellular concentrations can be measured at the start and at the end of the efflux; 3) the biliary clearance can be determined irrespective of the uptake; 4) the canalicular and the sinusoidal transport can be measured simultaneously; 5) drug-drug interactions concerning uptake and efflux transporters can be estimated independently. Depending on the degree of uptake, CLbil,app (calculated using the concentration of drugs in the medium) was significantly higher (sulfasalazine, fluvastatin, rosuvastatin, atorvastatin) or lower (pravastatin, procainamide) than CLbil,int (calculated using the intracellular concentration of drugs). When the uptake had no impact on the CLbil, the apparent and intrinsic CLbil did not differ significantly (lovastatin, rifampicin, quetiapine). Our results confirm that transporters may play a significant role in the uptake of drugs both with high and poor permeability and solubility.

Simultaneous determination of rosuvastatin and propranolol in their binary mixture by synchronous spectrofluorimetry.

PubMed

El-Abasawi, Nasr M; Attia, Khalid A M; Abo-Serie, Ahmad A M; Morshedy, Samir; Abdel-Fattah, Ashraf

2018-06-05

Simultaneous determination of rosuvastatin calcium and propranolol hydrochloride using the first derivative synchronous spectrofluorimetry was described. This method involves measuring the synchronous fluorescence of both drugs in ethanol using, ∆ λ = 60 nm then the first derivative was recorded and the peak amplitudes were measured at 350 and 374 nm for rosuvastatin calcium and propranolol hydrochloride, respectively. Under the optimum conditions, the linear ranges of rosuvastatin calcium and propranolol hydrochloride were 0.2-2 μg/mL and 0.1-1 μg/mL, respectively. The method was used for quantitative analysis of the drugs in raw materials and pharmaceutical dosage form. The validity of the proposed method was assessed according to an international conference on harmonization (ICH) guidelines. Copyright © 2018 Elsevier B.V. All rights reserved.

Protective effects of low-dose rosuvastatin on isoproterenol-induced chronic heart failure in rats by regulation of DDAH-ADMA-NO pathway.

PubMed

Zhou, Ru; Ma, Ping; Xiong, Aiqin; Xu, Yehua; Wang, Yang; Xu, Qingbin

2017-04-01

Cardiovascular disease is the leading cause of death with high morbidity and mortality, and chronic heart failure is the terminal phase of it. This study aimed to investigate the protective effects of the low-dose rosuvastatin on isoproterenol-induced chronic heart failure and to explore the possible related mechanisms. Male Sprague Dawley rats were given isoproterenol 5 mg/kg once a day for 7 days to establish heart failure model by subcutaneous injection. Simultaneously, low-dose rosuvastatin (5 mg/kg) was orally administrated from day 1 to day 14. Protective effects were evaluated by hemodynamic parameter, histopathological variables, serum asymmetric dimethylarginine (ADMA), cardiac troponin I (cTnI), brain natriuretic peptide (BNP) and myocardial nitric oxide (NO), and the levels of dimethylarginine dimethylaminohydrolase 2 (DDAH2), arginine methyltransferases 1 (PRMT1) and endothelial nitric oxide synthase (eNOS) expression were analyzed. Therapeutic rosuvastatin (5 mg/kg) significantly attenuated isoproterenol-induced hypertrophy, remodeling and dysfunction of ventricle, reduced the increased serum content of ADMA, cTnI, and BNP, and elevated myocardial NO in rats (P<.05). Besides, rosuvastatin also significantly inhibited fibrosis of myocardium, normalized the increased PRMT1 and decreased DDAH2 expression. Low-dose rosuvastatin exerted cardioprotective effects on isoproterenol-induced heart failure in rats by modulating DDAH-ADMA-NO pathway, and it may present the new therapeutic value in ameliorating chronic heart failure. © 2016 John Wiley & Sons Ltd.

Rosuvastatin Attenuates the Elevation in Blood Pressure Induced by Overexpression of Human C-Reactive Protein

PubMed Central

Li, Xuguang; Yang, Guangtian; Edin, Matthew L.; Zeldin, Darryl C.; Wang, Dao Wen

2014-01-01

Background Our previous studies demonstrated that C-reactive protein (CRP) acts as an inflammatory factor to induce endothelial dysfunction and hypertension in rats. The anti-inflammatory effects of statins suggest that they may attenuate CRP-induced endothelial dysfunction and hypertension in Sprague Dawley (SD) rats. Methods Male SD rats were injected with an adeno-associated virus (AAV) to induce overexpression of human CRP (AAV-hCRP) or GFP control (AAV-GFP). Two months after injection, rats were administered rosuvastatin by daily oral gavage (10 mg/kg) for two additional months. Blood pressure was monitored, serum hCRP concentrations were assessed by ELISA, and vascular levels of endothelial nitric oxide synthase (eNOS), PI3K/Akt, Rho kinase, angiotensin type 1 (AT1) receptor, MAPK, SOD-1, and NADPH oxidase was determined by immunoblotting. Results Rosuvastatin administration attenuated the increased blood pressure and loss of vascular eNOS expression in AAV-hCRP-treated rats. Rosuvastatin also activated PI3K/Akt, inhibited Rho kinase activity, and downregulated the AT1 receptor expression in aorta. Rosuvastatin reduced production of ROS through downregulation of NADPH oxidase subunit p22 phox and gp91 phox, and upregulation of SOD-1 expression. Conclusions Rosuvastatin attenuated the increase in blood pressure in AAV-hCRP-treated rats through endothelial protection and antioxidant effects. Our data reveals a novel mechanism through which statins may lower blood pressure and suggests the potential use of statins in the treatment of hypertension. PMID:21562509

Ascorbic acid co-administered with rosuvastatin reduces reproductive impairment in the male offspring from male rats exposed to the statin at pre-puberty.

PubMed

Leite, Gabriel Adan Araújo; Figueiredo, Thamiris Moreira; Guerra, Marina Trevizan; Borges, Cibele Dos Santos; Fernandes, Fábio Henrique; Anselmo-Franci, Janete Aparecida; Kempinas, Wilma De Grava

2018-05-18

Obesity during childhood and adolescence is closely related to dysfunctions on lipid profile in children. Rosuvastatin is a statin that decreases serum total cholesterol. Ascorbic acid is an important antioxidant compound for male reproduction. Pre-pubertal male rats were distributed into six experimental groups that received saline solution 0.9% (vehicle), 3 or 10 mg/kg/day of rosuvastatin, 150 mg/day of ascorbic acid, or 3 or 10 mg/kg/day of rosuvastatin co-administered with 150 mg/day of ascorbic acid by gavage from post-natal day (PND)23 until PND53. Rats were maintained until adulthood and mated with nulliparous females to obtain the male offspring, whose animals were evaluated at adulthood in relation to reproductive parameters. This study is a follow up of a previous paper addressing potential effects on F0 generation only (Leite et al., 2017). Male offspring from rosuvastatin-exposed groups showed increased sperm DNA fragmentation, androgen depletion and impairment on the testicular and epididymal structure. Ascorbic acid coadministered to the fathers ameliorated the reproductive damage in the offspring. In summary, paternal exposure to rosuvastatin may affect the reproduction in the male offspring; however, paternal supplementation with ascorbic acid was able to reduce the reproductive impairment in the male offspring caused by statin treatment to the fathers. Copyright © 2018 Elsevier Ltd. All rights reserved.

Limited Sampling Strategy for the Prediction of Area Under the Curve (AUC) of Statins: Reliability of a Single Time Point for AUC Prediction for Pravastatin and Simvastatin.

PubMed

Srinivas, N R

2016-02-01

Statins are widely prescribed medicines and are also available in fixed dose combinations with other drugs to treat several chronic ailments. Given the safety issues associated with statins it may be important to assess feasibility of a single time concentration strategy for prediction of exposure (area under the curve; AUC). The peak concentration (Cmax) was used to establish relationship with AUC separately for pravastatin and simvastatin using published pharmacokinetic data. The regression equations generated for statins were used to predict the AUC values from various literature references. The fold difference of the observed divided by predicted values along with correlation coefficient (r) were used to judge the feasibility of the single time point approach. Both pravastatin and simvastatin showed excellent correlation of Cmax vs. AUC values with r value ≥ 0.9638 (p<0.001). The fold difference was within 0.5-fold to 2-fold for 220 out of 227 AUC predictions and >81% of the predicted values were in a narrower range of >0.75-fold but <1.5-fold difference. Predicted vs. observed AUC values showed excellent correlation for pravastatin (r=0.9708, n=115; p<0.001) and simvastatin (r=0.9810; n=117; p<0.001) suggesting the utility of Cmax for AUC predictions. On the basis of the present work, it is feasible to develop a single concentration time point strategy that coincides with Cmax occurrence for both pravastatin and simvastatin from a therapeutic drug monitoring perspective. © Georg Thieme Verlag KG Stuttgart · New York.

Role of Glyceraldehyde-Derived AGEs and Mitochondria in Superoxide Production in Femoral Artery of OLETF Rat and Effects of Pravastatin.

PubMed

Hori, Eisei; Kikuchi, Chigusa; Nagami, Chie; Kajikuri, Junko; Itoh, Takeo; Takeuchi, Masayoshi; Matsunaga, Tamihide

2017-11-01

A complication of diabetes mellitus is the over-production of vascular superoxides, which contribute to the development of arteriosclerosis and peripheral arterial disease (PAD). Hyperglycemia induces the formation and accumulation of advanced glycation end-products (AGEs), which in turn stimulate vascular superoxide production. The mechanism underlying AGE-mediated vascular superoxide production remains to be clarified in lower limb complications associated with diabetes. In the present study, we investigated the role of AGEs and the mitochondrial respiratory complex in superoxide production in femoral arteries using the type 2 diabetes model Otsuka Long-Evans Tokushima Fatty (OLETF) rats [vs. non-diabetic Long-Evans Tokushima Otsuka (LETO) rats]. The effects of in vivo administration of pravastatin on superoxide production in femoral arteries were also examined. Using chemiluminescent assays, luminescence microscopy, and competitive enzyme-linked immunosorbent assay (ELISA), we determined that vascular superoxide production and serum glyceraldehyde-derived AGEs (Glycer-AGEs) increased in OLETF rats. Pravastatin inhibited these responses without changing serum total cholesterol concentrations. The mitochondrial complex II inhibitor thenoyltrifluoroacetone (TTFA) also inhibited vascular superoxide production. Application of Glycer-AGEs in situ increased superoxide production in the vascular wall of femoral arteries from pravastatin-treated OLETF rats, which was then inhibited by TTFA. These results suggest that hyperglycemia increases serum Glycer-AGEs, which subsequently induce superoxide production in the femoral artery of OLETF rats in a mitochondrial complex II-dependent manner. Collectively, our results have partially elucidated the pathological mechanisms leading to diabetes-related PAD, and indicate dual beneficial actions of pravastatin for the prevention of oxidative damage to the vascular wall.

A New Improved RP-HPLC Method for Assay of Rosuvastatin Calcium in Tablets

PubMed Central

Kaila, H. O.; Ambasana, M. A.; Thakkar, R. S.; Saravaia, H. T.; Shah, A. K.

2010-01-01

A reliable and sensitive isocratic stability indicating RP-HPLC method has been developed and validated for assay of rosuvastatin calcium in tablets and for determination of content uniformity. An isocratic separation of rosuvastatin calcium was achieved on YMC C8, 150×4.6 mm i.d., 5 μm particle size columns with a flow rate of 1.5 ml/min and using a photodiode array detector to monitor the eluate at 242 nm. The mobile phase consisted of acetonitrile: water (40:60, v/v) pH 3.5 adjusted with phosphoric acid. The drug was subjected to oxidation, hydrolysis, photolysis and thermal degradation. All degradation products in an overall analytical run time of approximately 10 min with the parent compound rosuvastatin eluting at approximately 5.2 min. Response was a linear function of drug concentration in the range of 0.5-80 μg/ml (r2= 0.9993) with a limit of detection and quantification of 0.1 and 0.5 μg/ml respectively. Accuracy (recovery) was between 99.6 and 101.7%. Degradation products resulting from the stress studies did not interfere with the detection of rosuvastatin and the assay is thus stability-indicating. PMID:21694991

Statins and nitric oxide donors affect thrombospondin 1-induced chemotaxis.

PubMed

Seymour, Keri; Stein, Jeffrey; Han, Xuan; Maier, Kristopher G; Gahtan, Vivian

2014-01-01

Thrombospondin 1 (TSP-1) induces vascular smooth muscle cell (VSMC) migration and intimal hyperplasia. Statins and nitric oxide (NO) donors decrease intimal hyperplasia. We previously showed that statins (long-term exposure) and NO donors inhibit TSP-1-induced VSMC chemotaxis. (1) Pretreatment with short-term statin will inhibit TSP-1-induced VSMC chemotaxis and (2) NO donors will enhance statin inhibition of TSP-1-induced or platelet-derived growth factor (PDGF)-induced VSMC chemotaxis. We examined these treatment effects on TSP-1-induced VSMC chemotaxis: (1) long-term (20 hours) versus short-term (20 minutes) pravastatin, (2) diethylenetriamine NONOate (DETA/NO) or S-nitroso-N-acetylpenicillamine (SNAP) in combination with pravastatin, and (3) comparison of TSP-1 to PDGF as a chemoattractant. Pravastatin (long term or short term) inhibited TSP-1-induced chemotaxis. Diethylenetriamine NONOate and SNAP impeded statin inhibition of TSP-1-induced chemotaxis. Platelet-derived growth factor and TSP-1 had opposite effects on DETA/NO-pravastatin treatment. Short-term statin pretreatment inhibited TSP-1-induced VSMC chemotaxis, suggesting a pleiotropic effect. High-dose NO reversed statin inhibition of TSP-1-induced chemotaxis, suggesting NO and statin combination therapies warrant further study. © The Author(s) 2014.

Efficacy of Statin Therapy in Inducing Coronary Plaque Regression in Patients with Low Baseline Cholesterol Levels

PubMed Central

Nozue, Tsuyoshi; Yamamoto, Shingo; Tohyama, Shinichi; Fukui, Kazuki; Umezawa, Shigeo; Onishi, Yuko; Kunishima, Tomoyuki; Sato, Akira; Miyake, Shogo; Morino, Yoshihiro; Yamauchi, Takao; Muramatsu, Toshiya; Hibi, Kiyoshi; Terashima, Mitsuyasu; Suzuki, Hiroshi; Michishita, Ichiro

2016-01-01

Aim: The efficacy of statin therapy in inducing coronary plaque regression may depend on baseline cholesterol levels. We aimed to determine the efficacy of statin therapy in inducing coronary plaque regression in statin-naïve patients with low cholesterol levels using serial intravascular ultrasound (IVUS) data from the treatment with statin on atheroma regression evaluated by virtual histology IVUS (TRUTH) study. Methods: The TRUTH study is a prospective, multicenter trial, comparing the efficacies of pitavastatin and pravastatin in coronary plaque regression in 164 patients. All patients were statin-naïve and received statin therapy only after study enrollment. The primary endpoint was the observation of coronary plaque progression, despite statin therapy. Results: Serial IVUS data, at baseline and after an 8-month follow-up, were available for 119 patients. The patients were divided into three groups based on non-high-density lipoprotein cholesterol (HDL-C) levels—low: ≤ 140 mg/dl, n = 38; moderate: 141–169 mg/dl, n = 42; and high: ≥ 170 mg/dl, n = 39. Coronary plaque progression was noted in the low cholesterol group, whereas plaque regression was noted in the moderate and high cholesterol groups [%Δplaque volume: 2.3 ± 7.4 vs. − 2.7 ± 10.7 vs. − 3.2 ± 7.5, p = 0.004 (analysis of variance)]. After adjusting for all variables, a low non-HDLC level (≤ 140 mg/dl) was identified as an independent predictor of coronary plaque progression [odds ratio, 3.7; 95% confidence interval, 1.5–9.1, p = 0.004]. Conclusion: Serial IVUS data analysis indicated that statin therapy was less effective in inducing coronary plaque regression in patients with low cholesterol levels but more effective in those with high cholesterol levels at baseline. University Hospital Medical Information Network (UMIN) (UMIN ID: C000000311). PMID:27040362

Prevention of atherosclerosis in patients living with HIV

PubMed Central

De Lorenzo, Ferruccio; Boffito, Marta; Collot-Teixeira, Sophie; Gazzard, Brian; McGregor, John L; Shotliff, Kevin; Xiao, Han

2009-01-01

Investigational product: Rosuvastatin (Crestor®; Astra Zeneca). Active ingredients: Rosuvastatin (5 mg). Study title: Prevention of Atherosclerosis in Patients Living with HIV. Phase of study: Phase III. Aims: Primary aim: To assess whether rosuvastatin therapy could slow the progression of the carotid intima-media thickness (C-IMT; as measured by the change in the mean IMT of the near and far walls of the distal common carotid arteries) over 2 years in HIV-infected patients (HIV-IP). Secondary aims: To assess whether rosuvastatin therapy could reduce highly sensitive C reactive protein (hs-CRP) inflammatory marker that is increased in HIV-IP.To assess the effect of rosuvastatin therapy on serum lipid levels (total cholesterol [TC], low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol and triglycerides [TG]) and apolipoproteins (APO A1, APO B and APO B/A1).To assess the safety of rosuvastatin in HIV-IP through the evaluation of clinical laboratory analyses (liver function tests and creatine kinase) and adverse events (AEs). Study design: Two-year randomized, double-blind, placebo-controlled, parallel group study. Planned sample size: 320 HIV-IP. Summary of eligibility criteria: HIV-IP who are aged between 30 and 60 years, with a CD4 count. greater than 200 cells/mm3. Patients must be stable on combination antiretroviral therapy (cART) for at least 12 months and have a 10-year CVD risk of less than 20% (using the Framingham risk score). Number of study centers: One. Duration of treatment: Two years (5 mg rosuvastatin or placebo once daily). Dose and route of administration: Oral rosuvastatin (5 mg) once daily. The incidence of cardiovascular disease (CVD) in HIV-IP is at least three times higher than in the general population and further increases each year with combination anti-retroviral therapy (cART). The carotid atherosclerosis progression rate is 10 times higher in HIV-IP than in uninfected individuals. The aim of this study is to assess whether therapy with 5 mg rosuvastatin could: 1) Slow the progression in the mean IMT of the distal common carotid arteries over two years in HIV-IP.2) Change the concentration in the inflammatory marker – hs-CRP, which is increased in HIV-IP.3) Change the concentrations of TC, LDL cholesterol, HDL cholesterol, TG, apolipoproteins (APO) B, APO A1 and APO B/A1.4) Be administered safely in the study population. Pharmacological intervention with rosuvastatin will be evaluated in a double-blind, placebo-controlled, randomized clinical trial in HIV-IP treated with cART not matching the published selection criteria for lipid-lowering therapy. For the first time, this study will investigate anti-inflammatory and anti-atherogenic effects of a pharmacological lipid-lowering agent in HIV-IP that may lead to the reduction of CVD. PMID:19436663

A simple assay for the simultaneous determination of rosuvastatin acid, rosuvastatin-5S-lactone, and N-desmethyl rosuvastatin in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

PubMed

Macwan, Joyce S; Ionita, Ileana A; Akhlaghi, Fatemeh

2012-01-01

A simple and sensitive assay was developed and validated for the simultaneous quantification of rosuvastatin acid (RST), rosuvastatin-5S-lactone (RST-LAC), and N-desmethyl rosuvastatin (DM-RST), in buffered human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). All the three analytes and the corresponding deuterium-labeled (d6) internal standards were extracted from 50 μL of buffered human plasma by protein precipitation. The analytes were chromatographically separated using a Zorbax-SB Phenyl column (2.1 mm × 100 mm, 3.5 μm). The mobile phase comprised of a gradient mixture of 0.1% v/v glacial acetic acid in 10% v/v methanol in water (solvent A) and 40% v/v methanol in acetonitrile (solvent B). The analytes were separated at baseline within 6.0 min using a flow rate of 0.35 mL/min. Mass spectrometry detection was carried out in positive electrospray ionization mode. The calibration curves for all three analytes were linear (R ≥ 0.9964, n = 3) over the concentration range of 0.1-100 ng/mL for RST and RST-LAC, and 0.5-100 ng/mL for DM-RST. Mean extraction recoveries ranged within 88.0-106%. Intra- and inter-run mean percent accuracy were within 91.8-111% and percent imprecision was ≤15%. Stability studies revealed that all the analytes were stable in matrix during bench-top (6 h on ice-water slurry), at the end of three successive freeze and thaw cycles and at -80°C for 1 month. The method was successfully applied in a clinical study to determine the concentrations of RST and the lactone metabolite over 12-h post-dose in patients who received a single dose of rosuvastatin.

Single-dose rosuvastatin ameliorates lung ischemia-reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension.

PubMed

Matsuo, Satoshi; Saiki, Yuriko; Adachi, Osamu; Kawamoto, Shunsuke; Fukushige, Shinichi; Horii, Akira; Saiki, Yoshikatsu

2015-03-01

Lung ischemia-reperfusion (IR) injury during cardiopulmonary surgery is associated with postoperative morbidity and mortality, particularly in patients with pulmonary hypertension (PH). Using a rat model for monocrotaline-induced PH, we investigated the protective effect of rosuvastatin against IR injury in lungs affected by PH and attempted to elucidate its mechanism of action. Male Sprague-Dawley monocrotaline-treated rats were divided into 4 groups (n = 8-9): sham, control + IR, statin + IR, and statin + mevalonolactone + IR. Lung ischemia was induced by left pulmonary artery occlusion (1 hour), followed by reperfusion (4 hours). Rosuvastatin (2 mg/kg) was injected 18 hours before reperfusion and mevalonolactone (1 mg/kg) was injected immediately before reperfusion. The arterial oxygen tension/inspired oxygen fraction ratio was used as a measure of lung oxygenation. Left lung tissue was analyzed for the wet-to-dry lung weight ratio and protein expression of endothelial nitric oxide synthase (eNOS) and phospho-eNOS. Macrophage recruitment was assessed by CD68 immunostaining. Our results showed that rosuvastatin decreased IR lung injury (control + IR vs statin + IR) in terms of the arterial oxygen tension/inspired oxygen fraction ratio (272 ± 43 vs 442 ± 13), wet-to-dry ratio (5.7 ± 0.7 vs 4.8 ± 0.6), and macrophage infiltration (8.0 ± 0.6/field vs 4.0 ± 0.5/field) (P < .05 for all). eNOS and phospho-eNOS were downregulated by IR, which was blocked by rosuvastatin. Effects of rosuvastatin were blunted by mevalonolactone. Single-dose rosuvastatin decreased IR injury in lungs affected by PH via 2 anti-inflammatory mechanisms: preserving eNOS function and inhibiting macrophage infiltration. Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Short-term rosuvastatin treatment for the prevention of contrast-induced acute kidney injury in patients receiving moderate or high volumes of contrast media: a sub-analysis of the TRACK-D study.

PubMed

Zhang, Jian; Li, Yi; Tao, Gui-Zhou; Chen, Yun-Dai; Hu, Tao-Hong; Cao, Xue-Bin; Jing, Quan-Min; Wang, Xiao-Zeng; Ma, Ying-Yan; Wang, Geng; Liu, Hai-Wei; Wang, Bin; Xu, Kai; Li, Jing; Deng, Jie; Han, Ya-Ling

2015-03-20

Current randomized trials have demonstrated the effects of short-term rosuvastatin therapy in preventing contrast-induced acute kidney injury (CIAKI). However, the consistency of these effects on patients administered different volumes of contrast media is unknown. In the TRACK-D trial, 2998 patients with type 2 diabetes and concomitant chronic kidney disease (CKD) who underwent coronary/peripheral arterial angiography with or without percutaneous intervention were randomized to short-term (2 days before and 3 days after procedure) rosuvastatin therapy or standard-of-care. This prespecified analysis compared the effects of rosuvastatin versus standard therapy in patients exposed to (moderate contrast volume [MCV], 200-300 ml, n = 712) or (high contrast volume [HCV], ≥ 300 ml, n = 220). The primary outcome was the incidence of CIAKI. The secondary outcome was a composite of death, dialysis/hemofiltration or worsened heart failure at 30 days. Rosuvastatin treatment was associated with a significant reduction in CIAKI compared with the controls (2.1% vs. 4.4%, P = 0.050) in the overall cohort and in patients with MCV (1.7% vs. 4.5%, P = 0.029), whereas no benefit was observed in patients with HCV (3.4% vs. 3.9%, P = 0.834). The incidence of secondary outcomes was significantly lower in the rosuvastatin group compared with control group (2.7% vs. 5.3%, P = 0.049) in the overall cohort, but it was similar between the patients with MCV (2.0% vs. 4.2%, P = 0.081) or HCV (5.1% vs. 8.8%, P = 0.273). Periprocedural short-term rosuvastatin treatment is effective in reducing CIAKI and adverse clinical events for patients with diabetes and CKD after their exposure to a moderate volume of contrast medium.

More Power to OATP1B1: An Evaluation of Sample Size in Pharmacogenetic Studies Using a Rosuvastatin PBPK Model for Intestinal, Hepatic, and Renal Transporter‐Mediated Clearances

PubMed Central

Burt, Howard; Abduljalil, Khaled; Neuhoff, Sibylle

2016-01-01

Abstract Rosuvastatin is a substrate of choice in clinical studies of organic anion‐transporting polypeptide (OATP)1B1‐ and OATP1B3‐associated drug interactions; thus, understanding the effect of OATP1B1 polymorphisms on the pharmacokinetics of rosuvastatin is crucial. Here, physiologically based pharmacokinetic (PBPK) modeling was coupled with a power calculation algorithm to evaluate the influence of sample size on the ability to detect an effect (80% power) of OATP1B1 phenotype on pharmacokinetics of rosuvastatin. Intestinal, hepatic, and renal transporters were mechanistically incorporated into a rosuvastatin PBPK model using permeability‐limited models for intestine, liver, and kidney, respectively, nested within a full PBPK model. Simulated plasma rosuvastatin concentrations in healthy volunteers were in agreement with previously reported clinical data. Power calculations were used to determine the influence of sample size on study power while accounting for OATP1B1 haplotype frequency and abundance in addition to its correlation with OATP1B3 abundance. It was determined that 10 poor‐transporter and 45 intermediate‐transporter individuals are required to achieve 80% power to discriminate the AUC0‐48h of rosuvastatin from that of the extensive‐transporter phenotype. This number was reduced to 7 poor‐transporter and 40 intermediate‐transporter individuals when the reported correlation between OATP1B1 and 1B3 abundance was taken into account. The current study represents the first example in which PBPK modeling in conjunction with power analysis has been used to investigate sample size in clinical studies of OATP1B1 polymorphisms. This approach highlights the influence of interindividual variability and correlation of transporter abundance on study power and should allow more informed decision making in pharmacogenomic study design. PMID:27385171

Adding exercise to rosuvastatin treatment: influence on C-reactive protein, monocyte toll-like receptor 4 expression, and inflammatory monocyte (CD14+CD16+) population.

PubMed

Coen, Paul M; Flynn, Michael G; Markofski, Melissa M; Pence, Brandt D; Hannemann, Robert E

2010-12-01

Statin treatment and exercise training can reduce markers of inflammation when administered separately. The purpose of this study was to determine the effect of rosuvastatin treatment and the addition of exercise training on circulating markers of inflammation including C-reactive protein (CRP), monocyte toll-like receptor 4 (TLR4) expression, and CD14+CD16+ monocyte population size. Thirty-three hypercholesterolemic and physically inactive subjects were randomly assigned to rosuvastatin (R) or rosuvastatin/exercise (RE) groups. A third group of physically active hypercholesterolemic subjects served as a control (AC). The R and RE groups received rosuvastatin treatment (10 mg/d) for 20 weeks. From week 10 to week 20, the RE group also participated in an exercise training program (3d/wk). Measurements were made at baseline (Pre), week 10 (Mid), and week 20 (Post), and included TLR4 expression on CD14+ monocytes and CD14+CD16+ monocyte population size as determined by 3-color flow cytometry. Serum CRP was quantified by enzyme-linked immunosorbent assay. TLR4 expression on CD14+ monocytes was higher in the R group at week 20. When treatment groups (R and RE) were combined, serum CRP was lower across time. Furthermore, serum CRP and inflammatory monocyte population size were lower in the RE group compared with the R group at the Post time point. When all groups (R, RE, and AC) were combined, TLR4 expression was greater on inflammatory monocytes (CD14+CD16+) compared with classic monocytes (CD14+CD16⁻) at all time points. In conclusion, rosuvastatin may influence monocyte inflammatory response by increasing TLR4 expression on circulating monocytes. The addition of exercise training to rosuvastatin treatment further lowered CRP and reduced the size of the inflammatory monocyte population, suggesting an additive anti-inflammatory effect of exercise. Copyright © 2010 Elsevier Inc. All rights reserved.

Evaluating the effectiveness of rosuvastatin in preventing the progression of diastolic dysfunction in aortic stenosis: A substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study

PubMed Central

2011-01-01

Background Tissue Doppler imaging (TDI) is a noninvasive echocardiographic method for the diagnosis of diastolic dysfunction in patients with varying degrees of aortic stenosis (AS). Little is known however, on the utility of TDI in the serial assessment of diastolic abnormalities in AS. Objective The aim of the current proposal was to examine whether treatment with rosuvastatin was successful in improving diastolic abnormalities in patients enrolled in the Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin (ASTRONOMER) study. Methods Conventional Doppler indices including peak early (E) and late (A) transmitral velocities, and E/A ratio were measured from spectral Doppler. Tissue Doppler measurements including early (E') and late (A') velocities of the lateral annulus were determined, and E/E' was calculated. Results The study population included 168 patients (56 ± 13 years), whose AS severity was categorized based on peak velocity at baseline (Group I: 2.5-3.0 m/s; Group II: 3.1-3.5 m/s; Group III: 3.6-4.0 m/s). Baseline and follow-up hemodynamics, LV dimensions and diastolic functional parameters were evaluated in all three groups. There was increased diastolic dysfunction from baseline to follow-up in each of the placebo and rosuvastatin groups. In patients with increasing severity of AS in Groups I and II, the lateral E' was lower and the E/E' (as an estimate of increased left ventricular end-diastolic pressure) was higher at baseline (p < 0.05). However, treatment with rosuvastatin did not affect the progression of diastolic dysfunction from baseline to 3.5 year follow-up between patients in any of the three predefined groups. Conclusion In patients with mild to moderate asymptomatic AS, rosuvastatin did not attenuate the progression of diastolic dysfunction. PMID:21299902

Statins and Risk of New-Onset Diabetes Mellitus

MedlinePlus

... hemoglobin A1c near 7.5% before starting statins, atorvastatin and rosuvastatin (2 potent and widely used statin ... Schalkwijk C , Wolffenbuttel B . Effects of rosuvastatin and atorvastatin on glycemic control in type 2 diabetes: the ...

JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP, but what does it mean?

PubMed Central

SHISHEHBOR, MEHDI H.; HAZEN, STANLEY L.

2010-01-01

The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) (N Engl J Med 2008; 359:2195–2207) compared rosuvastatin (Crestor) 20 mg daily vs placebo in apparently healthy people who had levels of low-density lipoprotein cholesterol (LDL-C) lower than 130 mg/dL but elevated levels (≥ 2 mg/L) of high-sensitivity C-reactive protein (hs-CRP). Rosuvastatin treatment lowered LDL-C levels by 50% and hs-CRP levels by 37%, accompanied by a 44% relative risk reduction in the composite end point of unstable angina, revascularization, and confirmed death from cardiovascular causes. In absolute terms, 95 people had to be treated over 2 years to prevent one event. There was, however, a higher incidence of diabetes in the rosuvastatin group. PMID:19122109

Rosuvastatin and the JUPITER trial: critical appraisal of a lifeless planet in the galaxy of primary prevention.

PubMed

López, Antonio; Wright, James M

2012-01-01

In November 2008, the JUPITER trial was published in the New England Journal of Medicine. JUPITER is an acronym for Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. It was an AstraZeneca sponsored randomized double-blind trial comparing rosuvastatin 20 mg with placebo in 17,802 apparently healthy men and women with LDL cholesterol <3.4 mmol/L and elevated C-reactive protein (CRP). The results of the JUPITER trial have been widely publicized, and based on the trial, the main regulatory agencies have approved rosuvastatin for the indication of primary prevention of vascular events. However, the interpretation and clinical implications of the JUPITER trial have been questioned and remain controversial. The objective of this commentary is to evaluate the relevance, design, results, and conclusions of the JUPITER study.

Erythrocyte membrane cholesterol and lipid core growth in a rabbit model of atherosclerosis: modulatory effects of rosuvastatin.

PubMed

Tziakas, Dimitrios; Chalikias, Georgios; Kapelouzou, Alkistis; Tentes, Ioannis; Schäfer, Katrin; Karayannakos, Panagiotis; Kostakis, Alkiviadis; Boudoulas, Harissios; Konstantinides, Stavros

2013-12-10

Lipid core expansion is partly responsible for the conversion of a stable atherosclerotic lesion to a rupture-prone plaque. Intraplaque hemorrhage contributes to the accumulation of cholesterol within unstable plaques. In the present study, we investigated, using a rabbit model of atherosclerosis, the extent to which diet-induced increases in cholesterol content of erythrocyte membranes (CEM) contribute to lipid core expansion and the modulatory effect of rosuvastatin use. Rabbits fed with atherogenic diet (0.75% cholesterol) for 5 months exhibited advanced atherosclerotic lesions (mean plaque area, 0.39 ± 0.03 mm(2)), and lipid core size was associated with the concentration-time integral (CTI) of CEM levels (r=0.567, P=0.004) independent of other established predictors of lipid core size. Further experiments were performed by feeding rabbits atherogenic diet (1% cholesterol) for 3 months, followed by either normal diet or normal diet plus rosuvastatin for the next 3 months. Although no differences were observed in total plaque area between both groups, administration of rosuvastatin was associated with significantly smaller lipid cores, fewer macrophages within the lipid core, less microvessels as well as with lower CTI of CEM levels compared to normal diet alone. Moreover, intraplaque erythrocyte membranes covered a smaller lipid core area in rabbits under rosuvastatin plus normal diet as opposed to rabbits under diet alone. Increased CEM levels, induced by high-cholesterol diet, are associated with lipid core growth. Ingestion of a potent HMG-CoA reductase inhibitor (rosuvastatin) may decrease CEM levels, and this effect may contribute to regression of the lipid core. © 2013.

LDL-Induced Impairment of Human Vascular Smooth Muscle Cells Repair Function Is Reversed by HMG-CoA Reductase Inhibition

PubMed Central

Padró, Teresa; Lugano, Roberta; García-Arguinzonis, Maisa; Badimon, Lina

2012-01-01

Growing human atherosclerotic plaques show a progressive loss of vascular smooth muscle cells (VSMC) becoming soft and vulnerable. Lipid loaded-VSMC show impaired vascular repair function and motility due to changes in cytoskeleton proteins involved in cell-migration. Clinical benefits of statins reducing coronary events have been related to repopulation of vulnerable plaques with VSMC. Here, we investigated whether HMG-CoA reductase inhibition with rosuvastatin can reverse the effects induced by atherogenic concentrations of LDL either in the native (nLDL) form or modified by aggregation (agLDL) on human VSMC motility. Using a model of wound repair, we showed that treatment of human coronary VSMC with rosuvastatin significantly prevented (and reversed) the inhibitory effect of nLDL and agLDL in the repair of the cell depleted areas. In addition, rosuvastatin significantly abolished the agLDL-induced dephosphorylation of myosin regulatory light chain as demonstrated by 2DE-electrophoresis and mass spectrometry. Besides, confocal microscopy showed that rosuvastatin enhances actin-cytoskeleton reorganization during lipid-loaded-VSMC attachment and spreading. The effects of rosuvastatin on actin-cytoskeleton dynamics and cell migration were dependent on ROCK-signalling. Furthermore, rosuvastatin caused a significant increase in RhoA-GTP in the cytosol of VSMC. Taken together, our study demonstrated that inhibition of HMG-CoA reductase restores the migratory capacity and repair function of VSMC that is impaired by native and aggregated LDL. This mechanism may contribute to the stabilization of lipid-rich atherosclerotic plaques afforded by statins. PMID:22719992

Suppressive effects of standard-dose rosuvastatin therapy on the progression of coronary atherosclerosis in Japanese patients: the APOLLO study.

PubMed

Amemiya, Kisaki; Yokoi, Hiroyoshi; Domei, Takenori; Shirai, Shinichi; Ando, Kenji; Goya, Masahiko; Iwabuchi, Masashi

2014-01-01

We used quantitative coronary angiography (QCA) to investigate whether coronary plaque progression can be inhibited by controlling lipids with rosuvastatin at Japanese standard doses following elective percutaneous coronary intervention (PCI). A total of 143 patients who underwent elective PCI were randomized to either the rosuvastatin (5 or 2.5mg/day) or non-statin group. Changes from baseline in the minimal lumen diameter (MLD) and average lumen diameter (ALD) measured using QCA were analyzed in both target and non-target lesions. The changes in MLD and ALD from baseline to 24 months in the non-target lesions were significantly smaller in the rosuvastatin group than in the non-statin group (-0.079 ± 0.014 mm vs.-0.135 ± 0.019 mm, p=0.022; -0.062 ± 0.012 mmvs. -0.109 ± 0.016mm, p=0.025). The changes in MLD from six to 24 months in the target lesions were significantly lower in the rosuvastatin group than in the non-statin group among the patients treated with drug-eluting stents (-0.046 ± 0.108 mm vs. -0.133 ± 0.108 mm, p=0.009) versus those treated with bare-metal stents (-0.011 ± 0.094 mm vs. -0.015 ± 0.040 mm, p=0.255). The present study demonstrated that the administration of a standard dose of rosuvastatin slows coronary plaque progression and may prevent the late catch-up phenomenon associated with drug-eluting stents in patients who undergo elective PCI.

Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin.

PubMed

Rodenburg, Jessica; Vissers, Maud N; Wiegman, Albert; Miller, Elizabeth R; Ridker, Paul M; Witztum, Joseph L; Kastelein, John J P; Tsimikas, Sotirios

2006-05-02

To assess the role of oxidized phospholipids (OxPLs) in children with familial hypercholesterolemia (FH) and the effect of pravastatin. Oxidized phospholipids are a major component of oxidized low-density lipoprotein (OxLDL) and are bound to lipoprotein (a) [Lp(a)]. The significance of OxPL markers in children is unknown. Children with FH were randomized to placebo (n = 88) or pravastatin (n = 90) after instruction on American Heart Association step II diet. Unaffected siblings (n = 78) served as controls. The OxPL content on apolipoprotein B-100 (apoB) detected by antibody E06 (OxPL/apoB ratio), immunoglobulin (Ig)G and IgM immune complexes per apoB (IC/apoB) and on all apoB particles (total apoB-IC = IC/apoB multiplied by plasma apoB levels), autoantibodies to malondialdehyde (MDA)-low-density lipoprotein (LDL), Lp(a), and apoB levels were measured at baseline and after two years of treatment. Compared with unaffected siblings, children with FH had significantly lower levels of OxPL/apoB but higher levels of IgG and IgM total apoB-IC and IgM MDA-LDL autoantibodies. From baseline to two-year follow-up, compared with placebo pravastatin treatment resulted in a greater mean percentage change in apoB (-18.7% vs. 0.3%; p = 0.001), total IgG apoB-IC (-31.9% vs. -12.2%; p < 0.001), and total IgM apoB-IC (-25.5% vs. 13.2%; p = 0.001). Interestingly, pravastatin also resulted in higher OxPL/apoB (48.7% vs. 29.3%; p = 0.028) and Lp(a) levels (21.9% vs. 10.7%; p = 0.044). Compared with unaffected siblings, children with FH are characterized by elevated levels of apoB-IC and IgM MDA-LDL autoantibodies. Compared with placebo, pravastatin led to a greater reduction in apoB-IC but also to a greater increase in OxPL/apoB and Lp(a), which may represent a novel mechanism of mobilization and clearance of OxPL.

Lipoprotein-associated phospholipase A2 mass and activity in children with heterozygous familial hypercholesterolemia and unaffected siblings: effect of pravastatin.

PubMed

Ryu, Sung Kee; Hutten, Barbara A; Vissers, Maud N; Wiegman, Albert; Kastelein, John J P; Tsimikas, Sotirios

2011-01-01

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an independent risk factor of cardiovascular disease and a target of treatment. Lp-PLA(2) levels in children have not been previously reported. The effect of statin therapy on Lp-PLA(2) mass and activity in children with familial hypercholesterolemia (FH) is also not known. Lp-PLA(2) mass and activity levels were measured at baseline and after 2 years in 178 children with FH randomized to pravastatin or placebo and in 78 unaffected and untreated siblings. At the end of the randomized period, all FH children were then placed on pravastatin for an additional 2 years, and Lp-PLA(2) mass and activity levels were correlated with changes in carotid intima-media thickness during 4 years of follow-up. Baseline levels of Lp-PLA(2) mass and activity were significantly greater in children with FH compared with unaffected siblings (mass: 240.3 ± 41.6 vs 222.1 ± 36.5 ng/mL, P = .002; activity: 205.7 ± 41.6 vs 124.3±23.0 nmol/min/mL, P < .0001). In the randomized FH cohort, after 2 years treatment, Lp-PLA(2) mass (217.8 ± 35.0 vs 231.5 ± 34.8 ng/mL, P = .001) and activity (178.8 ± 37.3 vs 206.2 ± 33.5 nmol/min/mL, P < .0001) were significantly reduced by pravastatin compared with placebo. Change in Lp-PLA(2) activity was related to change in low-density lipoprotein cholesterol (pravastatin: r = 0.53, P < .0001, placebo: r = 0.23, P < .001) but change in Lp-PLA(2) mass was not related to change in low-density lipoprotein cholesterol. Baseline levels of Lp-PLA(2) mass and activity were not significantly associated with carotid intima-media thickness at baseline or at 4 years. Lp-PLA(2) mass and activity are significantly elevated in children with heterozygous FH compared with unaffected siblings and are significantly reduced by pravastatin therapy. Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Effect of rosuvastatin on hepatic production of apolipoprotein B-containing lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia.

PubMed

Chong, Taryne; Naples, Mark; Federico, Lisa; Taylor, Denise; Smith, Graham J; Cheung, Raphael C; Adeli, Khosrow

2006-03-01

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the efficacy and mechanisms of action of rosuvastatin, a HMG-CoA reductase inhibitor, in ameliorating metabolic dyslipidemia in insulin-resistant states. Fructose feeding for a 2-week period induced insulin resistance and a significant increase in hepatic secretion of VLDL. This was followed by a fructose-enriched diet with or without 10 mg/kg rosuvastatin for 14 days. Fructose feeding in the first 2 weeks caused a significant increase in plasma total cholesterol and triglyceride in both groups (n=6, p<0.001). However, there was a significant decline (30%, n=8, p<0.05) in plasma triglyceride levels following rosuvastatin feeding (10 mg/kg). A significant decrease (n=6, p<0.05) was also observed in VLDL-apoB production in hepatocytes isolated from drug-treated hamsters, together with an increased apoB degradation (n=6, p<0.05). Similar results were obtained in parallel cell culture experiments in which primary hepatocytes were first isolated from chow-fed hamsters, and then treated in vitro with 15 microM rosuvastatin for 18 h. Rosuvastatin at 5 microM caused a substantial reduction in synthesis of unesterified cholesterol and cholesterol ester (98 and 25%, n=9, p<0.01 or p<0.05) and secretion of newly synthesized unesterified cholesterol, cholesterol ester, and triglyceride (95, 42, and 60% reduction, respectively, n=9, p<0.01 or p<0.05). This concentration of rosuvastatin also caused a significant reduction (75% decrease, n=4, p<0.01) in the extracellular secretion of VLDL-apoB100, accompanied by a significant increase in the intracellular degradation of apoB100. There was a 12% reduction (not significant, p>0.05) in hepatic MTP and no changes in ER-60 (a chaperone involved in apoB degradation) protein levels. Taken together, these data suggest that the assembly and secretion of VLDL particles in hamster hepatocytes can be acutely inhibited by rosuvastatin in a process involving enhanced apoB degradation. This appears to lead to a significant amelioration of hepatic VLDL-apoB overproduction observed in the fructose-fed, insulin-resistant hamster model.

Adherence to preferable behavior for lipid control by high-risk dyslipidemic Japanese patients under pravastatin treatment: the APPROACH-J study.

PubMed

Kitagawa, Yasuhisa; Teramoto, Tamio; Daida, Hiroyuki

2012-01-01

We evaluated the impact of adherence to preferable behavior on serum lipid control assessed by a self-reported questionnaire in high-risk patients taking pravastatin for primary prevention of coronary artery disease. High-risk patients taking pravastatin were followed for 2 years. Questionnaire surveys comprising 21 questions, including 18 questions concerning awareness of health, and current status of diet, exercise, and drug therapy, were conducted at baseline and after 1 year. Potential domains were established by factor analysis from the results of questionnaires, and adherence scores were calculated in each domain. The relationship between adherence scores and lipid values during the 1-year treatment period was analyzed by each domain using multiple regression analysis. A total of 5,792 patients taking pravastatin were included in the analysis. Multiple regression analysis showed a significant correlation in terms of "Intake of high fat/cholesterol/sugar foods" (regression coefficient -0.58, p=0.0105) and "Adherence to instructions for drug therapy" (regression coefficient -6.61, p<0.0001). Low-density lipoprotein cholesterol (LDL-C) values were significantly lower in patients who had an increase in the adherence score in the "Awareness of health" domain compared with those with a decreased score. There was a significant correlation between high-density lipoprotein (HDL-C) values and "Awareness of health" (regression coefficient 0.26; p= 0.0037), "Preferable dietary behaviors" (regression coefficient 0.75; p<0.0001), and "Exercise" (regression coefficient 0.73; p= 0.0002). Similar relations were seen with triglycerides. In patients who have a high awareness of their health, a positive attitude toward lipid-lowering treatment including diet, exercise, and high adherence to drug therapy, is related with favorable overall lipid control even in patients under treatment with pravastatin.

Effects of simvastatin and pravastatin on gonadal function in male hypercholesterolemic patients.

PubMed

Dobs, A S; Miller, S; Neri, G; Weiss, S; Tate, A C; Shapiro, D R; Musliner, T A

2000-01-01

Inhibition of cholesterol biosynthesis by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors could, in theory, adversely affect male gonadal function because cholesterol is a precursor of steroid hormones. The objective of this randomized double-blind trial was to compare the effects of simvastatin, pravastatin, and placebo on gonadal testosterone production and spermatogenesis. After a 6-week placebo and lipid-lowering diet run-in period, 159 male patients aged 21 to 55 years with type IIa or IIb hypercholesterolemia, low-density lipoprotein (LDL) cholesterol between 145 and 240 mg/dL, and normal basal levels of testosterone were randomly assigned to treatment with simvastatin 20 mg (n = 40), simvastatin 40 mg (n = 41), pravastatin 40 mg (n = 39), or placebo (n = 39) once daily. After 24 weeks of treatment, mean total cholesterol levels were decreased 24% to 27% and mean LDL cholesterol was decreased 30% to 34% in the 3 active-treatment groups (P < .001 for all comparisons to placebo). At 24 weeks, there were no statistically significant differences between the placebo group and any of the active-treatment groups for the change from baseline in testosterone, human chorionic gonadotropin (hCG)stimulated testosterone, free testosterone index, follicle-stimulating hormone (FSH), luteinizing hormone (LH), or sex hormone-binding globulin (SHBG). Moreover, there were no statistically significant differences at week 12 or week 24 for the change from baseline in sperm concentration, ejaculate volume, or sperm motility for any active treatment relative to placebo. Both simvastatin and pravastatin were well tolerated. In summary, we found no evidence for clinically meaningful effects of simvastatin or pravastatin on gonadal testosterone production, testosterone reserve, or multiple parameters of semen quality.

Rosuvastatin-Induced Carotid Plaque Regression in Patients With Inflammatory Joint Diseases: The Rosuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and Other Inflammatory Joint Diseases Study.

PubMed

Rollefstad, S; Ikdahl, E; Hisdal, J; Olsen, I C; Holme, I; Hammer, H B; Smerud, K T; Kitas, G D; Pedersen, T R; Kvien, T K; Semb, A G

2015-07-01

Patients with rheumatoid arthritis (RA) and carotid artery plaques have an increased risk of acute coronary syndromes. Statin treatment with the goal of achieving a low-density lipoprotein (LDL) cholesterol level of ≤1.8 mmoles/liter (≤70 mg/dl) is recommended for individuals in the general population who have carotid plaques. The aim of the ROsuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and other inflammatory joint diseases (RORA-AS) study was to evaluate the effect of 18 months of intensive lipid-lowering treatment with rosuvastatin with regard to change in carotid plaque height. Eighty-six patients (60.5% of whom were female) with carotid plaques and inflammatory joint disease (55 with RA, 21 with AS, and 10 with psoriatic arthritis) were treated with rosuvastatin to obtain the LDL cholesterol goal. Carotid plaque height was evaluated by B-mode ultrasonography. The mean ± SD age of the patients was 60.8 ± 8.5 years, and the median compliance with rosuvastatin treatment was 97.9% (interquartile range [IQR] 96.0-99.4). At baseline, the median number and height of the carotid plaques were 1.0 (range 1-8) and 1.80 mm (IQR 1.60-2.10), respectively. The mean ± SD change in carotid plaque height after 18 months of treatment with rosuvastatin was -0.19 ± 0.35 mm (P < 0.0001). The mean ± SD baseline LDL cholesterol level was 4.0 ± 0.9 mmoles/liter (154.7 ± 34.8 mg/dl), and the mean reduction in the LDL cholesterol level was -2.3 mmoles/liter (95% confidence interval [95% CI] -2.48, -2.15) (-88.9 mg/dl [95% CI -95.9, -83.1]). The mean ± SD LDL cholesterol level during the 18 months of rosuvastatin treatment was 1.7 ± 0.4 mmoles/liter (area under the curve). After adjustment for age/sex/blood pressure, no linear relationship between a reduction in carotid plaque height and the level of LDL cholesterol exposure during the study period was observed. Attainment of the LDL cholesterol goal of ≤1.8 mmoles/liter (≤70 mg/dl) or the amount of change in the LDL cholesterol level during the study period did not influence the degree of carotid plaque height reduction. Intensive lipid-lowering treatment with rosuvastatin induced atherosclerotic regression and reduced the LDL cholesterol level significantly in patients with inflammatory joint disease. © 2015, American College of Rheumatology.

The Relationship between Statins and Prostate Cancer Prevention

DTIC Science & Technology

2011-09-01

jnci.oxfordjournals.org JNCI | Articles 887 any of the following medications: atorvastatin , fluvastatin, lova- statin, pravastatin, or simvastatin. Statin users may...lovastatin and pravastatin doses by 2, dividing the fluvastatin dose by 4, and multiplying the atorvastatin dose by 2. We then determined the hazard...dif- ferent statin agent in the statin user group 1 year after statin initi- ation: simvastatin, 54.6%; lovastatin, 43.9%; atorvastatin , 1.2

Determination of statins by gas chromatography - EI/MRM - Tandem mass spectrometry: fermentation of pine samples with Pleurotus ostreatus.

PubMed

Sirén, Heli; Kaijanen, Laura; Kaartinen, Sini; Väre, Monna; Riikonen, Päivi; Jernström, Eeva

2014-06-01

Statins were separated and quantified with gas chromatography-mass spectrometry (GC-EI-MS/MS) using total ion monitoring (TIC) and multiple reactions monitoring (MRM). The MRM method in statins determination has a novelty value, since there are no previous studies on their simultaneous analysis in environmental or plant samples. The method development and optimization was challenging due to the physicochemical similarities of the silylated lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin. The results showed that the use of MRM decreased their detection and quantification limits by factors of 2-10 compared to that obtained in TIC monitoring. The concentration calibration was made between 247.5ng/L and 9900ng/L. Limits of detection and quantification were between 50ng/L (lovastatin)-500ng/L (pravastatin) and 250ng/L (lovastatin)-1000ng/L (pravastatin), respectively. Based on the MRM results, the wood bark and phloem samples contained lovastatin, lovastatin-lactone, simvastatin, simvastatin-lactone, and pravastatin. Their concentrations were 250-3000μg/L, i.e. 4.2-50mg/kg in phloem and bark. However, they were not detected in fluids made with Pleurotus ostreatus fermentation of wood core. Copyright © 2014 Elsevier B.V. All rights reserved.

A 68-year old male presenting with rhabdomyolysis-associated acute kidney injury following concomitant use of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate and pravastatin/fenofibrate: a case report.

PubMed

Suttels, Veronique; Florence, Eric; Leys, John; Vekemans, Marc; Van den Ende, Jef; Vlieghe, Erika; Kenyon, Chris

2015-09-08

We present what we believe to be the first case in the literature of rhabdomyolysis-induced renal failure caused by a probable drug interaction between elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) and pravastatin/fenofibrate. A 68-year old Caucasian man presented with progressive pain in both legs two weeks after commencing treatment with EVG/COBI/FTC/TDF. He was found to have biochemical evidence of rhabdomyolysis and acute renal failure. We emphasize the need for post marketing surveillance of adverse effects of new products. Pharmacokinetic studies are necessary to investigate the levels of pravastatin in patients taking COBI and fenofibrate with and without other comorbidities. Meanwhile, we suggest that creatine kinase levels should be monitored and patients advised to report myalgias when using concomitant EVG/COBI/FTC/TDF and pravastatin/fenofibrate. This case serves as an important reminder to use estimated glomerular filtration rates rather than serum creatinine levels when choosing new medications. If potentially nephrotoxic combinations are started in patients with borderline estimated glomerular filtration rates, it may be prudent to check these filtration rates more frequently than usual. In patients with reduced estimated glomerular filtration rates, potentially nephrotoxic combinations should be avoided wherever possible.

Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms.

PubMed

Carson, Ross A; Rudine, Anthony C; Tally, Serena J; Franks, Alexis L; Frahm, Krystle A; Waldman, Jacob K; Silswal, Neerupma; Burale, Suban; Phan, James V; Chandran, Uma R; Monaghan, A Paula; DeFranco, Donald B

2018-01-01

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs). To understand how statins could impact the developing brain, we studied effects of pravastatin and simvastatin on primary embryonic NSPC survival, proliferation, global transcription, and cell fate in vitro. We found that statins dose dependently decrease NSPC expansion by promoting cell death and autophagy of NSPCs progressing through the G1 phase of the cell cycle. Genome-wide transcriptome analysis demonstrates an increase in expression of CBP genes following pravastatin treatment, through activation of the SREBP2 transcription factor. Co-treatment with farnesyl pyrophosphate (FPP), a CBP metabolite downstream of HMG-CoA reductase, reduces SREBP2 activation and pravastatin-induced PARP cleavage. Finally, pravastatin and simvastatin differentially alter NSPC cell fate and mRNA expression during differentiation, through a non-CBP dependent pathway.

Effects of rosuvastatin and atorvastatin on the apolipoprotein B/apolipoprotein A-1 ratio in patients with an acute coronary syndrome: The CENTAURUS trial design.

PubMed

Lablanche, Jean-Marc; Danchin, Nicolas; Farnier, Michel; Tedgui, Alain; Vicaut, Eric; Alonso, Joaquim; Crean, Peter; Leone, Attilio; Morais, Joa; Santini, Massimo; Licour, Muriel; Farah, Mohamed; Tardif, Jean-Claude

2008-06-01

The mechanism underlying rapid, statin-induced event reduction in patients with an acute coronary syndrome (ACS) remains to be clarified. The primary objective is to compare the efficacy of rosuvastatin 20 mg/day and atorvastatin 80 mg/day in reducing the apolipoprotein B/apolipoprotein A-1 (apoB/apoA-1) ratio at three months, in ACS patients. Secondary objectives include a comparison of the effects of early-started rosuvastatin and placebo on inflammatory markers. This is a randomized, double-blind, parallel-group study. Patients with non-ST-segment elevation ACS, symptom onset less than 48 h before admission, and for whom a percutaneous coronary intervention is planned, are eligible for inclusion and are randomized into three groups (G1, G2 and G3). The study comprises two double-blind periods. Period 1 starts at hospital admission and lasts until Day 0 (discharge or less or equal to 6 days after admission); patients in G1 receive one tablet of rosuvastatin 20 mg/day and patients in G2 and G3 receive one matching placebo tablet per day. Period 2 starts at Day 0 and lasts for three months; patients in G1 continue to receive rosuvastatin 20 mg/day, patients in G2 receive rosuvastatin 20 mg/day and patients in G3 receive atorvastatin 80 mg/day. Recruitment of 1075 patients will ensure an 80 power to detect a 3% difference in percentage change in the apoB/apoA-1 ratio and a 20% difference in percentage change in high-sensitivity C-reactive protein. Inclusion phase is complete; results will be reported at a later date. This is the first trial investigating the effect of statins on apolipoproteins in ACS patients.

Effect of Low (5 mg) vs. High (20-40 mg) Rosuvastatin Dose on 24h Arterial Stiffness, Central Haemodynamics, and Non-Alcoholic Fatty Liver Disease in Patients with Optimally Controlled Arterial Hypertension.

PubMed

Mitsiou, Eudoxia; Boutari, Chrysoula; Kotsis, Vasilios; Georgianou, Eleni; Doumas, Michael; Karagiannis, Asterios; Athyros, Vasilios G

2018-01-01

Arterial Stiffness (AS) and Non-Alcoholic Fatty Liver Diseases (NAFLD) are 2 related, prevalent, risk predictors of Cardiovascular Disease (CVD). We assessed the effect of low dose (5 mg/day) vs. high dose (20-40 mg/day) rosuvastatin on aortic elasticity and central haemodynamics as well as on NAFLD in patients with Arterial Hypertension (AH). Forty patients with optimally controlled AH were randomised to 2 rosuvastatin doses and followed for 6 months. 24h AS was assessed by Mobil-O-Graph, which calculates (adjusted for age and gender) Pulse Wave Velocity (PWV), adjusted for Heart Rate (HR) augmentation index (AIx75%) and central haemodynamics. The diagnosis of NAFLD was based on >5% liver steatosis on ultrasound and moderately elevated serum levels of liver enzymes. Both doses of rosuvastatin reduced Central Pulse Pressure (cPP), PWV and AIx75% (adjusted for HR) to normal values (p = NS adjusted for age, gender and HR). Liver enzymes were reduced in those with NAFLD to normal, but steatosis was reduced more by the 20-40 mg/day rosuvastatin dose (p=0.01) compared with the 5 mg/day dose. Both doses of rosuvastatin had a beneficial effect on AS; the high dose was more efficient in reducing PWVs and central haemodynamics, and also the high dose was more effective in ameliorating NAFLD. Given that AH control was optimal and lipid values attained targets, 4 other CVD predictors were also addressed. Larger and longer term studies are needed to demonstrate the clinical benefit of such treatment preference. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients

PubMed Central

Yang, Juan; Li, Lu-jin; Wang, Kun; He, Ying-chun; Sheng, Yu-cheng; Xu, Ling; Huang, Xiao-hui; Guo, Feng; Zheng, Qing-shan

2011-01-01

Aim: To evaluate race differences in the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients using a population pharmacodynamic (PPD) model generated and validated using published clinical efficacy trials. Methods: Published studies randomized trials with rosuvastatin treatment for at least 4 weeks in hypercholesterolemia patients were used for model building and validation. Population pharmacodynamic analyses were performed to describe the dose-response relationship with the mean values of LDL-C reduction (%) from dose-ranging trials using NONMEM software. Baseline LDL-C and race were analyzed as the potential covariates. Model robustness was evaluated using the bootstrap method and the data-splitting method, and Monte Carlo simulation was performed to assess the predictive performance of the PPD model with the mean effects from the one-dose trials. Results: Of the 36 eligible trials, 14 dose-ranging trials were used in model development and 22 one-dose trials were used for model prediction. The dose-response of rosuvastatin was successfully described by a simple Emax model with a fixed E0, which provided a common Emax and an approximate twofold difference in ED50 for Westerners and Asians. The PPD model was demonstrated to be stable and predictive. Conclusion: The race differences in the pharmacodynamics of rosuvastatin are consistent with those observed in the pharmacokinetics of the drug, confirming that there is no significant difference in the exposure-response relationship for LDL-C reduction between Westerners and Asians. The study suggests that for a new compound with a mechanism of action similar to that of rosuvastatin, its efficacy in Western populations plus its pharmacokinetics in bridging studies in Asian populations may be used to support a registration of the new compound in Asian countries. PMID:21151159

Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients.

PubMed

Yang, Juan; Li, Lu-jin; Wang, Kun; He, Ying-chun; Sheng, Yu-cheng; Xu, Ling; Huang, Xiao-hui; Guo, Feng; Zheng, Qing-shan

2011-01-01

To evaluate race differences in the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients using a population pharmacodynamic (PPD) model generated and validated using published clinical efficacy trials. Published studies randomized trials with rosuvastatin treatment for at least 4 weeks in hypercholesterolemia patients were used for model building and validation. Population pharmacodynamic analyses were performed to describe the dose-response relationship with the mean values of LDL-C reduction (%) from dose-ranging trials using NONMEM software. Baseline LDL-C and race were analyzed as the potential covariates. Model robustness was evaluated using the bootstrap method and the data-splitting method, and Monte Carlo simulation was performed to assess the predictive performance of the PPD model with the mean effects from the one-dose trials. Of the 36 eligible trials, 14 dose-ranging trials were used in model development and 22 one-dose trials were used for model prediction. The dose-response of rosuvastatin was successfully described by a simple E(max) model with a fixed E(0), which provided a common E(max) and an approximate twofold difference in ED(50) for Westerners and Asians. The PPD model was demonstrated to be stable and predictive. The race differences in the pharmacodynamics of rosuvastatin are consistent with those observed in the pharmacokinetics of the drug, confirming that there is no significant difference in the exposure-response relationship for LDL-C reduction between Westerners and Asians. The study suggests that for a new compound with a mechanism of action similar to that of rosuvastatin, its efficacy in Western populations plus its pharmacokinetics in bridging studies in Asian populations may be used to support a registration of the new compound in Asian countries.

[Modern look at pharmacotherapy of osteoarthritis accomplished with cardiovascular disease].

PubMed

Хайменова, Галина С; Бабанина, Марина Ю; Волченко, Григорий В; Ткаченко, Максим В; Иваницкий, Игорь В; Ждан, Вячеслав Н

2016-01-01

ABSTR ACTCT Introduction: At present, the main pathogenetic link in the development of OA as atherosclerosis is chronic inflammation, which is based on the activation of pro-inflammatory mediators and disorders of cholesterol metabolism. The aim of the research was to study the efficiency of the use of rosuvastatin in the treatment of patients with osteoarthritis in the combined arterial disease. The study was conducted on the basis of the Poltava Regional Clinical Hospital. N.V. Sklifosovsky and Research Institute of Genetic and immunological bases of pathology and pharmacogenetics higher state educational institution of Ukraine "Ukrainian Medical Dental Academy" (HSEЕU «UMUMCA»). Results of treatment of 30 patients with osteoarthritis and hypertension who received treatment with rosuvastatin. It was concluded that the use of rosuvastatin in these patients can reduce pain, improve joint function, reduce disease activity and improve quality of life for patients. Besides rosuvastatin does not affect the level of systolic and diastolic blood pressure and can be used with concomitant hypertension.

Effects of rosuvastatin on the production and activation of matrix metalloproteinase-2 and migration of cultured rat vascular smooth muscle cells induced by homocysteine.

PubMed

Shi, Ya-fei; Chi, Ju-fang; Tang, Wei-liang; Xu, Fu-kang; Liu, Long-bin; Ji, Zheng; Lv, Hai-tao; Guo, Hang-yuan

2013-08-01

To test the influence of homocysteine on the production and activation of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of matrix metalloproteinase-2 (TIMP-2) and on cell migration of cultured rat vascular smooth muscle cells (VSMCs). Also, to explore whether rosuvastatin can alter the abnormal secretion and activation of MMP-2 and TIMP-2 and migration of VSMCs induced by homocysteine. Rat VSMCs were incubated with different concentrations of homocysteine (50-5000 μmol/L). Western blotting and gelatin zymography were used to investigate the expressions and activities of MMP-2 and TIMP-2 in VSMCs in culture medium when induced with homocysteine for 24, 48, and 72 h. Transwell chambers were employed to test the migratory ability of VSMCs when incubated with homocysteine for 48 h. Different concentrations of rosuvastatin (10(-9)-10(-5) mol/L) were added when VSMCs were induced with 1000 μmol/L homocysteine. The expressions and activities of MMP-2 and TIMP-2 were examined after incubating for 24, 48, and 72 h, and the migration of VSMCs was also examined after incubating for 48 h. Homocysteine (50-1000 μmol/L) increased the production and activation of MMP-2 and expression of TIMP-2 in a dose-dependent manner. However, when incubated with 5000 μmol/L homocysteine, the expression of MMP-2 was up-regulated, but its activity was down-regulated. Increased homocysteine-induced production and activation of MMP-2 were reduced by rosuvastatin in a dose-dependent manner whereas secretion of TIMP-2 was not significantly altered by rosuvastatin. Homocysteine (50-5000 μmol/L) stimulated the migration of VSMCs in a dose-dependent manner, but this effect was eliminated by rosuvastatin. Homocysteine (50-1000 μmol/L) significantly increased the production and activation of MMP-2, the expression of TIMP-2, and the migration of VSMCs in a dose-dependent manner. Additional extracellular rosuvastatin can decrease the excessive expression and activation of MMP-2 and abnormal migration of VSMCs induced by homocysteine.

Validation of membrane vesicle-based breast cancer resistance protein and multidrug resistance protein 2 assays to assess drug transport and the potential for drug-drug interaction to support regulatory submissions.

PubMed

Elsby, Robert; Smith, Veronica; Fox, Lisa; Stresser, David; Butters, Caroline; Sharma, Pradeep; Surry, Dominic D

2011-09-01

Breast cancer resistance protein (BCRP) and multidrug resistance protein 2 (MRP2) can play a role in the absorption, distribution, metabolism, and excretion of drugs, impacting on the potential for drug-drug interactions. This study has characterized insect cell- and mammalian cell-derived ABC-transporter-expressing membrane vesicle test systems and validated methodologies for evaluation of candidate drugs as substrates or inhibitors of BCRP or MRP2. Concentration-dependent uptake of BCRP ([³H]oestrone 3-sulfate, [³H]methotrexate, [³H]rosuvastatin) and MRP2 ([³H]oestradiol 17β-glucuronide, [³H]pravastatin, carboxydichlorofluorescein) substrates, and inhibitory potencies (IC₅₀) of BCRP (sulfasalazine, novobiocin, fumitremorgin C) and MRP2 (benzbromarone, MK-571, terfenadine) inhibitors were determined. The apparent K(m) for probes [³H]oestrone 3-sulfate and [³H]oestradiol 17β-glucuronide was determined in insect cell vesicles to be 7.4 ± 1.7 and 105 ± 8.3 µM, respectively. All other substrates exhibited significant uptake ratios. Positive control inhibitors sulfasalazine and benzbromarone gave IC₅₀ values of 0.74 ± 0.18 and 36 ± 6.1 µM, respectively. All other inhibitors exhibited concentration-dependent inhibition. There was no significant difference in parameters generated between test systems. On the basis of the validation results, acceptance criteria to identify substrates/inhibitors of BCRP and MRP2 were determined for insect cell vesicles. The approach builds on earlier validations to support drug registration and extends from those cell-based systems to encompass assay formats using membrane vesicles.

Toxicological Findings of Pilots Involved in Aviation Accidents Operated under 14 CFR Part 135

DTIC Science & Technology

2009-08-01

metoprolol (Lopressor® or Toprol XL®), pravas- tatin (Pravachol®), atorvastatin (Lipitor®), rosuvastatin (Crestor®), amlodipine (Norvasc®), benazepril... atorvastatin , and rosuvastatin are hy- droxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors used in the treatment of high blood cholesterol

Protective effect of co-administration of rosuvastatin and probucol on atherosclerosis in rats.

PubMed

Chen, Zuoyuan; Li, Shan; Zhao, Wenna; Chen, Xiuhua; Wang, Xiaxia

2014-10-01

This study aimed to study the combined effect of rosuvastatin and probucol on atherosclerosis (AS) in rats. In total, 95 male Wistar rats were divided into 5 groups: 25 in the control group (A), 25 in the model group (B), 15 in the rosuvastatin group (C), 15 in the probucol group (D), and 15 in the rosuvastatin combined probucol group (E). A high-lipid diet and vitamin D3 were administered to establish AS rat model. Groups C, D, and E received corresponding drugs. Blood lipids, oxidized low-density lipoprotein (OX-LDL), malonaldehyde (MDA), superoxide dismutase (SOD), adiponectin (APN), and vascular endothelial cadherin (VE-cadherin) were measured. Platelet endothelial cell adhesion molecule-1 (PECAM-1) was detected by immune histochemistry. In groups B-E, AS rat models were successfully constructed. In groups C-E, blood lipids, OX-LDL, VE-cadherin, MDA, PECAM-1, and intimal thickness were decreased (p < 0.01), while SOD and APN were increased (p < 0.05), compared with that in group B. Furthermore, group E had lower levels of OX-LDL, MDA, and PECAM-1 but higher levels of SOD and APN and attenuated intimal thickening compared with groups C or D (p < 0.05). Administering rosuvastatin and probucol could attenuate AS lesions through modulation of oxidative stress, PECAM-1, and APN. Both drugs might help slow the progression of AS.

Statin desensitization in a patient with probable familial hypercholesterolemia.

PubMed

Schultz, Amy E; Snider, Melissa J; Blais, Danielle M; Gulati, Martha

2015-01-01

With cardiovascular disease being the leading cause of morbidity and mortality in the United States, cholesterol-lowering medications have become a prominent focus of medical management and cardiovascular risk reduction, including the use of statins making them the most widely prescribed class of medications in the United States and are the cornerstone of management of hyperlipidemia. This case report describes a 29-year-old female with probable familial hypercholesterolemia (FH) who had allergic reactions to statin therapy on two separate occasions. She required statin therapy based on her elevated carotid intima media thickness test, historic LDL-C ≥ 190 mg/dL, elevated Lp(a), and family history significant for premature coronary heart disease. In this report, we document a case of successful oral desensitization to rosuvastatin and propose a replicable statin desensitization protocol. The patient was admitted for rosuvastatin desensitization following predetermined protocols, utilizing an interdisciplinary team, and monitored for 24 hours following completion of administration prior to discharge. She successfully completed desensitization to rosuvastatin 10mg by mouth daily without anaphylactic reaction. She continued to tolerate rosuvastatin 10mg daily through most recent follow-up, and with this addition, significant improvement in lipid levels was achieved. This case report presented a patient with probable FH who was previously intolerant to other statin therapies that underwent successful desensitization to rosuvastatin with subsequent achievement of therapy goals. Published by Elsevier Inc.

[IMPACT OF ATORVASTATIN AND ROSUVASTATIN ON RESIDUAL ON-CLOPIDOGREL TREATMENT PLATELET REACTIVITY IN PATIENTS WITH ISCHEMIC HEART DISEASE AND TYPE 2 DIABETES MELLITUS AFTER ACUTE CORONARY SYNDROME].

PubMed

Ovrakh, T; Serik, S; Kochubiei, O

2017-04-01

In patients with ischemic heart disease and type 2 diabetes mellitus in 4-6 weeks after acute coronary syndrome (ACS) on stable dual antiplatelet therapy (DAPT) with aspirin and clopidogrel co-adminstrated with rosuvastatin residual platelet reactivity on adenosine diphosphate was higher than in patients receiving atorvastatin. However, the rate of high residual on-clopidogrel treatment platelet reactivity (RCPR) in rosuvastatin-treated patients exceeded the rate of high RCPR in atorvastatin-treated patients insignificantly. In 6 months after ACS residual platelet reactivity did not differ between the groups. After 12 months of DAPT platelet reactivity increased as compared to baseline values both in patients receiving rosuvastatin and in patients receiving atorvastatin without switching. In patients, randomly switching from one statin type to another at 6 month of treatment, platelet reactivity did not change significantly in comparison to baseline and the prevalence of high RCPR was lower than in patients receiving statins without switching. Thus, in patients with diabetes with ACS on DAPT with acetylsalicylic acid and clopidogrel statin treatment should be started with atorvastatin and in 6 months after ACS atorvastatin should be switched to rosuvastatin. This approach will provide lower RCPR within at least first 4-6 weeks after ACS and prevent RCPR increase during 12 months of DATT use in this patients group.

Efficacy and Safety of Fixed-dose Combination Therapy With Telmisartan and Rosuvastatin in Korean Patients With Hypertension and Dyslipidemia: TELSTA-YU (TELmisartan-rosuvaSTAtin from YUhan), a Multicenter, Randomized, 4-arm, Double-blind, Placebo-controlled, Phase III Study.

PubMed

Oh, Gyu Chul; Han, Jung-Kyu; Han, Ki Hoon; Hyon, Min-Su; Doh, Joon Hyung; Kim, Moo Hyun; Jeong, Jin-Ok; Bae, Jang-Ho; Kim, Sang Hyun; Yoo, Byung-Su; Baek, Sang Hong; Rhee, Moo-Yong; Ihm, Sang-Hyun; Sung, Jung Hoon; Choi, Young Jin; Kim, Soo-Joong; Hong, Kyung-Soon; Lee, Byoung Kwon; Cho, JangHyun; Shin, Eun Seok; Rhew, Jay Young; Kim, Hyunsu; Kim, Hyo-Soo

2018-05-01

Hypertension and dyslipidemia are 2 risk factors of cardiovascular disease that often present simultaneously. Traditionally, treatment of these multiple conditions required separate medications for each disease, which may result in poor compliance and thus lead to possible treatment failure. Fixed-dose combination (FDC) therapy with a single pill may be a solution in these situations. This multicenter, 8-week, randomized, double-blind, Phase III study evaluated the efficacy and safety of FDC treatment with telmisartan (80 mg) and rosuvastatin calcium (20 mg) in Korean patients with mild to moderate hypertension and dyslipidemia. Patients were randomly assigned to 4 groups: (1) FDC drug (80 mg of telmisartan and 20 mg of rosuvastatin); (2) 80 mg of telmisartan; (3) 20 mg of rosuvastatin; or (4) placebo. After 8 weeks of treatment, the change in mean sitting systolic blood pressure (MSSBP) and mean sitting diastolic blood pressure (MSDBP) between the FDC group and the rosuvastatin group, and the percent change in LDL-C between the FDC group and the telmisartan group, were compared. A total of 210 patients were enrolled in the study (84 in the FDC group, 42 in the rosuvastatin group, 43 in the telmisartan group, and 41 in the placebo group). The reduction in blood pressure was significantly greater in the FDC group than in the rosuvastatin group after 8 weeks of treatment (least squares mean change from baseline, -16.1 [1.6] mm Hg vs -1.7 [2.2] mm Hg [P < 0.001] for MSSBP; -8.8 [1.0] mm Hg vs -1.6 [1.4] mm Hg [P < 0.001] for MSDBP). Least squares mean percent change in LDL-C from baseline was also significantly greater in the FDC group compared with the telmisartan group (-49.3% [2.2%] vs 1.5% [3.0%]; P < 0.001). FDC therapy also had a higher rate of achieving the treatment goal in both blood pressure (60% vs 45%; P = 0.024) and LDL-C (88.8% vs 16.3%; P < 0.001) compared with rosuvastatin or telmisartan alone, respectively. In regression analysis, higher baseline MSSBP, female sex, and lower body mass index were associated with increased reductions in MSSBP, whereas higher baseline LDL-C level and lower body mass index were associated with greater reductions in LDL-C. There were 48 adverse events in 36 patients (17.3% [36 of 208]), and 17 adverse drug reactions in 12 patients (5.8% [12 of 208]), indicating no significant differences in short-term safety among study groups. Treatment with an FDC drug containing telmisartan and rosuvastatin showed similar efficacy in lowering blood pressure and LDL-C levels compared with that of each single drug. ClinicalTrials.gov identifier: NCT01914432. Copyright © 2018. Published by Elsevier Inc.

Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers

USDA-ARS?s Scientific Manuscript database

We measured plasma markers of cholesterol synthesis (lathosterol) and absorption (campesterol, sitosterol, and cholestanol) in order to compare the effects of maximal doses of rosuvastatin with atorvastatin and investigate the basis for the significant individual variation in lipid lowering response...

Low-dose pravastatin and age-related differences in risk factors for cardiovascular disease in hypercholesterolaemic Japanese: analysis of the management of elevated cholesterol in the primary prevention group of adult Japanese (MEGA study).

PubMed

Nakaya, Noriaki; Mizuno, Kyoichi; Ohashi, Yasuo; Teramoto, Tamio; Yokoyama, Shinji; Hirahara, Katsumi; Mizutani, Masahiro; Nakamura, Haruo

2011-09-01

Limited data are available regarding the relationship between age and the effect of HMG-CoA reductase inhibitor (statin) treatment. The aim of the present analysis was to evaluate the relationships between age, baseline patient characteristics, and pravastatin treatment with respect to the development of cardiovascular disease (CVD) in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, a large-scale clinical study conducted in Japanese patients with mild or moderate hyperlipidaemia to evaluate the primary preventive effect of pravastatin against coronary heart disease. To compare the prevalence of CVD risk factors, the incidence of CVD in relation to each risk factor, and final values and changes in lipid parameters, the 7832 patients were classified into six age groups: <45, 45-49, 50-54, 55-59, 60-64 and ≥65 years. The relationship between pravastatin (10-20 mg/day) treatment efficacy and aging and the incidence of events in relation to the age groups were compared using the multivariable Cox proportional hazards model. The prevalences of diabetes mellitus and hypertension were higher in older men than in younger men, while the prevalences of smoking and obesity were higher in younger men. However, a similar difference in risk factors was not seen in women. High-density lipoprotein cholesterol was higher in women than in men across all age groups. Triglycerides were higher in younger men than in older men and all groups of women. The mean follow-up levels of total cholesterol and low-density lipoprotein cholesterol were lower in older patients than in younger patients. Pravastatin (10-20 mg/day) reduced the risk of CVD by about 30-40% across all age groups, and there was no difference between men and women. Of particular note in this analysis, CVD risk was markedly reduced in older women compared with younger women (53% vs 30% in women aged ≥65 vs ≥45 years). A similar satisfactory risk reduction for CVD was achieved with low-dose pravastatin in all men and in older women in particular, despite differences in the prevalence of risk factors. ClinicalTrials.gov Identifier: NCT00211705.

Increased risk for cardiovascular outcomes and effect of cholesterol-lowering pravastatin therapy in patients with diabetes mellitus in the pravastatin anti-atherosclerosis trial in the elderly (PATE).

PubMed

Ishikawa, Toshitsugu; Ito, Hideki; Ouchi, Yasuyoshi; Ohashi, Yasuo; Saito, Yasushi; Nakamura, Haruo; Orimo, Hajime; Pate Investigators

2005-01-01

The Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE) was the first large-scale, prospective clinical trial to show that cholesterol-lowering therapy with pravastatin is effective in reducing the risk for cardiovascular events (CVEs) in elderly (aged ≥60 years) patients with hypercholesterolemia. PATE also included a subgroup of patients with diabetes mellitus (DM). The aim of this post hoc analysis was to assess the effects of lon-gtermpravastatin therapy on cardiovascular outcomes in the subgroup of patients with DM compared with a subgroup without it. PATE was conducted at 50 hospitals, universities, and clinics acrossJapan. Patients were randomly allocated to 1 of 2 treatment groups: low-dose pravastatin (5 mg PO QD; L group) or standard-lose pravastatin (in Japan, 10 mg PO QD; S group). Treatment was given for 3 to 5 years. Serum cholesterol levels were measured and the prevalence of CVEs was determined. The primary end point of the study was the S:L risk ratio for fatal or nonfatal CVEs. The secondary end point was the effect of diabetic patients' glycemic control on CVEs. A total of 665 patients (527 women, 138 men; mean [SD] age, 72.8[5.7] years) were followed up for a mean of 3.9 years (range, 3-5 years). Among these, 199 patients had DM; 104 patients with DM were allocated to the L group and 95 to the S group. Four hundred sixty-six patients did not have DM (L group, 230 patients; S group, 236 patients). Overall, between 3 months and 3 years after the initiation of treatment, patients in the L group (mean dose, 4.5 mg/d) experienced reductions from baseline total cholesterol level of 11% to 13%. Those in the S group (mean dose, 8.3 mg/d) experienced reductions from baseline of 15% to 17%. Decreases in low-density lipoprotein cholesterol (LDL-C) levels were 17% to 20% and 23% to 26% in the L and S groups, respectively. Statistically similar reductions were noted between patients with DM and those without it in response to either dose. The DM subgroup experienced 32 CVEs (L group, 17; S group, 15) compared with 39 CVEs (L group, 25; S group, 14) in the subgroup without DM. The S:L CVE risk ratio (primary end point) was 0.94 (95% Cl, 0.46-1.92) in patients with DM and 0.54 (95% Cl, 0.28-1.05) in those without DM; the differences between the treatment groups were not statistically significant. The risk for CVEs in patients with DM whose glycosylated hemoglobin concentrations were <8.0% and ≥8.0% were, respectively, 1.87-fold (95% Cl, 1.09-3.20; P = 0.02) and 3.79-fold (95% Cl, 1.92-7.48; P < 0.01) higher than that in patients without DM. In this post hoc analysis of the effects of long-term cholesterol-loweringtherapy (low- and standard-dose pravastatin) on cardiovascular outcomes in elderly patients with DM, dose had no effect on the risk for CVEs in these patients as it did in those without DM. Poorer glycemic control in patients with DM was related to a higher risk for CVEs. The lack of pravastatin efficacy found in the subgroup with DM may have been attributable to the small differences in LDL-C levels found between the 2 treatment groups and/or the small sample size of the study.

The role of hepatic transport and metabolism in the interactions between pravastatin or repaglinide and two rOatp inhibitors in rats.

PubMed

Badolo, Lassina; Bundgaard, Christoffer; Garmer, Mats; Jensen, Bente

2013-07-16

A change in the function or expression of hepatic drug transporters may have significant effect on the efficacy or safety of orally administered drugs. Although a number of clinical drug-drug interactions associated with hepatic transport proteins have been reported, in practice it is not always straightforward to discriminate other pathways (e.g. drug metabolism) from being involved in these interactions. The present study was designed to assess the interactions between organic anion transporting polypeptide (Oatp) substrates (pravastatin or repaglinide) and inhibitors (spironolactone or diphenhydramine) in vivo in rats. The mechanisms behind the interactions were then investigated using in vitro tools (isolated hepatocytes and rat liver microsomes). The results showed a significant increase in the systemic exposures of pravastatin (2.5-fold increase in AUC) and repaglinide (1.8-fold increase in AUC) after co-administration of spironolactone to rats. Diphenhydramine increased the AUC of repaglinide by 1.4-fold. The in vivo interactions observed in rats between Oatp substrates and inhibitors may a priori be classified as transport-mediated drug-drug interactions. However, mechanistic studies performed in vitro using both isolated rat hepatocytes and rat liver microsomes showed that the interaction between pravastatin and spironolactone may be solely linked to the inhibition of pravastatin uptake in liver. On the contrary, the inhibition of cytochrome P450 seemed to be the reason for the interactions observed between repaglinide and spironolactone. Although the function and structure of transport proteins may vary between rats and humans, the approach used in the present study can be applied to humans and help to understand the role of drug transport and drug metabolism in a given drug-drug interaction. This is important to predict and mitigate the risk of drug-drug interactions for a candidate drug in pre-clinical development, it is also important for the optimal design of drug-drug interactions studies in the clinic. Copyright © 2013 Elsevier B.V. All rights reserved.

Progression of kidney disease in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

PubMed

Rahman, Mahboob; Baimbridge, Charles; Davis, Barry R; Barzilay, Joshua; Basile, Jan N; Henriquez, Mario A; Huml, Anne; Kopyt, Nelson; Louis, Gail T; Pressel, Sara L; Rosendorff, Clive; Sastrasinh, Sithiporn; Stanford, Carol

2008-09-01

Dyslipidemia is common in patients with chronic kidney disease. The role of statin therapy in the progression of kidney disease is unclear. Prospective randomized clinical trial, post hoc analyses. 10,060 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) stratified by baseline estimated glomerular filtration rate (eGFR): less than 60, 60 to 89, and 90 or greater mL/min/1.73 m(2). Mean follow-up was 4.8 years. Randomized; pravastatin, 40 mg/d, or usual care. Total, high-density lipoprotein, and low-density lipoprotein cholesterol; end-stage renal disease (ESRD), eGFR. Through year 6, total cholesterol levels decreased in the pravastatin (-20.7%) and usual-care groups (-11.2%). No significant differences were seen between groups for rates of ESRD (1.36 v 1.45/100 patient-years; P = 0.9), composite end points of ESRD and 50% or 25% decrease in eGFR, or rate of change in eGFR. Findings were consistent across eGFR strata. In patients with eGFR of 90 mL/min/1.73 m(2) or greater, the pravastatin arm tended to have a higher eGFR. Proteinuria data unavailable, post hoc analyses, unconfirmed validity of the Modification of Diet in Renal Disease Study equation in normal eGFR range, statin drop-in rate in usual-care group with small cholesterol differential between groups. In hypertensive patients with moderate dyslipidemia and decreased eGFR, pravastatin was not superior to usual care in preventing clinical renal outcomes. This was consistent across the strata of baseline eGFR. However, benefit from statin therapy may depend on the degree of the cholesterol level decrease achieved.

Progression of Kidney Disease in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin Versus Usual Care: A Report From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

PubMed Central

Rahman, Mahboob; Baimbridge, Charles; Davis, Barry R.; Barzilay, Joshua; Basile, Jan N.; Henriquez, Mario A.; Huml, Anne; Kopyt, Nelson; Louis, Gail T.; Pressel, Sara L.; Rosendorff, Clive; Sastrasinh, Sithiporn; Stanford, Carol

2009-01-01

Background Dyslipidemia is common in patients with chronic kidney disease. The role of statin therapy on the progression of kidney disease is unclear. Study Design Prospective randomized clinical trial, post hoc analyses. Setting and participants 10,060 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (lipid-lowering component) stratified by baseline eGFR: <60, 60–89, ≥90 mL/min/1.73 m2. Mean follow-up was 4.8 years. Intervention Randomized, pravastatin 40 mg/day or usual care. Outcomes and measurements Total cholesterol, HDL- and LDL-cholesterol; end stage renal disease (ESRD), estimated glomerular filtration rate (eGFR). Results Through year six, total cholesterol declined in the pravastatin (−20.7%) and usual care groups (−11.2%). No significant differences were seen between the groups for rates of ESRD (1.36 vs 1.45/100 patient years, P=0.9), composite endpoints of ESRD and 50% or 25% decline in eGFR, or rate of change of eGFR. Findings were consistent across eGFR strata. In patients with eGFR≥90 mL/min/1.73 m2, the pravastatin arm tended to have a higher eGFR. Limitations Proteinuria data unavailable, post hoc analyses, unconfirmed validity of the Modification of Diet in Renal Disease Study equation in normal eGFR range, statin drop-in rate in usual care group with small cholesterol differential between groups. Conclusions In hypertensive patients with moderate dyslipidemia and reduced eGFR, pravastatin was not superior to usual care in preventing clinical renal outcomes. This was consistent across the strata of baseline eGFR. However, benefit from statin therapy may depend on degree of cholesterol reduction achieved. PMID:18676075

QRS/T-wave and calcium alternans in a type I diabetic mouse model for spontaneous postmyocardial infarction ventricular tachycardia: A mechanism for the antiarrhythmic effect of statins.

PubMed

Jin, Hongwei; Welzig, Charles M; Aronovitz, Mark; Noubary, Farzad; Blanton, Robert; Wang, Bo; Rajab, Mohammad; Albano, Alfred; Link, Mark S; Noujaim, Sami F; Park, Ho-Jin; Galper, Jonas B

2017-09-01

The incidence of sudden arrhythmic death is markedly increased in diabetics. The purpose of this study was to develop a mouse model for postmyocardial infarction (post-MI) ventricular tachycardia (VT) in the diabetic heart and determine the mechanism of an antiarrhythmic effect of statins. ECG transmitters were implanted in wild-type (WT), placebo, and pravastatin-treated type I diabetic Akita mice. MIs were induced by coronary ligation, and Ca 2+ transients were studied by optical mapping, and Ca 2+ transients and sparks in left ventricular myocytes (VM) by the Ionoptix system and confocal microscopy. Burst pacing of Akita mouse hearts resulted in rate-related QRS/T-wave alternans, which was attenuated in pravastatin-treated mice. Post-MI Akita mice developed QRS/T-wave alternans and VT at 2820 ± 879 beats per mouse, which decreased to 343 ± 115 in pravastatin-treated mice (n = 13, P <.05). Optical mapping demonstrated pacing-induced VT originating in the peri-infarction zone and Ca 2+ alternans, both attenuated in hearts of statin-treated mice. Akita VM displayed Ca 2+ alternans, and triggered activity as well as increased Ca 2+ transient decay time (Tau), Ca 2+ sparks, and cytosolic Ca 2+ and decreased SR Ca 2+ stores all of which were in part reversed in cells from statin treated mice. Homogenates of Akita ventricles demonstrated decreased SERCA2a/PLB ratio and increased ratio of protein phosphatase (PP-1) to the PP-1 inhibitor PPI-1 which were reversed in homogenates of pravastatin-treated Akita mice. Pravastatin decreased the incidence of post-MI VT and Ca 2+ alternans in Akita mouse hearts in part by revering abnormalities of Ca 2+ handling via the PP-1/PPI-1 pathway. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Effects of maximal atorvastatin and rosuvastatin treatment on markers of glucose homeostasis and inflammation

USDA-ARS?s Scientific Manuscript database

Recent studies show that statin therapy, while effective at lowering the risk of cardiovascular disease (CVD), may be associated with an increased risk of diabetes. To test the effects of maximal dosages of rosuvastatin and atorvastatin (80mg/day and 40mg/day, respectively) we obtained frozen serum ...

Plasma Drug Concentrations of Orally Administered Rosuvastatin in Hispaniolan Amazon Parrots (Amazona ventralis).

PubMed

Beaufrère, Hugues; Papich, Mark G; Brandão, João; Nevarez, Javier; Tully, Thomas N

2015-03-01

Atherosclerotic diseases are common in pet psittacine birds, in particular Amazon parrots. While hypercholesterolemia and dyslipidemia have not definitely been associated with increased susceptibility to atherosclerosis in parrots, these are important and well-known risk factors in humans. Therefore statin drugs such as rosuvastatin constitute the mainstay of human treatment of dyslipidemia and the prevention of atherosclerosis. No pharmacologic studies have been performed in psittacine birds despite the high prevalence of atherosclerosis in captivity. Thirteen Hispaniolan Amazon parrots were used to test a single oral dose of 10 mg/kg of rosuvastatin with blood sampling performed according to a balanced incomplete block design over 36 hours. Because low plasma concentrations were produced in the first study, a subsequent pilot study using a dose of 25 mg/kg in 2 Amazon parrots was performed. Most plasma samples for the 10 mg/kg dose and all samples for the 25 mg/kg dose had rosuvastatin concentration below the limits of quantitation. For the 10 mg/kg study, the median peak plasma concentration and time to peak plasma concentration were 0.032 μg/mL and 2 hours, respectively. Our results indicate that rosuvastatin does not appear suitable in Amazon parrots as compounded and used at the dose in this study. Pharmacodynamic studies investigating lipid-lowering effects of statins rather than pharmacokinetic studies may be more practical and cost effective in future studies to screen for a statin with more ideal properties for potential use in psittacine dyslipidemia and atherosclerotic diseases.

Effects of HMG-COA Reductase Inhibitor Therapy on LDL Cholesterol Blood Levels in Hyperlipidemia: A Longitudinal Retrospective Anlaysis Using a Department of Defense Integrated Database.

DTIC Science & Technology

1998-05-21

United States. They are atorvastatin (Lipitor® by Bristol-Myers Squibb), fluvastatin (Lescol® by Sandoz), lovastatin (Mevacor® by Merck), pravastatin...34first- and-a-half40 generation statin (semi-synthetic), fluvastatin being a second generation statin (a racemic synthetic), and atorvastatin being a...third generation 27 statin (a pure enantiomer synthetic). Atorvastatin , fluvastatin, and pravastatin are taken in the active hydroxy-acid form114

Cost Effectiveness of Statin Drug Therapy in the Lowering of Cholesterol in Patients at Dwight D. Eisenhower Army Medical Center

DTIC Science & Technology

2000-05-01

significant increase in the LDL-C levels of patients (p=.113 for atorvastatin to simvastatin conversion, p=.072 for pravastatin to simvastatin conversion...the ability for a patient to reach their LDL-C goal (p=.571 for atorvastatin to simvastatin conversion, p=.579 for pravastatin to simvastatin...two were available under special order criteria ( atorvastatin and fluvastatin) during the period of FY 97 to FY 99. Due to double-digit inflation in the

The effect of rosuvastatin on oestrogen & progestin pharmacokinetics in healthy women taking an oral contraceptive

PubMed Central

Simonson, Steven G; Martin, Paul D; Warwick, Mike J; Mitchell, Patrick D; Schneck, Dennis W

2004-01-01

Aims To assess the effect of rosuvastatin on oestrogen and progestin pharmacokinetics in women taking a commonly prescribed combination oral contraceptive steroid (OCS); the effect on endogenous hormones and the lipid profile was also assessed. Methods This open-label, nonrandomised trial consisted of 2 sequential menstrual cycles. Eighteen healthy female volunteers received OCS (Ortho Tri-Cyclen®) on Days 1–21 and placebo OCS on Days 22–28 of Cycles A and B Rosuvastatin 40 mg was also given on Days 1–21 of Cycle B. Results Co-administration did not result in lower exposures to the exogenous oestrogen or progestin OCS components. Co-administration increased AUC[0–24] for ethinyl oestradiol (26%; 90% CI ratio 1.19–1.34), 17-desacetyl norgestimate (15%; 90% CI 1.10–1.20), and norgestrel (34%; 90% CI 1.25–1.43), and increased Cmax for ethinyl oestradiol (25%; 90% CI 1.17–1.33) and norgestrel (23%; 90% CI 1.14–1.33). The increases in exposure were attributed to a change in bioavailability rather than a decrease in clearance. Luteinizing and follicle-stimulating hormone concentrations were similar between cycles. There were no changes in the urinary excretion of cortisol and 6β-hydroxycortisol. Rosuvastatin significantly decreased low-density lipoprotein cholesterol [-55%], total cholesterol [-27%], and triglycerides [-12%], and significantly increased high-density lipoprotein cholesterol[11%]. Co-administration was well tolerated. Conclusions Rosuvastatin can be coadministered with OCS without decreasing OCS plasma concentrations, indicating that contraceptive efficacy should not be decreased. The results are consistent with an absence of induction of CYP3A4 by rosuvastatin. The expected substantial lipid-regulating effect was observed in this study, and there was no evidence of an altered lipid-regulating effect with OCS coadministration. PMID:14998424

Pharmacological characterization of mechanisms involved in the vasorelaxation produced by rosuvastatin in aortic rings from rats with a cafeteria-style diet

PubMed Central

López-Canales, Jorge Skiold; Lozano-Cuenca, Jair; López-Canales, Oscar Alberto; Aguilar-Carrasco, José Carlos; Aranda-Zepeda, Lidia; López-Sánchez, Pedro; Castillo-Henkel, Enrique Fernando; López-Mayorga, Ruth Mery; Valencia-Hernández, Ignacio

2015-01-01

The present study aimed to investigate the possible influence of several inhibitors and blockers on the vascular effect produced by the acute in vitro application of rosuvastatin to phenylephrine-precontracted aortic rings from rats with a semi-solid, cafeteria-style (CAF) diet. It also aimed to examine the effects of rosuvastatin on the expression of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase, constitutive cyclooxygenase, and inducible cyclooxygenase in aortic rings from rats with a CAF diet. From comparisons of the effect on phenylephrine-precontracted aortic rings extracted from rats with two different diets (a standard and a CAF diet), it was found that 10−9–10−5-mol/L rosuvastatin produced lower concentration-dependent vasorelaxation on rings from the CAF diet group. The vasorelaxant effect was unaffected by the vehicle, but it was significantly attenuated by 10−5-mol/L NG-nitro-l-arginine methyl ester, 10−2-mol/L tetraethylammonium, 10−3-mol/L 4-aminopyridine, 10−7-mol/L apamin plus 10−7-mol/L charybdotoxin, 10−5-mol/L indomethacin, or 10−5-mol/L cycloheximide. Moreover, in aortic rings from rats with a CAF diet, rosuvastatin enhanced the expression of eNOS, inducible nitric oxide synthase, constitutive cyclooxygenase, and inducible cyclooxygenase. The acute in vitro application of rosuvastatin to phenylephrine-precontracted aortic rings from rats with a CAF diet had a vasorelaxant effect. Overall, the present results suggest that the stimulation of eNOS, the opening of Ca2+-activated and voltage-activated K+ channels, the stimulation of prostaglandin synthesis and enhanced protein levels of eNOS, inducible nitric oxide synthase, constitutive cyclooxygenase, and inducible cyclooxygenase are involved in this relaxant effect. PMID:25881486

The Hypolipidemic and Pleiotropic Effects of Rosuvastatin Are Not Enhanced by Its Association with Zinc and Selenium Supplementation in Coronary Artery Disease Patients: A Double Blind Randomized Controlled Study

PubMed Central

Sena-Evangelista, Karine Cavalcanti Maurício; Pedrosa, Lucia Fatima Campos; Paiva, Maria Sanali Moura Oliveira; Dias, Paula Cristina Silveira; Ferreira, Diana Quitéria Cabral; Cozzolino, Sílvia Maria Franciscato; Faulin, Tanize Espírito Santo; Abdalla, Dulcinéia Saes Parra

2015-01-01

Objective Statins treatment may modify the levels of zinc and selenium, minerals that can improve vascular function and reduce oxidative damage and inflammation in atherosclerotic patients. This study aimed to evaluate the effects of rosuvastatin, alone or associated with zinc and selenium supplementation, on lipid profile, antioxidant enzymes and mineral status in coronary artery disease patients. Material and Methods A double-blind randomized clinical trial was performed in which patients (n = 76) were treated with 10 mg rosuvastatin over 4 months associated or not with zinc (30 mg/d) and selenium (150 μg/d) supplementation. The following parameters were analyzed before and after the intervention: anthropometric measurements, lipid profile, high sensitivity C-reactive protein (hs-CRP), electronegative low density lipoprotein (LDL(-)) concentrations, activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), zinc and selenium concentrations in blood plasma and erythocytes. Significance was determined using an α of 5% (two-tailed). Results We found that rosuvastatin therapy was efficient in reducing total cholesterol, LDL-cholesterol, non-HDL cholesterol, triglycerides, and hs-CRP independently of mineral supplementation. Neither treatment was associated with significant changes in LDL(-). Similarly, the antioxidant enzymes GPx and SOD activity were unchanged by treatments. Neither treatment was associated with significant differences in concentrations of zinc or selenium in blood plasma and erythocytes of studied groups. Conclusion Rosuvastatin treatment did not affect zinc and selenium levels in coronary artery disease patients. The zinc and selenium supplementation at doses used in this study did not change lipid profile or SOD and GPx activity in patients receiving rosuvastatin. Further studies should be focused on testing alternative doses and supplements in different populations to contribute for a consensus on the ideal choice of antioxidants to be used as possible complementary therapies in atherosclerotic patients. Trial Registration ClinicalTrials.gov NCT01547377 PMID:25785441

Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the SLCO1B1 or CYP2C9 genetic polymorphism affect these drug interactions?

PubMed Central

Kim, Choon Ok; Oh, Eun Sil; Kim, Hohyun; Park, Min Soo

2017-01-01

To improve cardiovascular outcomes, dyslipidemia in patients with diabetes needs to be treated. Thus, these patients are likely to take glimepiride and rosuvastatin concomitantly. Therefore, this study aimed to evaluate the pharmacokinetic (PK) interactions between these two drugs in healthy males and to explore the effect of SLCO1B1 and CYP2C9 polymorphisms on their interactions in two randomized, open-label crossover studies. Glimepiride was studied in part 1 and rosuvastatin in part 2. Twenty-four participants were randomly assigned to each part. All subjects (n=24) completed part 1, and 22 subjects completed part 2. A total of 38 subjects among the participants of the PK interaction studies were enrolled in the genotype study to analyze their SLCO1B1 and CYP2C9 polymorphisms retrospectively (n=22 in part 1, n=16 in part 2). Comparison of the PK and safety of each drug alone with those of the drugs in combination showed that both glimepiride and rosuvastatin did not interact with each other and had tolerable safety profiles in all subjects. However, with regard to glimepiride PK, the SLCO1B1 521TC group had a significantly higher maximum plasma concentration (Cmax,ss) and area under the plasma concentration–time curve during the dose interval at steady state (AUCτ,ss) for glimepiride in combination with rosuvastatin than those for glimepiride alone. However, other significant effects of the SLCO1B1 or CYP2C9 polymorphism on the interaction between the two drugs were not observed. In conclusion, there were no significant PK interactions between the two drugs; however, the exposure to glimepiride could be affected by rosuvastatin in the presence of the SLCO1B1 polymorphism. PMID:28260863

Effects of Rosuvastatin on the expression of the genes involved in cholesterol metabolism in rats: adaptive responses by extrahepatic tissues.

PubMed

Ahmadi, Yasin; Haghjoo, Amir Ghorbani; Dastmalchi, Siavoush; Nemati, Mahboob; Bargahi, Nasrin

2018-06-30

Statins mostly target the liver; therefore, increase in the synthesis of cholesterol by extra-hepatic tissues and then transferring this cholesterol to the liver can be regarded as adaptive responses by these tissues. In addition to cholesterol, these adaptive responses can increase isoprenoid units as the byproducts of the cholesterol biosynthesis pathway; isoprenoids play a key role in regulating cell signaling pathways and cancer development. Thus, there is a primary need for in vivo investigation of the effects of statins on the cholesterol metabolism in the extra-hepatic tissues. Eighteen male Sprague-Dawley rats were randomly divided into control (n = 9) and treatment (n = 9) groups. The treatment group was orally given 10 mg/kg/day of Rosuvastatin for 6 weeks. Then, serum lipid profile, expression levels of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), ABCA1, ABCG1 and ApoA1, and activity of HMGCR were measured in the liver, intestine and adipose tissues. Rosuvastatin significantly reduced total cholesterol and LDL-C. The expression levels of ABCA1, ABCG1, and ApoA1 in the liver and HMGCR in both liver and intestine were significantly increased in the Rosuvastatin treated-group. However, in the intestine, there were no significant differences in the expression levels of ABCA1 and ABCG1 between the study groups. Rosuvastatin had no effect on the adipose tissue. The HMGCR activity was significantly increased in the liver and intestine of the Rosuvastatin-treated group. In spite of the adipose tissue, the intestine efficiently responses to the reduced levels of cholesterol and increases its cholesterogenesis capacity. However, adipose tissue seems to play a small role in correcting cholesterol deficiency during the course of statin therapy. Copyright © 2018. Published by Elsevier B.V.

pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1.

PubMed

Varma, Manthena V; Rotter, Charles J; Chupka, Jonathan; Whalen, Kevin M; Duignan, David B; Feng, Bo; Litchfield, John; Goosen, Theunis C; El-Kattan, Ayman F

2011-08-01

The human organic anion transporting polypeptide 2B1 (OATP2B1, SLCO2B1) is ubiquitously expressed and may play an important role in the disposition of xenobiotics. The present study aimed to examine the role of OATP2B1 in the intestinal absorption and tissue uptake of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors (statins). We first investigated the functional affinity of statins to the transporter as a function of extracellular pH, using OATP2B1-transfeced HEK293 cells. The results indicate that OATP2B1-mediated transport is significant for rosuvastatin, fluvastatin and atorvastatin, at neutral pH. However, OATP2B1 showed broader substrate specificity as well as enhanced transporter activity at acidic pH. Furthermore, uptake at acidic pH was diminished in the presence of proton ionophore, suggesting proton gradient as the driving force for OATP2B1 activity. Notably, passive transport rates are predominant or comparable to active transport rates for statins, except for rosuvastatin and fluvastatin. Second, we studied the effect of OATP modulators on statin uptake. At pH 6.0, OATP2B1-mediated transport of atorvastatin and cerivastatin was not inhibitable, while rosuvastatin transport was inhibited by E-3-S, rifamycin SV and cyclosporine with IC(50) values of 19.7 ± 3.3 μM, 0.53 ± 0.2 μM and 2.2 ± 0.4 μM, respectively. Rifamycin SV inhibited OATP2B1-mediated transport of E-3-S and rosuvastatin with similar IC(50) values at pH 6.0 and 7.4, suggesting that the inhibitor affinity is not pH-dependent. Finally, we noted that OATP2B1-mediated transport of E-3-S, but not rosuvastatin, is pH sensitive in intestinal epithelial (Caco-2) cells. However, uptake of E-3-S and rosuvastatin by Caco-2 cells was diminished in the presence of proton ionophore. The present results indicate that OATP2B1 may be involved in the tissue uptake of rosuvastatin and fluvastatin, while OATP2B1 may play a significant role in the intestinal absorption of several statins due to their transporter affinity at acidic pH.

Effect of a hydrophilic and a hydrophobic statin on cardiac salvage after ST-elevated acute myocardial infarction - a pilot study.

PubMed

Chitose, Tadasuke; Sugiyama, Seigo; Sakamoto, Kenji; Shimomura, Hideki; Yamashita, Takuro; Hokamaki, Jun; Tsunoda, Ryusuke; Shiraishi, Shinya; Yamashita, Yasuyuki; Ogawa, Hisao

2014-11-01

Early statin therapy after acute coronary syndrome reduces atherothrombotic vascular events. This study aimed to compare the effects of hydrophilic and hydrophobic statins on myocardial salvage and left ventricular (LV) function in patients with ST-elevated myocardial infarction (STEMI). Seventy-five STEMI patients who had received emergency reperfusion therapy were enrolled and randomized into the hydrophilic statin group (rosuvastatin; 5 mg/day, n = 38) and hydrophobic statin group (atorvastatin; 10 mg/day, n = 37) for 6 months. LV ejection fraction (LVEF), and B-type natriuretic peptide (BNP) and co-enzyme Q10 (CoQ10) levels were measured at baseline and the end of treatment. The myocardial salvage index was assessed by single photon emission computed tomography with (123-)I-β-methyl-iodophenylpentadecanoic acid (ischemic area-at-risk at onset of STEMI: AAR) and (201-)thallium scintigraphy (area-at-infarction at 6 months: AAI) [myocardial salvage index = (AAR-AAI) × 100/AAR (%)]. Onset-to-balloon time and maximum creatine phosphokinase levels were comparable between the groups. After 6 months, rosuvastatin (-37.6% ± 17.2%) and atorvastatin (-32.4% ± 22.4%) equally reduced low-density lipoprotein-cholesterol (LDL-C) levels (p = 0.28). However, rosuvastatin (+3.1% ± 5.9%, p < 0.05), but not atorvastatin (+1.6% ± 5.7%, p = 0.15), improved LVEF. Rosuvastatin reduced BNP levels compared with atorvastatin (-53.3% ± 48.8% versus -13.8% ± 82.9%, p < 0.05). The myocardial salvage index was significantly higher in the rosuvastatin group than the atorvastatin group (78.6% ± 29.1% versus 52.5% ± 38.0%, p < 0.05). CoQ10/LDL-C levels at 6 months were increased in the rosuvastatin group (+23.5%, p < 0.01) and percent changes in CoQ10/LDL-C were correlated with the myocardial salvage index (r = 0.56, p < 0.01). Rosuvastatin shows better beneficial effects on myocardial salvage than atorvastatin in STEMI patients, including long-term cardiac function, associated with increasing CoQ10/LDL-C. URL http://www.umin.ac.jp/ctr/index.htm Unique Identifier: UMIN000003893. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Rosuvastatin enhances the catabolism of LDL apoB-100 in subjects with combined hyperlipidemia in a dose dependent manner

USDA-ARS?s Scientific Manuscript database

Dose-associated effects of rosuvastatin on the metabolism of apolipoprotein (apo) B-100 in triacylglycerol rich lipoprotein (TRL, d < 1.019 g/ml) and low density lipoprotein (LDL) and of apoA-I in high density lipoprotein (HDL) were assessed in subjects with combined hyperlipidemia. Our primary hypo...

[Comparison of pravastatin and diet in the treatment of hypercholesterolemia].

PubMed

Palazzuoli, V; Mondillo, S; Faglia, S; D'Aprile, N; Mangiacotti, L

1995-10-01

Aim of this study is to point out a correct therapy for the treatment of poligenic hypercholesterolemia resistant to dietetic treatment. There have been studied 40 patients which, after repeated haematochemical controls, resulted affected by dyslipidaemia with prevalent increase of the cholesterol levels. After 30 days of standard hypo-caloric dietetic treatment were enrolled 23 patients, 13 males and 10 females, who presented a plasmatic cholesterol level superior to 250 mg% and LDL superior to 160 mg%. All the patients continued the dietetic treatment; 10 patients began pravastatin therapy at a dose of 20 mg/die while to the rest of them was given placebo. The 30th, 60th, 120th day were controlled the following haematochemical parameters: lipidic frame haematology, hepatic and renal function, glycemia and CPK. After 4 months of treatment the average plasmatic levels of cholesterol resulted different in the two groups: mg% (p < 0.001) in the pravastatin group and 262 mg% (P = ns) in the control group. Then, the pravastatin therapy was suspended and all 23 patients continued for 30 days, dietetic treatment and placebo. After 6 months a new control of the lipidic frame was performed. Our results showed that the hypocholesterolic therapy must be continued for ever. In fact, the suspension of the treatment is followed by an immediate rebound of the dislipidaemia which plasmatic cholesterol levels even superior to the basic levels with probable negative repercussion on the cardiovascular system.

Assessing Impact of High-Dose Pitavastatin on Carotid Artery Elasticity with Speckle-Tracking Strain Imaging.

PubMed

Kim, Chee Hae; Wang, Shuang; Park, Jun-Bean; Jung, Keun-Hwa; Yoon, Yeonyee E; Lee, Seung-Pyo; Kim, Hyung-Kwan; Kim, Yong-Jin; Cho, Goo-Yeong; Sohn, Dae-Won

2018-03-07

Speckle-tracking imaging has been introduced for the precise assessment of vessel mechanics. However, there are no data on the role of this imaging tool in assessing the changes in vasculature with statin therapy, which is known to enhance vascular elasticity. This study was a prospective study including 48 statin-naïve patients (age, 58.2±8.4 years; 29.2% male) with hypercholesterolemia. Circumferential carotid artery strain (CAS) and stiffness index (β 2 ) were measured using speckle-tracking imaging before and after 3 months of high-dose pitavastatin treatment (4 mg daily). For the comparison, we measured conventional carotid elasticity parameters and intima-media thickness using B-mode ultrasound at the same time points. Compared with baseline, there was significant improvement in circumferential CAS (2.98%±1.18% to 3.40%±1.43%, p=0.008) and β 2 (0.19±0.07 to 0.17±0.08, p=0.047) after statin therapy. Contrariwise, there were no significant changes in all conventional carotid elasticity metrics and intima-media thickness. When stratifying patients into two subgroups by 10 year atherosclerotic cardiovascular disease (ASCVD) risk, speckle-tracking-derived circumferential CAS and β 2 improved significantly only in patients with ASCVD risk ≥ 7.5%. Short-term treatment with high-dose pitavastatin improved carotid artery elasticity measured by speckle-tracking method, but not conventional parameters by B-mode ultrasound. Speckle-tracking-based measurements may allow the early noninvasive assessment of statin effects on vascular function in hypercholesterolemic patients.

Enhancement of human oral bioavailability and in vitro antitumor activity of rosuvastatin via spray dried self-nanoemulsifying drug delivery system.

PubMed

Kamel, Amany O; Mahmoud, Azza A

2013-01-01

The purpose of this study was to develop spray dried self-nanoemulsifying drug delivery system (SNEDDS) tablets of rosuvastatin using mannitol as a carrier. SNEDDS were prepared using Capryol 90, poloxamer 407 and Transcutol P or triacetin as oil, surfactant and cosurfactants, respectively. The prepared systems were characterized and their cytotoxicity was evaluated using Caco-2 cell lines. A comparative bioavailability study was performed in human volunteers relative to the conventional commercial product. Results showed better self-nanoemulsifying ability of systems containing triacetin compared to Transcutol P. SNEDDS formed uni-modal nanoemulsion droplet size distributions with droplet size less than 50 nm and polydispersity index values ranging from 0.127 to 0.275. The solubilizing capacity of rosuvastatin was affected by both surfactant and cosurfactant concentrations. Upon spray drying, systems prepared using Transcutol P tended to be soft and tacky and were sticking to the walls of the dryer. The redispersion of rosuvastatin from solid SNEDDS was very fast (100% within 5 minutes). Optimized SNEDDS prepared with triacetin were safe with no cytotoxic effect on Caco-2 cells. The anticancer effect of rosuvastatin was enhanced when incorporated in SNEDDS (IC50 value decreased from 4 to 3 microg/ml) due to the increase in penetration of SNEDDS inside the cells. The relative bioavailability for SNEDDS tablets compared to the commercial tablets was 167%. The effective solubilization, penetration and enhancement in bioavailability of SNEDDS tablets proves their potential as a safe, and effective drug delivery system for poorly-soluble drugs.

A Review on Pharmacokinetic Modeling and the Effects of Environmental Stressors on Pharmacokinetics for Operational Medicine: Operational Pharmacokinetics

DTIC Science & Technology

2009-09-01

hypercholesterolemia Two-compartment model Ezzet, Krishna et al. 2001 Antilipemics Statins: simvastatin, rosuvastatin, atorvastatin Treatment of...Pharmacokinetic model* & rosuvastatin Scopus 14 3 PubMed 9 3 Pharmacokinetic model* & atorvastatin Scopus 49 4 Pharmacokinetic model* & zaleplon...Fentanyl & pharmacokinetic & heat 9 2 Fentanyl & pharmacokinetic & cold 4 0 Fentanyl & pharmacokinetic & blood loss 19 5 Atorvastatin

Involvement of 2-C-methyl-D-erythritol-4-phosphate pathway in biosynthesis of aphidicolin-like tetracyclic diterpene of Scoparia dulcis.

PubMed

Nkembo, Marguerite Kasidimoko; Lee, Jung-Bum; Nakagiri, Takeshi; Hayashi, Toshimitsu

2006-05-01

Specific inhibitors of the MVA pathway (pravastatin) and the MEP pathway (fosmidomycin) were used to interfere with the biosynthetic flux which leads to the production of aphidicolin-like diterpene in leaf organ cultures of Scoparia dulcis. Treatment of leaf organs with fosmidomycin resulted in dose dependent inhibition of chlorophylls, carotenoids, scopadulcic acid B (SDB) and phytol production, and no effect on sterol production was observed. In response to the pravastatin treatment, a significant decrease in sterol and perturbation of SDB production was observed.

The effect of Na+/taurocholate cotransporting polypeptide (NTCP) c.800C > T polymorphism on rosuvastatin pharmacokinetics in Chinese healthy males.

PubMed

Lou, Xiao-Ya; Zhang, Wei; Wang, Guo; Hu, Dong-Li; Guo, Dong; Tan, Zhi-Rong; Zhou, Hong-Hao; Chen, Yao; Bao, Hei-Hua

2014-10-01

This study was designed to investigate the potential association between NTCP c.800C >T polymorphism and rosuvastatin pharmacokinetics in Chinese healthy males. 305 individuals were enrolled to identify NTCP c.800C > T, OATP1B1 c.521T > C and BCRP c.421C > A genotypes by direct sequencing and pyrosequencing methods, respectively. 17 healthy volunteers who were OATP1B1 c.521TT and BCRP c.421CC wild-type homozygotes with different NTCP c.800C > T genotype were selected to participate in this pharmacokinetic study. Nine were NTCP c.800CC wild-type homozygotes and the other eight subjects were carriers with at least one c.800T variant allele (seven subjects with c.800CT genotype and one was homozygote of c.800TT). All the subjects received a single oral dose of 10 mg rosuvastatin. The plasma concentrations of rosuvastatin were measured up to 72 h by a LC-MS method. NTCP c.800C > T genetic polymorphism markedly effected rosuvastatin pharmacokinetics. The AUC(o-72) and AUC(0 --> ∞) in subjects with NTCP c.800CT + TT genotype were 56% (162.64 ± 37.55 vs. 103.99 ± 28.15 ng x h/ml, P = 0.016) and 57% greater (178.51 ± 42.75 vs. 113.60 ± 33.73 ng x h/ml, P = 0.020) than those in the c.800CC wild-type subjects, respectively. In the c.800CT + TT mutant group, the C(max) was about 78% higher than those in c.800CC genotype (14.31 ± 3.63 vs. 8.04 ± 1.72 ng x h/ml, P = 0.004). The oral clearance (CL/F) of rosuvastatin in subjects with the c.800CT+TT genotype was only 63% of those in the c.800CC genotype (58.32 ± 12.16 vs. 93.04 ± 20.61 ng x h/ml, P = 0.009). The half-time (T1/2) and the T(max) had no significant difference between two groups (p = 0.466 and 0.713, respectively). NTCP c.800C > T polymorphism play a critical role in the individual variability of rosuvastatin pharmacokinetics in Chinese healthy males after excluding the impact of OATP1B1 c.521T > C and BCRP c.421C > A polymorphisms.

Effect of rosuvastatin dose-loading on serum sLox-1, hs-CRP, and postoperative prognosis in diabetic patients with acute coronary syndromes undergoing selected percutaneous coronary intervention (PCI).

PubMed

Jiao, Yungen; Hu, Feng; Zhang, Zhengang; Gong, Kaizheng; Sun, Xiaoning; Li, Aihua; Liu, Naifeng

2015-01-01

To investigate the effect of rosuvastatin dose-loading on serum levels of lectin-like oxidized low-density lipoprotein receptor-1 (Lox-1) and high-sensitivity c-reactive protein (hs-CRP) and postoperative prognosis in patients with diabetes and non-ST segment elevation acute coronary syndromes (NSTEACS) undergoing selected percutaneous coronary intervention (PCI). A total of 72 patients with diabetes and NSTEACS were randomized to either the group treated with 20 mg rosuvastatin 12 hours prior to PCI with a second dose administered just before PCI (n = 33), or a control group treated with standard method according guideline (n = 39). Serum levels of sLox-1, hs-CRP, CK-MB, and cTnI were measured prior to PCI, and at 24 hours and 30 days after PCI. The 30-day incidence of major adverse cardiac events (MACE) was recorded in both groups. Compared to pre-PCI, serum levels of sLox-1 and hs-CRP of the two groups were increased at 24 hours after PCI (P < 0.05); the levels of CK-MB and cTnI were also improved (P < 0.01); however, the ascended values of sLox-1, hs-CRP, CK-MB, and cTnI were significantly lower in the loading-dose rosuvastatin-treated group than in the control-treated group. Serum levels of sLox-1 and hs-CRP were higher in the loading-dose rosuvastatin-treated group than in the control-treated group at 30 days after PCI (P < 0.05); compared to pre-PCI, the levels of TC and LDL-C were not changed at 24 hours after PCI (P > 0.05) until 30 days after PCI (P < 0.05), but there were no difference between the two groups. The levels of ALT and Scr had no significant difference between the two groups before and after PCI; the 30-day incidence of MACE occurred in 6.06% of patients in the loading-dose rosuvastatin-treated group and in 23.08% of patients in the control-treated group (P < 0.05). The therapy of dose-loading rosuvastatin for patients with diabetes and non-ST segment elevation acute coronary syndromes undergoing selected percutaneous coronary intervention can attenuate the increase of serum levels of sLox-1, reduce myocardial injury and inflammatory reaction caused by PCI, and also reduce the occurrence of MACE 30 days after PCI.

Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.

PubMed

Ridker, Paul M; Danielson, Eleanor; Fonseca, Francisco A H; Genest, Jacques; Gotto, Antonio M; Kastelein, John J P; Koenig, Wolfgang; Libby, Peter; Lorenzatti, Alberto J; MacFadyen, Jean G; Nordestgaard, Børge G; Shepherd, James; Willerson, James T; Glynn, Robert J

2008-11-20

Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.) 2008 Massachusetts Medical Society

Pravastatin reduces Marfan aortic dilation.

PubMed

McLoughlin, Darren; McGuinness, Jonathan; Byrne, John; Terzo, Eloisa; Huuskonen, Vilhelmiina; McAllister, Hester; Black, Alexander; Kearney, Sinead; Kay, Elaine; Hill, Arnold D K; Dietz, Harry C; Redmond, J Mark

2011-09-13

The sequelae of aortic root dilation are the lethal consequences of Marfan syndrome. The root dilation is attributable to an imbalance between deposition of matrix elements and metalloproteinases in the aortic medial layer as a result of excessive transforming growth factor-beta signaling. This study examined the efficacy and mechanism of statins in attenuating aortic root dilation in Marfan syndrome and compared effects to the other main proposed preventative agent, losartan. Marfan mice heterozygous for a mutant allele encoding a cysteine substitution in fibrillin-1 (C1039G) were treated daily from 6 weeks old with pravastatin 0.5 g/L or losartan 0.6 g/L. The end points of aortic root diameter (n=25), aortic thickness, and architecture (n=10), elastin volume (n=5), dp/dtmax (maximal rate of change of pressure) (cardiac catheter; n=20), and ultrastructural analysis with stereology (electron microscopy; n=5) were examined. The aortic root diameters of untreated Marfan mice were significantly increased in comparison to normal mice (0.161 ± 0.001 cm vs 0.252 ± 0.004 cm; P<0.01). Pravastatin (0.22 ± 0.003 cm; P<0.01) and losartan (0.221 ± 0.004 cm; P<0.01) produced a significant reduction in aortic root dilation. Both drugs also preserved elastin volume within the medial layer (pravastatin 0.23 ± 0.02 and losartan 0.29 ± 0.03 vs untreated Marfan 0.19 ± 0.02; P=0.01; normal mice 0.27 ± 0.02). Ultrastructural analysis showed a reduction of rough endoplasmic reticulum in smooth muscle cells with pravastatin (0.022 ± 0.004) and losartan (0.013 ± 0.001) compared to untreated Marfan mice (0.035 ± 0.004; P<0.01). Statins are similar to losartan in attenuating aortic root dilation in a mouse model of Marfan syndrome. They appear to act through reducing the excessive protein manufacture by vascular smooth muscle cells, which occurs in the Marfan aorta. As a drug that is relatively well-tolerated for long-term use, it may be useful clinically.

Effect of rosuvastatin on atherosclerotic plaque stability: An intravascular ultrasound elastography study.

PubMed

Li, Zhaohuan; Wang, Lin; Hu, Xiaobo; Zhang, Pengfei; Chen, Yifei; Liu, Xinxin; Xu, Mingjun; Zhang, Yun; Zhang, Mei

2016-05-01

The present study aimed to investigate the effect of potent rosuvastatin therapy on plaque mechanical stabilization as seen on IVUSE. 14 purebred New Zealand rabbits were fed a high-cholesterol diet; the abdominal aorta endothelium was balloon-injured after 2 weeks; at week 13, 7 rabbits received rosuvastatin (1.5 mg/kg/day), and the other 7 received an equal volume of saline. IVUS images of abdominal aortas were acquired, and 2 consecutive frames near the end-diastole images in situ were used to construct an IVUS elastogram. Control rabbits showed a significant increase in shear strain (SS) and area strain (AS) in total plaques. The rosuvastatin group showed no change in SS and AS, but serum TG and LDL-C levels were reduced, with less lipid deposition, macrophage infiltration, production of proinflammatory cytokines and apoptosis in plaques. The changes in SS and AS from baseline between groups significantly differed (SS: 1.15 (1.96) % vs. -0.99 ± 2.83%, p = 0.013; AS: 1.25 (2.29) % vs. -1.67 ± 5.05%, p = 0.022). At follow-up, for controls, strain values were increased in the shoulder of eccentric plaques (SS: 2.66 ± 1.31% vs. 4.86 ± 1.93%, p = 0.016; AS: 4.45 ± 2.33% vs. 7.91 ± 2.74%, p = 0.009) but not the plaque body. Changes in SS and AS in the plaque shoulder differed between the control and rosuvastatin groups (SS: 2.20 ± 2.17% vs. -0.87 ± 3.31%, p = 0.028; AS: 2.10 (4.61) % vs. -2.75 ± 5.97%, p = 0.009). Rosuvastatin therapy in rabbits with atherosclerotic plaques led to less vulnerable plaque features. IVUSE is a very sensitive technique for detecting pharmacologically-induced mechanical changes in rabbit atherosclerotic plaques. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of fimasartan, amlodipine, and rosuvastatin using partial replicated design in healthy adult subjects.

PubMed

Oh, Minkyung; Ghim, Jong-Lyul; Park, Sung-Eun; Kim, Eun-Young; Shin, Jae-Gook

2018-01-01

The aim of this study was to compare the pharmacokinetics (PK) and safety profiles of a fixed-dose combination (FDC) formulation of fimasartan, amlodipine, and rosuvastatin with the co-administration of the two products by using a replicated crossover study design in healthy male subjects. This was an open-label, randomized, three-sequence, three-period replicated crossover study in healthy male subjects. The replicated crossover design was done because of high coefficient of variation of PK parameter for fimasartan, that is, >30%. With a 14 days washout period, an FDC tablet containing 60 mg fimasartan, 10 mg amlodipine, and 20 mg rosuvastatin was administered only once, and separate formulations of fimasartan/amlodipine 60 mg/10 mg FDC tablet and 20 mg rosuvastatin tablet administered twice. Blood samples were collected up to 72 hours following drug administration. The plasma concentrations of fimasartan, amlodipine, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was assessed by evaluating vital signs, clinical laboratory parameters, physical examinations, and medical interviews. The geometric mean ratios and 90% confidence intervals (CIs) for the maximum plasma concentration (C max ) and area under the curve from time zero to the last measurable sampling time (AUC t ) were 1.0776 (0.9201-1.2622) and 0.9978 (0.9538-1.0439) for fimasartan, 1.0038 (0.9782-1.0301) and 1.0055 (0.9828-1.0288) for amlodipine, and 1.0006 (0.9290-1.0776) and 0.9986 (0.9532-1.0461) for rosuvastatin, respectively. A total of 22 adverse events (AEs) were reported by 60 subjects; there were no significant differences in the incidence of AEs between the two groups. The 90% CI of the C max of fimasartan was within the widened acceptance limit, ln(0.6984)-ln(1.4319). The 90% CIs of the other PK parameters for drugs were between ln(0.8) and ln(1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile, to the co-administration of its three constituent drugs.

Adding exercise training to rosuvastatin treatment: influence on serum lipids and biomarkers of muscle and liver damage.

PubMed

Coen, Paul M; Flynn, Michael G; Markofski, Melissa M; Pence, Brandt D; Hannemann, Robert E

2009-07-01

Statin treatment and exercise training can improve lipid profile when administered separately. The efficacy of exercise and statin treatment combined, and its impact on myalgia and serum creatine kinase (CK) have not been completely addressed. The purpose of this study was to determine the effect of statin treatment and the addition of exercise training on lipid profile, including oxidized low-density lipoprotein (oxLDL), and levels of CK and alanine transaminase. Thirty-one hypercholesterolemic and physically inactive subjects were randomly assigned to rosuvastatin (R) or rosuvastatin/exercise (RE) group. A third group of physically active hypercholesterolemic subjects served as an active control group (AC). The R and RE groups received rosuvastatin treatment (10 mg/d) for 20 weeks. From week 10 to week 20, the RE group also participated in a combined endurance and resistive exercise training program (3 d/wk). Lipid profile was determined for all subjects at week 0 (Pre), week 10 (Mid), and week 20 (Post). The CK and alanine transaminase levels were measured at the same time points in the RE and R groups and 48 hours after the first and fifth exercise bout in the RE group. Each RE subject was formally queried about muscle fatigue, soreness, and stiffness before each training session. Total, LDL, and oxLDL cholesterol was lower in the RE and R groups at Mid and Post time points when compared with Pre. Oxidized LDL was lower in the RE group compared with the R group at the Post time point. When treatment groups (R and RE) were combined, high-density lipoprotein levels were increased and triglycerides decreased across time. Creatine kinase increased in the RE group 48 hours after the first exercise bout, but returned to baseline levels 48 hours after the fifth exercise bout. Rosuvastatin treatment decreased total, LDL, and oxLDL cholesterol. The addition of an exercise training program resulted in a further decrease in oxLDL. There was no abnormal sustained increase in CK or reports of myalgia after the addition of exercise training to rosuvastatin treatment.

Drug–drug Interaction between Pravastatin and Gemfibrozil (Antihyperlipidemic) with Gliclazide (Antidiabetic) in Rats

PubMed Central

Sultanpur, CM; Satyanarayana, S; Reddy, NS; Kumar, KE; Kumar, S

2010-01-01

Diabetes mellitus is a condition of increased blood glucose level in the body. Antihyperlipidemic drugs like statins and fibrates are widely used for prophylactic treatment in dyslipideamia and atherosclerosis. Diabetic dislipidemia exists with increased triglycerides, low HDL and high LDL levels. Hence, with oral hypoglycemic drugs, the addition of a lipid-lowering drug is necessary for controlling dislipidemia. In such a situation, there may be chances of drug–drug interactions between antidiabetic and antihyperlipidemic drugs. The present study is planned to evaluate the safety of gliclazide (antidiabetic) in the presence of pravastatin and gemfibrozil (antihyperlpidemic) in rats. Studies in normal and alloxan-induced diabetic rats were conducted with oral doses of gliclazide and their combination with pravastatin and gemfibrozil, with an adequate washout period in between the treatments. Blood samples were collected in rats by retroorbital puncture at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h. All the blood samples were analyzed for glucose by GOD –POD. Gliclazide (½ TD) produced hypoglycemic activity in normal and diabetic rats, with peak activity at 2 and 8 h. Pravastatin (TD) + gemfibrozil (TD) combination treatment increased the hypoglycemic effect of gliclazide in normal rats or diabetic rats when administered together. The interaction observed due to inhibition of both the enzymes (CYP 450 2C9 and CYP 450 3A4) responsible for the metabolism of gliclazide showed increased half-life, which was seen in the present study. Because concomitant administration of gliclazide with provastatin and gemfibrozil in diabetes is associated with atherosclerosis, it should be contraindicated or used with caution. PMID:21264118

Statins and daptomycin: safety assessment of concurrent use and evaluation of drug interaction liability.

PubMed

Golightly, Larry K; Barber, Gerard R; Barron, Michelle A; Page, Robert L

2013-01-01

Acute muscle injury and potentially fatal rhabdomyolysis may occur with use of statins and certain interacting medications. This investigation assessed risk for myopathy in patients receiving treatment with a statin in combination with daptomycin, a medication also associated with muscle injury. Patients hospitalized from July 1, 2005, through June 30, 2010, who received simvastatin or rosuvastatin concurrently with daptomycin were identified and their medical records were examined. Patients were judged to have treatment-related muscle injury if their records contained evidence of myalgia with or without weakness and secondarily impaired mobility together with elevated creatine kinase (CK) levels. These assessments were compared with similar data from hospitalized patients who received a statin alone. A total of 52 patients received 66 courses of concurrent treatment with simvastatin or rosuvastatin and daptomycin. Of these, no patient (0%) met evidentiary requirements for diagnosis of myopathy or related complications. No patient (0%) developed muscle pain or discomfort and none developed markedly elevated CK levels. The incidence of asymptomatic elevations of CK in these simvastatin or rosuvastatin plus daptomycin recipients (9%) was statistically indistinguishable from the incidence of CK elevations found in a cohort of 105 inpatients who received simvastatin or rosuvastatin alone (21%; p=0.135). In patients receiving treatment with simvastatin or rosuvastatin and daptomycin, no symptoms or objective evidence of muscle injury attributable to a drug interaction were identified. These findings are consistent with data indicating that the myopathic effects of statins and daptomycin are incited by disparate and perhaps unique pharmacological mechanisms. Risk of muscle injury therefore appears to be no greater when a statin is administered with daptomycin than when either medication is used alone.

Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin.

PubMed

Quinn, Amelia L; Dean, Olivia M; Davey, Christopher G; Kerr, Melissa; Harrigan, Susy M; Cotton, Sue M; Chanen, Andrew M; Dodd, Seetal; Ratheesh, Aswin; Amminger, G Paul; Phelan, Mark; Williams, Amber; Mackinnon, Andrew; Giorlando, Francesco; Baird, Shelley; Rice, Simon; O'Shea, Melissa; Schäfer, Miriam R; Mullen, Edward; Hetrick, Sarah; McGorry, Patrick; Berk, Michael

2018-02-01

There is growing support for the role of inflammation and oxidative stress in the pathophysiology of major depressive disorder (MDD). This has led to the development of novel strategies targeting inflammation in the treatment of depression. Rosuvastatin and aspirin have well-documented, anti-inflammatory and antioxidant properties. The aim of the Youth Depression Alleviation: Augmentation with an anti-inflammatory agent (YoDA-A) study is to determine whether individuals receiving adjunctive anti-inflammatory agents, aspirin and rosuvastatin experience a reduction in the severity of MDD compared with individuals receiving placebo. YoDA-A is a 12-week triple-blind, randomized controlled trial funded by the National Health and Medical Research Council, Australia. Participants aged 15-25, with moderate-to-severe MDD, are allocated to receive either 10 mg/day rosuvastatin, 100 mg/day aspirin, or placebo, in addition to treatment as usual. Participants are assessed at baseline and at weeks 4, 8, 12 and 26. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. The study is planned to be completed in 2017. At date of publication, 85 participants have been recruited. Timely and targeted intervention for youth MDD is crucial. Given the paucity of new agents to treat youth MDD, adjunctive trials are not only pragmatic and 'real-world', but additionally aim to target shortfalls in conventional medications. This study has the potential to first provide two new adjunctive treatment options for youth MDD; aspirin and rosuvastatin. Second, this study will serve as proof of principle of the role of inflammation in MDD. © 2015 Wiley Publishing Asia Pty Ltd.

The Effect of High Dose Cilostazol and Rosuvastatin on Periprocedural Myocardial Injury in Patients with Elective Percutaneous Coronary Intervention

PubMed Central

H., Ari; N., Emlek; S., Ari; S., Coşar; K., Doğanay; C., Aydin; E., Tenekecioğlu; A., Tütüncü; O.C., Yontar; M., Gürdoğan; T., Bozat; M., Melek

2015-01-01

Background The aim of our study was to assess the effect of pretreatment with cilostazol and rosuvastatin combination before elective percutaneous coronary intervention (PCI) on peri-procedural myocardial injury (PPMIJ). Methods We randomly assigned 172 patients with stable angina pectoris scheduled for elective PCI to pre- treatment with Cilostazol 200mg and Rosuvastatin 40 mg (group 1), or to pretreatment with Rosuvastatin 40 mg group (group 2). The primary end-point was the occurrence of PPMIJ defined as any cardiac troponin I (Tn I) level elevated above the upper normal limit (UNL). The occurrence of peri-procedural myocardial infarction (PPMIN) was defined as a post-procedural increase in cTnI level ≥ 5 times above the UNL. Results There was no significant difference in baseline characteristics between group 1 (n = 86) and group 2 (n = 86). The rate of PPMIJ (21% vs. 24%, p = 0.58) and PPMIN (2.3% vs. 7%, p = 0.27) were similar between the two study groups. Subgroup analysis performed on those patients without statin therapy before PCI (53 patients in group 1 and 50 patients in group 2) showed that the incidence of PPMIJ was significantly lower in the group 1 patients without chronic statin treatment [17% (9/53) versus 34% (17/50); p = 0.04], but the rate of PPMIN was similar between the two groups for those patients without chronic statin treatment [1.9% (1/53) versus 10% (5/50); p = 0.07]. Conclusions We found that adjunct cilostazol and rosuvastatin pre-treatment did not significantly reduce PPMIJ after elective PCI in patients with stable angina pectoris. However, adjunct cilostazol pre-treatment could reduce PPMIJ in patients without chronic statin therapy before elective PCI. PMID:27122885

Effect of Steady-State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open-Label, Fixed-Sequence Crossover Study.

PubMed

Huang, Fenglei; Marzin, Kristell; Koenen, Rüdiger; Kammerer, Klaus Peter; Strelkowa, Natalja; Elgadi, Mabrouk; Quinson, Anne-Marie; Haertter, Sebastian

2017-10-01

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus protease. It inhibits multiple cytochrome P-450 enzymes and multiple membrane transporters. The objective of this study was to evaluate the effect of steady-state faldaprevir on the pharmacokinetics (PK) of a single dose of atorvastatin or rosuvastatin. In this single-center, open-label, fixed-sequence crossover study, 33 healthy adult male and female volunteers were given either atorvastatin 10 mg (n = 16) or rosuvastatin 10 mg (n = 17) on day 1. Subjects subsequently received 240 mg twice daily of faldaprevir (loading dose) on day 5, followed by 240 mg faldaprevir once daily from day 6 to day 10, with an additional single dose of atorvastatin (10 mg) or rosuvastatin (10 mg) given on day 10. PK samples for the statins were collected on days 1-3 and days 10-12. Concomitant administration with faldaprevir led to approximately 9-fold and 34-fold increases in AUC 0-∞ and C max , respectively, of atorvastatin and approximately 15-fold and 33-fold increases in AUC 0-∞ and C max , respectively, of rosuvastatin, compared with the statins given alone. Exposure to the major metabolites (ortho-hydroxyatorvastatin and N-desmethylrosuvastatin) was increased to a similar magnitude as that of the parent compounds. The marked drug-drug interaction observed is most likely related to the inhibitory effects of faldaprevir on transporters, particularly hepatic uptake transporters such as OTAP1B1 and OATP1B3. Given the significant increase in exposure to statins in healthy volunteers, coadministration of faldaprevir with statins should be avoided. © 2017, The American College of Clinical Pharmacology.

The Effect of High Dose Cilostazol and Rosuvastatin on Periprocedural Myocardial Injury in Patients with Elective Percutaneous Coronary Intervention.

PubMed

H, Ari; N, Emlek; S, Ari; S, Coşar; K, Doğanay; C, Aydin; E, Tenekecioğlu; A, Tütüncü; O C, Yontar; M, Gürdoğan; T, Bozat; M, Melek

2015-07-01

The aim of our study was to assess the effect of pretreatment with cilostazol and rosuvastatin combination before elective percutaneous coronary intervention (PCI) on peri-procedural myocardial injury (PPMIJ). We randomly assigned 172 patients with stable angina pectoris scheduled for elective PCI to pre- treatment with Cilostazol 200mg and Rosuvastatin 40 mg (group 1), or to pretreatment with Rosuvastatin 40 mg group (group 2). The primary end-point was the occurrence of PPMIJ defined as any cardiac troponin I (Tn I) level elevated above the upper normal limit (UNL). The occurrence of peri-procedural myocardial infarction (PPMIN) was defined as a post-procedural increase in cTnI level ≥ 5 times above the UNL. There was no significant difference in baseline characteristics between group 1 (n = 86) and group 2 (n = 86). The rate of PPMIJ (21% vs. 24%, p = 0.58) and PPMIN (2.3% vs. 7%, p = 0.27) were similar between the two study groups. Subgroup analysis performed on those patients without statin therapy before PCI (53 patients in group 1 and 50 patients in group 2) showed that the incidence of PPMIJ was significantly lower in the group 1 patients without chronic statin treatment [17% (9/53) versus 34% (17/50); p = 0.04], but the rate of PPMIN was similar between the two groups for those patients without chronic statin treatment [1.9% (1/53) versus 10% (5/50); p = 0.07]. We found that adjunct cilostazol and rosuvastatin pre-treatment did not significantly reduce PPMIJ after elective PCI in patients with stable angina pectoris. However, adjunct cilostazol pre-treatment could reduce PPMIJ in patients without chronic statin therapy before elective PCI. Cilostazol; Myocardial injury; Percutaneous coronary intervention; Statin.

Postischemic alterations of BDNF, NGF, HSP 70 and ubiquitin immunoreactivity in the gerbil hippocampus: pharmacological approach.

PubMed

Himeda, Toshiki; Tounai, Hiroko; Hayakawa, Natsumi; Araki, Tsutomu

2007-03-01

1. We investigated the immunohistochemical alterations of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus 1 h to 14 days after transient cerebral ischemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pitavastatin against the changes of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus after cerebral ischemia in the hippocampus after ischemia. 2. The transient cerebral ischemia was carried out by clamping the carotid arteries with aneurismal clips for 5 min. 3. In the present study, the alteration of HSP 70 and ubiquitin immunoreactivity in the hippocampal CA1 sector was more pronounced than that of BDNF and NGF immunoreactivity after transient cerebral ischemia. In double-labeled immunostainings, BDNF, NGF and ubiquitin immunostaining was observed both in GFAP-positive astrocytes and MRF-1-positive microglia in the hippocampal CA1 sector after ischemia. Furthermore, prophylactic treatment with pitavastatin prevented the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after ischemia. 4. These findings suggest that the expression of stress protein including HSP 70 and ubiquitin may play a key role in the protection against the hippocampal CA1 neuronal damage after transient cerebral ischemia in comparison with the expression of neurotrophic factor such as BDNF and NGF. The present findings also suggest that the glial BDNF, NGF and ubiquitin may play some role for helping surviving neurons after ischemia. Furthermore, our present study indicates that prophylactic treatment with pitavastatin can prevent the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after transient cerebral ischemia. Thus our study provides further valuable information for the pathogenesis after transient cerebral ischemia.

Increased risk for cardiovascular outcomes and effect of cholesterol-lowering pravastatin therapy in patients with diabetes mellitus in the pravastatin anti-atherosclerosis trial in the elderly (PATE)

PubMed Central

Ishikawa, Toshitsugu; Ito, Hideki; Ouchi, Yasuyoshi; Ohashi, Yasuo; Saito, Yasushi; Nakamura, Haruo; Orimo, Hajime; PATE Investigators

2005-01-01

Background: The Pravastatin Anti-atherosclerosis Trial in the Elderly (PATE) was the first large-scale, prospective clinical trial to show that cholesterol-lowering therapy with pravastatin is effective in reducing the risk for cardiovascular events (CVEs) in elderly (aged ≥60 years) patients with hypercholesterolemia. PATE also included a subgroup of patients with diabetes mellitus (DM). Objective: The aim of this post hoc analysis was to assess the effects of lon-gtermpravastatin therapy on cardiovascular outcomes in the subgroup of patients with DM compared with a subgroup without it. Methods: PATE was conducted at 50 hospitals, universities, and clinics acrossJapan. Patients were randomly allocated to 1 of 2 treatment groups: low-dose pravastatin (5 mg PO QD; L group) or standard-lose pravastatin (in Japan, 10 mg PO QD; S group). Treatment was given for 3 to 5 years. Serum cholesterol levels were measured and the prevalence of CVEs was determined. The primary end point of the study was the S:L risk ratio for fatal or nonfatal CVEs. The secondary end point was the effect of diabetic patients' glycemic control on CVEs. Results: A total of 665 patients (527 women, 138 men; mean [SD] age, 72.8[5.7] years) were followed up for a mean of 3.9 years (range, 3–5 years). Among these, 199 patients had DM; 104 patients with DM were allocated to the L group and 95 to the S group. Four hundred sixty-six patients did not have DM (L group, 230 patients; S group, 236 patients). Overall, between 3 months and 3 years after the initiation of treatment, patients in the L group (mean dose, 4.5 mg/d) experienced reductions from baseline total cholesterol level of 11% to 13%. Those in the S group (mean dose, 8.3 mg/d) experienced reductions from baseline of 15% to 17%. Decreases in low-density lipoprotein cholesterol (LDL-C) levels were 17% to 20% and 23% to 26% in the L and S groups, respectively. Statistically similar reductions were noted between patients with DM and those without it in response to either dose. The DM subgroup experienced 32 CVEs (L group, 17; S group, 15) compared with 39 CVEs (L group, 25; S group, 14) in the subgroup without DM. The S:L CVE risk ratio (primary end point) was 0.94 (95% Cl, 0.46–1.92) in patients with DM and 0.54 (95% Cl, 0.28–1.05) in those without DM; the differences between the treatment groups were not statistically significant. The risk for CVEs in patients with DM whose glycosylated hemoglobin concentrations were <8.0% and ≥8.0% were, respectively, 1.87-fold (95% Cl, 1.09–3.20; P = 0.02) and 3.79-fold (95% Cl, 1.92–7.48; P < 0.01) higher than that in patients without DM. Conclusions: In this post hoc analysis of the effects of long-term cholesterol-loweringtherapy (low- and standard-dose pravastatin) on cardiovascular outcomes in elderly patients with DM, dose had no effect on the risk for CVEs in these patients as it did in those without DM. Poorer glycemic control in patients with DM was related to a higher risk for CVEs. The lack of pravastatin efficacy found in the subgroup with DM may have been attributable to the small differences in LDL-C levels found between the 2 treatment groups and/or the small sample size of the study. PMID:24672112

Effect of a single gemfibrozil dose on the pharmacokinetics of rosuvastatin in bile and plasma in healthy volunteers.

PubMed

Bergman, Ebba; Matsson, Elin M; Hedeland, Mikael; Bondesson, Ulf; Knutson, Lars; Lennernäs, Hans

2010-09-01

The effect of a single intrajejunal dose of gemfibrozil (600 mg) on the plasma pharmacokinetics and biliary excretion of a single intrajejunal dose of rosuvastatin (20 mg) was investigated by using a multichannel catheter positioned in the distal duodenum-proximal jejunum in 8 healthy volunteers. Bile and plasma samples were collected every 20 minutes for 200 minutes, with additional plasma samples being drawn for up to 48 hours. Gemfibrozil did not affect the bioavailability of rosuvastatin, although it increased the apparent absorption phase during the initial 200 minutes (AUC(plasma,200min)) by 1.56-fold (95% confidence interval, 1.14-2.15). The interaction was less pronounced in this single-dose study than in a previous report when gemfibrozil was administered repeatedly; nevertheless, the interaction coincided with the highest exposure to gemfibrozil. The plausible reason why the interaction in this investigation was only minor is the low exposure to gemfibrozil (and its metabolites), suggesting that the total plasma concentration of gemfibrozil needs to be above 20 µM to affect the disposition of rosuvastatin. This study demonstrates the value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation.

The West of Scotland coronary prevention study: economic benefit analysis of primary prevention with pravastatin.

PubMed Central

Caro, J.; Klittich, W.; McGuire, A.; Ford, I.; Norrie, J.; Pettitt, D.; McMurray, J.; Shepherd, J.

1997-01-01

OBJECTIVE: To estimate the economic efficiency of using pravastatin to prevent the transition from health to cardiovascular disease in men with hypercholesterolaemia. DESIGN: Economic benefit analysis based on data from the West of Scotland coronary prevention study. Treatment specific hazards of developing cardiovascular disease according to various definitions were estimated. Scottish record linkage data provided disease specific survival. Cost estimates were based on extracontractual tariffs and event specific average lengths of stay calculated from the West of Scotland coronary prevention study. SUBJECTS: Men with hypercholesterolaemia similar to the subjects in the West of Scotland coronary prevention study. MAIN OUTCOME: Cost consequences, the number of transitions from health to cardiovascular disease prevented, the number needed to start treatment, and cost per life year gained. RESULTS: If 10,000 of these men started taking pravastatin, 318 of them would not make the transition from health to cardiovascular disease (number needed to treat, 31.4), at a net discounted cost of 20m Pounds over 5 years. These benefits imply an undiscounted gain of 2,460 years of life, and thus 8121 Pounds per life year gained, or 20,375 Pounds per life year gained if benefits are discounted. Restriction to the 40% of men at highest risk reduces the number needed to treat to 22.5 (5601 Pounds per life year gained (undiscounted) and 13,995 Pounds per life year gained (discounted)). CONCLUSIONS: In subjects without evidence of prior myocardial infarction but who have hypercholesterolaemia, the use of pravastatin yields substantial health benefits at a cost that is not prohibitive overall and can be quite efficient in selected high risk subgroups. PMID:9437275

A Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): Screening Experience and Baseline Characteristics

PubMed Central

Ford, Ian; Blauw, Gerard Jan; Murphy, Michael B; Shepherd, James; Cobbe, Stuart M; Bollen, Edward LEM; Buckley, Brendan M; Jukema, J Wouter; Hyland, Michael; Gaw, Allan; Lagaay, A Margot; Perry, Ivan J; Macfarlane, Peter; Norrie, John; Meinders, A Edo; Sweeney, Brian J; Packard, Chris J; Westendorp, Rudi GJ; Twomey, Cillian; Stott, David J

2002-01-01

Background PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option. Methods The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. Results In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0–9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women). Conclusions Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002. PMID:12097148

Biopolymeric mucoadhesive bilayer patch of pravastatin sodium for buccal delivery and treatment of patients with atherosclerosis.

PubMed

Yedurkar, Pramod; Dhiman, Munish Kumar; Petkar, Kailash; Sawant, Krutika

2013-05-01

Mucoadhesive bilayer buccal patch has been developed to improve the bioavailability and therapeutic efficacy along with providing sustained release of pravastatin sodium. Buccal patches comprising of varying composition of Carbopol 934P and HPMC K4M were designed and characterized for surface pH, swelling index, in vitro bioadhesion, mechanical properties, in vitro drug release and in vivo pharmacokinetic and pharmacodynamics performance. All formulations exhibited satisfactory technological parameters and followed non-fickian drug release mechanism. Bilayer buccal patch containing Carbopol 934P and HPMC K4M in 4:6 ratio (PBP5) was considered optimum in terms of swelling, mucoadhesion, mechanical properties and in vitro release profile. Pharmacokinetic studies in rabbits showed significantly higher (p < 0.05) Cmax (75.63 ± 6.98 ng/mL), AUC(0-8) (311.10 ± 5.89 ng/mL/h) and AUC(0-∞) (909.42 ± 5.89 ng/mL/h) than pravastatin oral tablet (Cmax - 67.40 ± 9.23 ng/mL, AUC(0-8)-130.33 ± 10.25 ng/mL/h and AUC(0-∞)-417.17 ± 5.89 ng/mL/h)). While, increased tmax of buccal patch indicated its sustained release property in comparison to oral tablet. Pharmacodynamic studies in rabbits showed statistically significant difference (p < 0.005) in the reduction of TG (131.10 ± 10.23 mg/dL), VLDL (26.00 ± 2.56 mg/dL) and LDL level (8.99 ± 3.01 mg/dL) as compared to oral conventional tablet. In conclusion, bioavailability from the developed buccal patch of pravastatin was 2.38 times higher than the oral dosage form, indicating its therapeutic potential in the treatment of atherosclerosis.

A mechanistic framework for in vitro-in vivo extrapolation of liver membrane transporters: prediction of drug-drug interaction between rosuvastatin and cyclosporine.

PubMed

Jamei, M; Bajot, F; Neuhoff, S; Barter, Z; Yang, J; Rostami-Hodjegan, A; Rowland-Yeo, K

2014-01-01

The interplay between liver metabolising enzymes and transporters is a complex process involving system-related parameters such as liver blood perfusion as well as drug attributes including protein and lipid binding, ionisation, relative magnitude of passive and active permeation. Metabolism- and/or transporter-mediated drug-drug interactions (mDDIs and tDDIs) add to the complexity of this interplay. Thus, gaining meaningful insight into the impact of each element on the disposition of a drug and accurately predicting drug-drug interactions becomes very challenging. To address this, an in vitro-in vivo extrapolation (IVIVE)-linked mechanistic physiologically based pharmacokinetic (PBPK) framework for modelling liver transporters and their interplay with liver metabolising enzymes has been developed and implemented within the Simcyp Simulator(®). In this article an IVIVE technique for liver transporters is described and a full-body PBPK model is developed. Passive and active (saturable) transport at both liver sinusoidal and canalicular membranes are accounted for and the impact of binding and ionisation processes is considered. The model also accommodates tDDIs involving inhibition of multiple transporters. Integrating prior in vitro information on the metabolism and transporter kinetics of rosuvastatin (organic-anion transporting polypeptides OATP1B1, OAT1B3 and OATP2B1, sodium-dependent taurocholate co-transporting polypeptide [NTCP] and breast cancer resistance protein [BCRP]) with one clinical dataset, the PBPK model was used to simulate the drug disposition of rosuvastatin for 11 reported studies that had not been used for development of the rosuvastatin model. The simulated area under the plasma concentration-time curve (AUC), maximum concentration (C max) and the time to reach C max (t max) values of rosuvastatin over the dose range of 10-80 mg, were within 2-fold of the observed data. Subsequently, the validated model was used to investigate the impact of coadministration of cyclosporine (ciclosporin), an inhibitor of OATPs, BCRP and NTCP, on the exposure of rosuvastatin in healthy volunteers. The results show the utility of the model to integrate a wide range of in vitro and in vivo data and simulate the outcome of clinical studies, with implications for their design.

Facile LC-UV methods for simultaneous monitoring of ciprofloxacin and rosuvastatin in API, formulations and human serum.

PubMed

Arayne, M Saeed; Sultana, Najma; Tabassum, Arman

2015-02-01

An efficient, selective and cost-effective liquid chromatographic assay was developed and validated for the simultaneous quantification of ciprofloxacin and rosuvastatin in Active Pharmaceutical Ingredients (API), pharmaceutical formulations and in human serum. The chromatographic system consisted of mobile phase methanol-water, 90:10 v/v at pH 3.0 adjusted with o-phosphoric acid, pumped at 1.0 mL/min through a prepacked Purospher Star C18 (5 µm, 25 × 0.46 cm) column and effluent was monitored at the isosbestic point (255 nm) as well as at the λmax of individual drugs (243 and 271 nm). The method was validated over a linear concentration range of 0.25-15 µg/mL for ciprofloxacin and 0.33-20 µg/mL for rosuvastatin (r(2)  ≥ 0.999). The ranges of reliable response (limits of detection and quantitation) for ciprofloxacin were 3-15 and 9-45 ng/mL and 17-29 and 52-88 ng/mL, respectively, for rosuvastatin in all API, pharmaceutical formulations and human serum. Analytical recovery from human serum was >98% and relative standard deviation (RSD) was <2. The accuracies were 97.13-102.55 and 97.41-101.31% and precisions in RSD were 0.04-1.90 and 0.02-1.23% for ciprofloxacin and rosuvastatin, respectively. No matrix interferences, ion suppression/enhancement and carry-over were detected. The total assay run time was less than 5 min. In another study, for optimum performance the detector was programmed for multiwavelength scanning at the absorption maxima of each component. Consequently, the linearity range was improved and limit of detection and quantitation values were down to 1-4 and 4-12 ng/mL for ciprofloxacin and 3-5 and 9-15 ng/mL for rosuvastatin, respectively. The validation parameters fitted ICH guidelines through the isosbestic and individual λmax approach. The small sample volume and simplicity of preparation make this method suitable for use in human serum samples, pharmaceutical formulations, quality control, drug-drug interaction studies, clinical laboratories, drug research centers and forensic medical centers. Copyright © 2014 John Wiley & Sons, Ltd.

Molecular and Clinical Based Cardiovascular Care Program and Military Medical Molecular Initiative (M3I) - Integrative Cardiac Health Project. Addendum

DTIC Science & Technology

2008-11-01

PLAC-1 k pravastatin 40 ~26 1918 + 292 -25.5 VCU e atorvastatin 10 12 2562 + 77 g -31.4 LZ (nm) PLAC-1 j pravastatin 20-40 ~26 20.7 + 0.5 +0.3...MC l diet & exercise --- 19 20.6 + 0.2 g +1.5 VCU e atorvastatin 10 12 19.8 + 0.1 g +1.5 TJU h niacin ER i 1000 12 20.0 +2.0 TJU h niacin ER i...University – 53 ( atorvastatin ) or 48 (niacin) men and women with atherogenic dyslipidemia, treatment followed a 6-week lead-in period on a National

Spectrophotometric method for simultaneous determination of valsartan and substances from the group of statins in binary mixtures.

PubMed

Stolarczyk, Mariusz; Apola, Anna; Maślanka, Anna; Kwiecień, Anna; Opoka, Włodzimierz

2017-12-20

Applicability of derivative spectrophotometry for the determination of valsartan in the presence of a substance from the group of statins was checked. The obtained results indicate that the proposed method may be effective by using appropriate derivatives: for valsartan and fluvastatin - D1, D2 and D3, for valsartan and pravastatin - D1 and D3, for valsartan and atorvastatin - D2 and D3. The method was characterized by high sensitivity and accuracy. Linearity was maintained in the following ranges: 9.28-32.48 mg mL-1 for valsartan, 8.16-28.56 mg mL-1 f or fluvastatin, 14.40-39.90 mg mL-1 for atorvastatin and 9.60-48.00 mg mL-1 for pravastatin. Determination coefficients were in the range of 0.989-0.999 depending on the analyte and the order of derivative. The precision of the method was high with RSD from 0.1 to 2.5 % and recovery of individual components was within the range of 100 ± 5 %. The developed method was successfully applied to the determination of valsartan combined with fluvastatin, atorvastatin and pravastatin in laboratory prepared mixtures and in pharmaceutical preparations.

Effect of ezetimibe plus pravastatin on endothelial dysfunction in patients with systemic lupus erythematosus.

PubMed

Vera-Lastra, O; Méndez-Flores, S; Cruz-Dominguez, M P; Medina, G; Calderón-Aranda, E; Jara, L J

2016-06-01

Patients with systemic lupus erythematosus (SLE) have a higher risk for cardiovascular disease (CVD), not fully explained by the conventional risk factors. These patients have endothelial dysfunction (ED) as an early process of atherosclerosis, which can be reversed with therapy. To determine the effect of ezetimibe plus pravastatin on endothelial function in patients with SLE after 12 months of treatment. An open study, before and after, which assessed the effect of ezetimibe plus pravastatin treatment, was performed. Twenty two patients (21 women and one man) with diagnosis of SLE were studied, with a mean age 40 ± 5 years. Endothelial dysfunction was evaluated using vascular ultrasound of the brachial artery in order to measure the flow-mediated vasodilation (FMV) basal and after 12 months of treatment with pravastatin 40 mg/day plus ezetimibe 10 mg/day. In addition, a lipid profile: total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and serum C-reactive protein (CRP), was done. We found a basal FMV of 7.58% and 18.22% after 12 months of treatment, with an improvement of 10.64 points 95% CI (7.58-13.58), p < 0.001. TC decreased from 201.3 ± 58.9 mg/dL to 158.06 ± 50.13 mg/dL (p < 0.01); LDL-C from 125.78 ± 44.4 mg/dL to 78.8 ± 32.9 mg/dL (p < 0.001); HDL-C increased from 49.0 ± 16.8 mg/dL to 52.2 ± 13.8 mg/dL (p = 0.077). The basal and final concentrations of CRP were 4.49 and 2.8, respectively, with a mean decrease of 2.11 mg/dL, 95% CI (0.908-3.32), p < 0.002. Both drugs were well tolerated. Ezetimibe plus pravastatin significantly improved FMV in patients with SLE, decreasing ED and the lipid profile. This treatment ameliorated an early process of atherosclerosis and a risk factor for CVD. © The Author(s) 2016.

Prognostic effects of rosuvastatin in patients with co-existing chronic obstructive pulmonary disease and chronic heart failure: A sub-analysis of GISSI-HF trial.

PubMed

Rossi, Andrea; Inciardi, Riccardo M; Rossi, Andrea; Temporelli, Pier Luigi; Lucci, Donata; Gonzini, Lucio; Marchioli, Roberto; Nicolosi, Gian Luigi; Tavazzi, Luigi

2017-06-01

Rising evidences showed a possible protective role of statins in chronic obstructive pulmonary disease (COPD). We aimed to evaluate in a post-hoc analysis of the GISSI-HF trial the prognostic effect of the use of rosuvastatin in patients with co-existing COPD and HF, assuming that the anti-inflammatory properties of these drugs may imply a potential beneficial effect in these associated chronic inflammatory conditions. We analyzed patients with chronic HF and history of COPD deriving from the GISSI-HF study. Of all 4574 patients eligible to statin, 1060 ambulatory patients with HF and concomitant COPD were enrolled and randomly assigned to rosuvastatin 10 mg daily (538 patients) or placebo (522 patients). The primary end-point was to compare all cause death rate in patients randomized to rosuvastatin or placebo. Further, we assessed the effects of rosuvastatin (10 mg daily) on cardiovascular (CV) death, non-CV death and hospital admissions. Median follow-up was 3.9 years with an interquartile range (IQR) of 3.0-4.4. During the follow-up 438 (41.3%) patients died, 304 (28.6%) for CV death and 687 (64.8%) had at least one hospitalization. The two patient groups had similar outcome, irrespective of randomization, in terms of all-cause mortality (log-rank test p = 0.30) CV, non CV-death (p = 0.88 and 0.09 respectively) and all-cause hospitalization (p = 0.82). Cox regression analysis did not show a favorable association between the use of statin and the examined end-points both on unadjusted and adjusted models. Statin use is not associated with a beneficial effects on all cause, CV, non CV mortality and hospitalization in patients with coexistent chronic HF and history of COPD. ClinicalTrials.gov Identifier: NCT00336336. Copyright © 2017. Published by Elsevier Ltd.

The therapeutic effect of Rosuvastatin on cardiac remodelling from hypertrophy to fibrosis during the end-stage hypertension in rats

PubMed Central

Zhang, WB; Du, QJ; Li, H; Sun, AJ; Qiu, ZH; Wu, CN; Zhao, G; Gong, H; Hu, K; Zou, YZ; Ge, JB

2012-01-01

End-stage hypertensive heart disease is an increasing cause of cardiac mortality. Therefore, the current study focused on the cardiac remodelling from hypertrophy to fibrosis in old-aged spontaneously hypertensive rats (SHRs), and explored the therapeutic effects of Rosuvastatin and its possible mechanism(s) of action. Spontaneously hypertensive rats at age 52 weeks were randomly divided into three groups, the first two to receive Rosuvastatin at a dose of 20 mg/kg/day and 40 mg/kg/day, respectively, and the third to receive placebo, which was to be compared with Wistar-Kyoto as controls. After 2-month treatment, SBP, heart to body weight ratio (HW/BW%) and echocardiographic features were evaluated, followed by haematoxylin and eosin and Masson trichrome staining in conjunction with qPCR of foetal gene expressions. Transferase-mediated dUTP nick-end labelling assay and immunofluorescent labelling for active caspase-3 were used to detect the apoptotic cardiomyocytes. Signaling pathways involved were examined by using western blot. Old-aged SHR developed end-stage hypertensive heart disease characterized by significant enhancement of HW/BW%, LVAWd and LVPWd, and decreased LVEF and LVFS, accompanied by cardiomyocytes enlargement and fibrosis along with activation of foetal gene programme. Cardiac apoptosis increased significantly during the transition process. Rosuvastatin reduced hypertrophy significantly via AT1 Receptor-PKCβ2/α-ERK-c-fos pathway; protected myocardium against apoptosis via Akt-FOXO1, Bcl-2 family and survivin pathways and consequently suppressed the caspase-3 activity. The present study revealed that old-aged SHRs developed cardiac remodelling from hypertrophy to fibrosis via cardiac apoptosis during the end stage of hypertensive heart disease. These pathological changes might be the consequence of activation of AT1 Receptor-PKCβ2/α-ERK-c-fos and AKT-FOXO1/Bcl-2/survivin/Caspase3 signaling. Rosuvastatin effectively attenuated the structural changes by reversing the signaling transductions involved. PMID:22288611

Treatment with telmisartan/rosuvastatin combination has a beneficial synergistic effect on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis.

PubMed

Liu, Zhendong; Zhao, Yingxin; Wei, Fang; Ye, Lin; Lu, Fanghong; Zhang, Hua; Diao, Yutao; Song, Hongbin; Qi, Zaiwen

2014-03-01

To explore synergistic effect between angiotensin II receptor blockers (ARBs) and statins on Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. This study was a 2 × 2 factorial randomized, prospective, double-blind, placebo-controlled trial. One hundred and fifty nine hypertensive patients with carotid atherosclerosis were randomized to the administration of control group, telmisartan group, rosuvastatin group, and combination group (telmisartan plus rosuvastatin) base on hydrochlorothiazide treatment. Carotid ultrasonography, parameters of Th17/Treg functional axis, interleukin (IL)-1β, IL-2, interferon (IFN)-γ, hypersensitive C-reactive protein (hsCRP), monocyte chemotactic protein (MCP)-1 were evaluated. Blood pressure level markedly reduced in four groups. There was significantly synergistic effect of combination of telmisartan with rosuvastatin on reducing carotid imtima-media thickness (IMT), Th17 cells frequency, IL-17, IL-6, IL-23, tumor necrosis factor (TNF)-α, expression of retinoic acid receptor-related orphan receptor (ROR)γt mRNA, Th17/Treg ratio, IL-1β, IL-2, IFN-γ, hsCRP, and MCP-1, and increasing Treg cells frequency, IL-10, transforming growth factor(TGF)-β1, and expression of forkhead/winged helix transcription factor (Foxp3) mRNA (all P<0.05). Change rate of IMT statistical positively related to descent rates of Th17 cells frequency, IL-17, IL-6, IL-23, TNF-α, expression of RORγt mRNA, Th17/Treg ratio, IL-1β, IL-2, IFN-γ, hsCRP, and MCP-1, and negatively related to increased rates of Treg frequency, IL-10, TGF-β1, and expression of Foxp3 mRNA, respectively (all P<0.05). There is a synergistic effect of combination of telmisartan with rosuvastatin on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Beneficial Effects of Sarpogrelate and Rosuvastatin in High Fat Diet/Streptozotocin-Induced Nephropathy in Mice

PubMed Central

Ku, Sae-Kwang; Park, Jeong-hyeon; Oh, Euichaul; Kwak, Mi-Kyoung

2016-01-01

Chronic kidney disease (CKD) is a major complication of metabolic disorders such as diabetes mellitus, obesity, and hypertension. Comorbidity of these diseases is the factor exacerbating CKD progression. Statins are commonly used in patients with metabolic disorders to decrease the risk of cardiovascular complications. Sarpogrelate, a selective antagonist of 5-hydroxytryptamine (5-HT) 2A receptor, inhibits platelet aggregation and is used to improve peripheral circulation in diabetic patients. Here, we investigated the effects of sarpogrelate and rosuvastatin on CKD in mice that were subjected to a high fat diet (HFD) for 22 weeks and a single low dose of streptozotocin (STZ, 40 mg/kg). When mice were administrated sarpogrelate (50 mg/kg, p.o.) for 13 weeks, albuminuria and urinary cystatin C excretion were normalized and histopathological changes such as glomerular mesangial expansion, tubular damage, and accumulations in lipid droplets and collagen were significantly improved. Sarpogrelate treatment repressed the HFD/STZ-induced CD31 and vascular endothelial growth factor receptor-2 expressions, indicating the attenuation of glomerular endothelial proliferation. Additionally, sarpogrelate inhibited interstitial fibrosis by suppressing the increases in transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1). All of these functional and histological improvements were also seen in rosuvastatin (20 mg/kg) group and, notably, the combinatorial treatment with sarpogrelate and rosuvastatin showed additive beneficial effects on histopathological changes by HFD/STZ. Moreover, sarpogrelate reduced circulating levels of PAI-1 that were elevated in the HFD/STZ group. As supportive in vitro evidence, sarpogrelate incubation blocked TGF-β1/5-HT-inducible PAI-1 expression in murine glomerular mesangial cells. Taken together, sarpogrelate and rosuvastatin may be advantageous to control the progression of CKD in patients with comorbid metabolic disorders, and particularly, the use of sarpogrelate as adjunctive therapy with statins may provide additional benefits on CKD. PMID:27097221

Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease – a perspective

PubMed Central

Kones, Richard

2010-01-01

The major public health concern worldwide is coronary heart disease, with dyslipidemia as a major risk factor. Statin drugs are recommended by several guidelines for both primary and secondary prevention. Rosuvastatin has been widely accepted because of its efficacy, potency, and superior safety profile. Inflammation is involved in all phases of atherosclerosis, with the process beginning in early youth and advancing relentlessly for decades throughout life. C-reactive protein (CRP) is a well-studied, nonspecific marker of inflammation which may reflect general health risk. Considerable evidence suggests CRP is an independent predictor of future cardiovascular events, but direct involvement in atherosclerosis remains controversial. Rosuvastatin is a synthetic, hydrophilic statin with unique stereochemistry. A large proportion of patients achieve evidence-based lipid targets while using the drug, and it slows progression and induces regression of atherosclerotic coronary lesions. Rosuvastatin lowers CRP levels significantly. The Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was designed after the observation that when both low density lipoprotein and CRP were reduced, patients fared better than when only LDL was lowered. Advocates and critics alike acknowledge that the benefits of rosuvastatin in JUPITER were real. After a review, the US Food and Drug Administration extended the indications for rosuvastatin to include asymptomatic JUPITER-eligible individuals with one additional risk factor. The American Heart Association and Centers of Disease Control and Prevention had previously recognized the use of CRP in persons with “intermediate risk” as defined by global risk scores. The Canadian Cardiovascular Society guidelines went further and recommended use of statins in persons with low LDL and high CRP levels at intermediate risk. The JUPITER study focused attention on ostensibly healthy individuals with “normal” lipid profiles and high CRP values who benefited from statin therapy. The backdrop to JUPITER during this period was an increasing awareness of a rising cardiovascular risk burden and imperfect methods of risk evaluation, so that a significant number of individuals were being denied beneficial therapies. Other concerns have been a high level of residual risk in those who are treated, poor patient adherence, a need to follow guidelines more closely, a dual global epidemic of obesity and diabetes, and a progressively deteriorating level of physical activity in the population. Calls for new and more effective means of reducing risk for coronary heart disease are intensifying. In view of compelling evidence supporting earlier and aggressive therapy in people with high risk burdens, JUPITER simply offers another choice for stratification and earlier risk reduction in primary prevention patients. When indicated, and in individuals unwilling or unable to change their diet and lifestyles sufficiently, the benefits of statins greatly exceed the risks. Two side effects of interest are myotoxicity and an increase in the incidence of diabetes. PMID:21267417

Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease--a perspective.

PubMed

Kones, Richard

2010-12-09

The major public health concern worldwide is coronary heart disease, with dyslipidemia as a major risk factor. Statin drugs are recommended by several guidelines for both primary and secondary prevention. Rosuvastatin has been widely accepted because of its efficacy, potency, and superior safety profile. Inflammation is involved in all phases of atherosclerosis, with the process beginning in early youth and advancing relentlessly for decades throughout life. C-reactive protein (CRP) is a well-studied, nonspecific marker of inflammation which may reflect general health risk. Considerable evidence suggests CRP is an independent predictor of future cardiovascular events, but direct involvement in atherosclerosis remains controversial. Rosuvastatin is a synthetic, hydrophilic statin with unique stereochemistry. A large proportion of patients achieve evidence-based lipid targets while using the drug, and it slows progression and induces regression of atherosclerotic coronary lesions. Rosuvastatin lowers CRP levels significantly. The Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was designed after the observation that when both low density lipoprotein and CRP were reduced, patients fared better than when only LDL was lowered. Advocates and critics alike acknowledge that the benefits of rosuvastatin in JUPITER were real. After a review, the US Food and Drug Administration extended the indications for rosuvastatin to include asymptomatic JUPITER-eligible individuals with one additional risk factor. The American Heart Association and Centers of Disease Control and Prevention had previously recognized the use of CRP in persons with "intermediate risk" as defined by global risk scores. The Canadian Cardiovascular Society guidelines went further and recommended use of statins in persons with low LDL and high CRP levels at intermediate risk. The JUPITER study focused attention on ostensibly healthy individuals with "normal" lipid profiles and high CRP values who benefited from statin therapy. The backdrop to JUPITER during this period was an increasing awareness of a rising cardiovascular risk burden and imperfect methods of risk evaluation, so that a significant number of individuals were being denied beneficial therapies. Other concerns have been a high level of residual risk in those who are treated, poor patient adherence, a need to follow guidelines more closely, a dual global epidemic of obesity and diabetes, and a progressively deteriorating level of physical activity in the population. Calls for new and more effective means of reducing risk for coronary heart disease are intensifying. In view of compelling evidence supporting earlier and aggressive therapy in people with high risk burdens, JUPITER simply offers another choice for stratification and earlier risk reduction in primary prevention patients. When indicated, and in individuals unwilling or unable to change their diet and lifestyles sufficiently, the benefits of statins greatly exceed the risks. Two side effects of interest are myotoxicity and an increase in the incidence of diabetes.

Effects of pitavastatin add-on therapy on chronic kidney disease with albuminuria and dyslipidemia.

PubMed

Ohsawa, Masato; Tamura, Kouichi; Wakui, Hiromichi; Kanaoka, Tomohiko; Azushima, Kengo; Uneda, Kazushi; Haku, Sona; Kobayashi, Ryu; Ohki, Kohji; Haruhara, Kotaro; Kinguchi, Sho; Toya, Yoshiyuki; Umemura, Satoshi

2015-12-09

In non-dialysis chronic kidney disease (CKD) patients with dyslipidemia, statin therapy is recommended to prevent cardiovascular complications. Dyslipidemia has been also shown to be an independent risk factor for the progression of CKD. However, it is still unclear whether statin therapy exerts an inhibitory effect on renal deterioration in CKD patients with dyslipidemia. The purpose of the present study was to examine possible therapeutic effects of statin add-on therapy on renal function as well as parameters of lipid and glucose metabolism, arterial stiffness and oxidative stress, in comparison to diet therapy, in CKD patients with dyslipidemia. This study was a randomized, open-label, and parallel-group trial consisted of a 12-months treatment period in non-dialysis CKD patients with alubuminuria and dyslipidemia. Twenty eight patients were randomly assigned either to receive diet counseling alone (diet therapy group) or diet counseling plus pitavastatin (diet-plus-statin therapy group), to achieve the LDL-cholesterol (LDL-C) target of <100 mg/dl. The statin treatment by pitavastatin was well tolerated in all of the patients without any significant adverse events and the average dose of pitavastatin was 1.0 ± 0.0 mg daily after treatment. After the 12-months treatment period, LDL-C was significantly lower in the diet-plus-statin therapy group compared with the diet therapy group (diet vs diet-plus-statin: LDL-C, 126 ± 5 vs 83 ± 4 mg/dL, P < 0.001). On the other hand, the diet-plus-statin therapy did not significantly reduce albuminuria or delay the decline in eGFR compared with the diet therapy, and there was no relationship between the change in LDL-C and the change in eGFR or albuminuria. However, diet therapy as well as diet-plus-statin therapy exerted similar lowering effects on the pentosidine levels (diet therapy group, baseline vs 12 months: 40 ± 4 vs 24 ± 3 ng/mL, P = 0.001; diet-plus-statin therapy, 46 ± 7 vs 34 ± 6 ng/mL, P = 0.008). Furthermore, the results of multivariate regression analysis indicated that the change in pentosidine was a significant contributor to the change in eGFR (β = -0.536, P = 0.011). Although statin add-on therapy did not show additive renal protective effects, the diet therapy as well as the diet-plus-statin therapy could contribute to the reduction in plasma pentosidine in CKD patients with albuminuria and dyslipidemia.

Effect of high-dose rosuvastatin loading before percutaneous coronary intervention in Chinese patients with acute coronary syndrome: A systematic review and meta-analysis

PubMed Central

Su, Qiang; Guo, Wenqin; Dai, Weiran; Li, Hongqing; Yang, Huafeng; Li, Lang

2017-01-01

Background Acute coronary syndrome (ACS) is an important disease threatening human life and health. Many studies have shown that the loading dose of atorvastatin can significantly improve the prognosis of patients with ACS, and reduce the mortality. However, this conclusion is not consistent. Thus, we aimed to evaluate the effect of high-dose rosuvastatin loading before percutaneous coronary intervention (PCI) in Chinese patients with ACS using a meta-analysis based on a systematic review of published articles. Methods We systematically reviewed published studies, evaluating the effect of high-dose rosuvastatin loading before percutaneous coronary intervention in Chinese patients with ACS. The retrieval time is limited from inception to 2 November 2016, and the retrieved databases included PubMed, Embase, the Cochrane Library, Web of Science, CBM, CNKI, the VIP database and the Wang Fang database. Two researchers independently assessed the quality of the included studies and then extracted the data. Stata 11.0 was used for data analysis. Results In total, 11 articles, which included 802 patients, were included in our meta-analysis. Among these patients, 398 patients were in the high-dose group (20 mg/day) and 404 patients were in the conventional dose group (10 mg/day). Meta-analysis results showed that compared with the conventional dose group: 1) The loading dose of rosuvastatin can significantly reduce the hs-CRP level after PCI, including at 24 hours (SMD = -0.65, 95%CI -0.84 ~ -0.47, P = 0.000), 48 hours (SMD = -0.40, 95%CI -0.68 ~ -0.11, P = 0.006), and four weeks (SMD = -1.64, 95%CI -2.01 ~ -1.26, P = 0.000). 2) The loading dose of rosuvastatin can significantly reduce the levels of LDL-C and cTnT, including the level of LDL-C at 30 d after PCI (SMD = -0.89, 95%CI -1.10 ~ -0.69, P = 0.000), and the level of cTnT at 24 h after PCI (SMD = -1.93, 95%CI -2.28 ~ -1.59, P = 0.000), and increase the level of HDL-C at 48 h after PCI (SMD = 0.61, 95%CI 0.34 ~ 0.88, P = 0.000). 3) The loading dose of rosuvastatin can significantly reduce the levels of TG and TC, including the level of TG at 30 d after PCI (SMD = -0.94, 95%CI -1.17 ~ -0.71, P = 0.000), the level of TC at 48 h after PCI (SMD = -0.35, 95%CI -0.68 ~ -0.01, P = 0.043), and the level of TC at 30 d after PCI (SMD = -0.77, 95%CI -0.98 ~ -0.56, P = 0.000). Conclusions Our systematic review and meta-analysis showed that, compared with the conventional dose, the loading dose of rosuvastatin was more beneficial to patients with ACS in China and is suitable for clinical application. Due to the limitations of the quality and quantity of included articles, this conclusion still needs to be confirmed by multicenter clinical trials. PMID:28231287

The therapeutic effect of rosuvastatin on cardiac remodelling from hypertrophy to fibrosis during the end-stage hypertension in rats.

PubMed

Zhang, W B; Du, Q J; Li, H; Sun, A J; Qiu, Z H; Wu, C N; Zhao, G; Gong, H; Hu, K; Zou, Y Z; Ge, J B

2012-09-01

End-stage hypertensive heart disease is an increasing cause of cardiac mortality. Therefore, the current study focused on the cardiac remodelling from hypertrophy to fibrosis in old-aged spontaneously hypertensive rats (SHRs), and explored the therapeutic effects of Rosuvastatin and its possible mechanism(s) of action. Spontaneously hypertensive rats at age 52 weeks were randomly divided into three groups, the first two to receive Rosuvastatin at a dose of 20 mg/kg/day and 40 mg/kg/day, respectively, and the third to receive placebo, which was to be compared with Wistar-Kyoto as controls. After 2-month treatment, SBP, heart to body weight ratio (HW/BW%) and echocardiographic features were evaluated, followed by haematoxylin and eosin and Masson trichrome staining in conjunction with qPCR of foetal gene expressions. Transferase-mediated dUTP nick-end labelling assay and immunofluorescent labelling for active caspase-3 were used to detect the apoptotic cardiomyocytes. Signaling pathways involved were examined by using western blot. Old-aged SHR developed end-stage hypertensive heart disease characterized by significant enhancement of HW/BW%, LVAWd and LVPWd, and decreased LVEF and LVFS, accompanied by cardiomyocytes enlargement and fibrosis along with activation of foetal gene programme. Cardiac apoptosis increased significantly during the transition process. Rosuvastatin reduced hypertrophy significantly via AT(1) Receptor-PKCβ2/α-ERK-c-fos pathway; protected myocardium against apoptosis via Akt-FOXO1, Bcl-2 family and survivin pathways and consequently suppressed the caspase-3 activity. The present study revealed that old-aged SHRs developed cardiac remodelling from hypertrophy to fibrosis via cardiac apoptosis during the end stage of hypertensive heart disease. These pathological changes might be the consequence of activation of AT(1) Receptor-PKCβ2/α-ERK-c-fos and AKT-FOXO1/Bcl-2/survivin/Caspase3 signaling. Rosuvastatin effectively attenuated the structural changes by reversing the signaling transductions involved. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Localized rosuvastatin via implantable bioerodible sponge and its potential role in augmenting bone healing and regeneration.

PubMed

Ibrahim, Howida Kamal; Fahmy, Rania Hassan

2016-11-01

Statins proved potential bone healing properties. Rosuvastatin is a synthetic, hydrophilic, potent and highly efficacious statin. In the current work, an attempt was investigated to develop, evaluate various bioerodible composite sponges enclosing rosuvastatin and explore their potential in augmenting bone healing and regeneration. Twelve lyophilized sponge formulae were prepared adapting a 4 1 .3 1 full factorial design. Xanthan gum, polycarbophil, Carbopol® and sodium alginate were investigated as anionic polymers, each at three chitosan:anionic polymer ratios (1:3, 1:1, 3:1). The formula of choice was implanted in fractured rat femora. Visual and microscopic examination showed flexible homogenous porous structures with considerable bending ability. Polyelectrolyte complex formation was proved by DSC and FT-IR for all chitosan/anionic combinations except with xanthan gum where chitosan probably bound to the drug rather than xanthan gum. Statistical analysis proved that anionic polymer type and chitosan: polymer ratio, as well as, their interactions, exhibited significant effects on the release parameters at p ≤ 0.05. The optimum chitosan/anionic polymer complexation ratios were 3:1 for polycarbophil and 1:1 for Carbopol and alginate. The release at these ratios followed Fiction diffusion while other ratios had anomalous diffusion. Imwitor® 900K and HPMC K100M were added as release retarardants for further release optimization. The formula of choice was implanted in fractured rat femora. Histopathological examination revealed advanced stages of healing in treated femora compared to control ones. Biodegradable sponges for local rosuvastatin delivery proved significantly enhanced wound healing and regeneration properties to fractured bones.

Survival analysis using inverse probability of treatment weighted methods based on the generalized propensity score.

PubMed

Sugihara, Masahiro

2010-01-01

In survival analysis, treatment effects are commonly evaluated based on survival curves and hazard ratios as causal treatment effects. In observational studies, these estimates may be biased due to confounding factors. The inverse probability of treatment weighted (IPTW) method based on the propensity score is one of the approaches utilized to adjust for confounding factors between binary treatment groups. As a generalization of this methodology, we developed an exact formula for an IPTW log-rank test based on the generalized propensity score for survival data. This makes it possible to compare the group differences of IPTW Kaplan-Meier estimators of survival curves using an IPTW log-rank test for multi-valued treatments. As causal treatment effects, the hazard ratio can be estimated using the IPTW approach. If the treatments correspond to ordered levels of a treatment, the proposed method can be easily extended to the analysis of treatment effect patterns with contrast statistics. In this paper, the proposed method is illustrated with data from the Kyushu Lipid Intervention Study (KLIS), which investigated the primary preventive effects of pravastatin on coronary heart disease (CHD). The results of the proposed method suggested that pravastatin treatment reduces the risk of CHD and that compliance to pravastatin treatment is important for the prevention of CHD. (c) 2009 John Wiley & Sons, Ltd.

Long-term follow-up of moderately hypercholesterolemic hypertensive patients following randomization to pravastatin vs. usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)

PubMed Central

Margolis, Karen L.; Davis, Barry R.; Baimbridge, Charles; Ciocon, Jerry O.; Cuyjet, Aloysius B.; Dart, Richard A.; Einhorn, Paula T.; Ford, Charles E.; Gordon, David; Hartney, Thomas J; Haywood, L. Julian; Holtzman, Jordan; Mathis, David E.; Oparil, Suzanne; Probstfield, Jeffrey L.; Simpson, Lara M.; Stokes, John D.; Wiegmann, Thomas B.; Williamson, Jeff D.

2015-01-01

A randomized, controlled, multicenter trial assigned well-controlled hypertensive participants ≥55 years, with moderate hypercholesterolemia to receive pravastatin (n=5170) or usual care (n=5185) for 4-8 years, when trial therapy was discontinued. Passive surveillance using national databases to ascertain deaths and hospitalizations continued for total follow-up of 8-13 years to assess whether mortality and morbidity differences persisted or new differences developed. During the post-trial period, fatal and nonfatal outcomes were available for 98% and 64% of participants, respectively. Primary outcome was all-cause mortality; secondary outcomes included cardiovascular mortality, coronary heart disease (CHD), stroke, heart failure, cardiovascular disease, and end-stage renal disease. No significant differences appeared in mortality for pravastatin versus usual care (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03), or other secondary outcomes. Similar to the previously reported in-trial result, there was a significant treatment effect for CHD in Blacks (HR, 0.79; 95% CI, 0.64-0.98). However, the in-trial result showing a significant treatment by race effect did not remain significant over the entire follow-up (P=.08). These findings are consistent with evidence from other large trials that show statins prevent CHD and add evidence that they are effective for CHD prevention in Blacks. PMID:23889716

Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study.

PubMed

Ashton, Emma; Windebank, Emma; Skiba, Marina; Reid, Christopher; Schneider, Hans; Rosenfeldt, Franklin; Tonkin, Andrew; Krum, Henry

2011-02-03

Statins are often prescribed for prevention of atherosclerotic outcomes in patients who have chronic heart failure (CHF), if this has an ischaemic etiology. These agents may also possess additional properties, independent of effects on blood lipid levels, which may have an effect on cardiac remodeling. However, beneficial effects were not observed in the recent UNIVERSE trial. We prospectively planned a sub-study of UNIVERSE to explore relevant mechanistic effects of rosuvastatin, including effects on collagen turnover and plasma coenzyme Q10 (CoQ) levels. Additionally, CoQ levels in CHF patients receiving chronic statin therapy were measured. CoQ levels were significantly reduced after 26 weeks of rosuvastatin statin therapy (n = 32), compared to placebo (n = 37) in CHF patients in UNIVERSE trial. Patients with CHF (n = 56) matched for age, gender and severity of disease who had been taking statins for 12 months or longer had CoQ levels of 847 ± 344 nmol/L, significantly lower than 1065.4 ± 394 nmol/L in UNIVERSE patients at baseline (p = 0.0001). Serum types I and III N-terminal procollagen peptide (PINP and PIIINP), measures of collagen turnover which can contribute to cardiac fibrosis were significantly increased in the rosuvastatin group compared to baseline in UNIVERSE patients (PINP: p = 0.03, PIIINP: p = 0.001). In conclusion putative beneficial effects of statin therapy on cardiac remodeling in UNIVERSE may have been negated by increases in collagen turnover markers as well as a reduction in plasma CoQ levels in these patients with CHF. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Quantitative determination of rosuvastatin in human plasma by liquid chromatography with electrospray ionization tandem mass spectrometry.

PubMed

Xu, Dong-Hang; Ruan, Zou-Rong; Zhou, Quan; Yuan, Hong; Jiang, Bo

2006-01-01

A simple and sensitive liquid chromatography/tandem mass spectrometry method was developed and validated for determining rosuvastatin in human plasma, a new synthetic hydroxymethylglutaryl-coenzyme A reductase inhibitor. The analyte and internal standard (IS; cilostazol) were extracted by simple one-step liquid/liquid extraction with ether. The organic layer was separated and evaporated under a gentle stream of nitrogen at 40 degrees C. The chromatographic separation was performed on an Atlantis C18 column (2.1 mm x 150 mm, 5.0 microm) with a mobile phase consisting of 0.2% formic acid/methanol (30:70, v/v) at a flow rate of 0.20 mL/min. The analyses were carried out by multiple reaction monitoring (MRM) using the precursor-to-product combinations of m/z 482 --> 258 and m/z 370 --> 288. The areas of peaks from the analyte and the IS were used for quantification of rosuvastatin. The method was validated according to the FDA guidelines on bioanalytical method validation. Validation results indicated that the lower limit of quantification (LLOQ) was 0.2 ng/mL and the assay exhibited a linear range of 0.2-50.0 ng/mL and gave a correlation coefficient (r) of 0.9991 or better. Quality control samples (0.4, 8, 25 and 40 ng/mL) in six replicates from three different runs of analysis demonstrated an intra-assay precision (RSD) 7.97-15.94%, an inter-assay precision 3.19-15.27%, and an overall accuracy (relative error) of < 3.7%. The method can be applied to pharmacokinetic or bioequivalence studies of rosuvastatin.

Continuing Exposure to Low-Dose Nonylphenol Aggravates Adenine-Induced Chronic Renal Dysfunction and Role of Rosuvastatin Therapy

PubMed Central

2012-01-01

Background Nonylphenol (NP), an environmental organic compound, has been demonstrated to enhance reactive-oxygen species (ROS) synthesis. Chronic exposure to low-dose adenine (AD) has been reported to induce chronic kidney disease (CKD). Methods In this study, we tested the hypothesis that chronic exposure to NP will aggravate AD-induced CKD through increasing generations of inflammation, ROS, and apoptosis that could be attenuated by rosuvastatin. Fifty male Wistar rats were equally divided into group 1 (control), group 2 (AD in fodder at a concentration of 0.25%), group 3 (NP: 2 mg/kg/day), group 4 (combined AD & NP), and group 5 (AD-NP + rosuvastatin: 20 mg/kg/day). Treatment was continued for 24 weeks for all animals before being sacrificed. Results By the end of 24 weeks, serum blood urea nitrogen (BUN) and creatinine levels were increased in group 4 than in groups 1–3, but significantly reduced in group 5 as compared with group 4 (all p < 0.05). Histopathology scorings of renal-parenchymal and tubular damages were significantly higher in group 4 than in groups 1–3, but remarkably lower in group 5 compared with group 4 (all p < 0.01). Both gene and protein levels of inflammation, oxidative stress, ROS, and cellular apoptosis were remarkably higher in group 4 compared with groups 1–3, but lowered in group 5 than in group 4 (all p < 0.001). Conversely, both gene and protein levels of anti-oxidants, anti-inflammation and anti-apoptosis were markedly increased in group 5 compared with group 4 (all p < 0.001). Conclusion NP worsened AD-induced CKD that could be reversed by rosuvastatin therapy. PMID:22812704

Combined treatment with bexarotene and rosuvastatin reduces angiotensin-II-induced abdominal aortic aneurysm in apoE-/- mice and angiogenesis

PubMed Central

Escudero, P; Navarro, A; Ferrando, C; Furio, E; Gonzalez-Navarro, H; Juez, M; Sanz, M J; Piqueras, L

2015-01-01

Background and Purpose Abdominal aortic aneurysm (AAA) is a degenerative vascular disease associated with angiogenesis. Bexarotene is a retinoid X receptor (RXR) ligand with anti-angiogenic activity. Statins also exert anti-angiogenic activity and activate PPARs. Because RXR ligands form permissive heterodimers with PPARs and a single anti-angiogenic drug may not be sufficient to combat the wide array of angiogenic factors produced during AAA, we evaluated the effect of combined low doses of bexarotene and rosuvastatin in a mouse model of AAA. Experimental Approach The effect of the combined treatment was investigated in a murine model of angiotensin II-induced AAA in apoE−/− mice. This combination therapy was also evaluated in in vivo (Matrigel plug assay) and in vitro (endothelial cell differentiation assay) models of angiogenesis as well as the underlying mechanisms involved. Key Results Co-treatment with bexarotene plus rosuvastatin reduced aneurysm formation, inflammation and neovascularization compared with each single treatment. In HUVEC, the combination of suboptimal concentrations of bexarotene and rosuvastatin inhibited angiotensin II-induced morphogenesis, proliferation and migration. These effects were accompanied by diminished production of pro-angiogenic chemokines (CXCL1, CCL2 or CCL5) and VEGF, and seemed to be mediated by RXRα/PPARα and RXRα/PPARγ activation. This combined therapy reduced the activation of members of the downstream PI3K pathway (Akt/mTOR and p70S6K1) in vivo and in vitro. Conclusions and Implications The combination of RXR agonists with statins at low doses synergistically interferes with the signalling pathways that modulate inflammation and angiogenesis and may constitute a new and safer therapeutic treatment for the control of AAA. PMID:25630951

Clinical and Pharmacogenetic Predictors of Circulating Atorvastatin and Rosuvastatin Concentration in Routine Clinical Care

PubMed Central

DeGorter, Marianne K.; Tirona, Rommel G.; Schwarz, Ute I.; Choi, Yun-Hee; Dresser, George K.; Suskin, Neville; Myers, Kathryn; Zou, GuangYong; Iwuchukwu, Otito; Wei, Wei-Qi; Wilke, Russell A.; Hegele, Robert A.; Kim, Richard B.

2014-01-01

Background A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. Methods and Results In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for gender, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C (p < 0.001) and ABCG2 c.421C>A (p < 0.01) were important to rosuvastatin concentration (adjusted R2 = 0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G (p < 0.01) and c.521T>C (p < 0.05), and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R2 = 0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient's risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. Conclusions Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine if this approach reduces incidence of statin-myopathy. PMID:23876492

The use of plaque score measurements to assess changes in atherosclerotic plaque burden induced by lipid-lowering therapy over time: the METEOR study.

PubMed

Peters, Sanne A E; Dogan, Soner; Meijer, Rudy; Palmer, Mike K; Grobbee, Diederick E; Crouse, John R; O'Leary, Daniel H; Evans, Gregory W; Raichlen, Joel S; Bots, Michiel L

2011-01-01

To evaluate whether plaque scoring measurements are able to track changes in atherosclerotic plaque burden over time and to study whether this is affected by lipid-lowering therapy. Data used were from METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation Of Rosuvastatin), a randomized controlled trial of rosuvastatin 40 mg among 984 low-risk patients with modest carotid intima-media thickening (CIMT). In this analysis, duplicate ultrasound images from 12 carotid sites were collected at the baseline and end of the study from 495 European patients and were evaluated for plaque presence and severity. Plaques were scored from near and far walls of the 12 sites (0= none; 1= minimal; 2= moderate; 3= severe) and plaque scores (PS) were combined into two summary measures for each examination. The MeanMaxPS is the mean over the 12 carotid sites of the maximum score at each site and the MaxMaxPS reflects the most severe lesion at any site. Baseline MeanMaxPS and MaxMaxPS were 0.31 (SD: 0.20) and 1.15 (SD: 0.51), respectively. Changes in MeanMaxPS and MaxMaxPS significantly differed between rosuvastatin and placebo (mean difference: -0.03 [SE: 0.01; p =0.016] and -0.09 [SE: 0.04; p =0.027], respectively). In contrast to rosuvastatin, which demonstrated no change from the baseline, placebo showed significant progression in MeanMaxPS and MaxMaxPS (p =0.002; both). The plaque-scoring method proved capable of assessing the change in atherosclerotic plaque burden over time and proved useful to evaluate lipid-lowering in asymptomatic individuals with a low risk of cardiovascular disease and subclinical atherosclerosis.

Pravastatin stimulates angiogenesis in a murine hindlimb ischemia model: a positron emission tomography imaging study with (64)Cu-NOTA-TRC105.

PubMed

Orbay, Hakan; Hong, Hao; Koch, Jill M; Valdovinos, Hector F; Hacker, Timothy A; Theuer, Charles P; Barnhart, Todd E; Cai, Weibo

2013-01-01

In this study, (64)Cu-NOTA-TRC105 (TRC105 is an anti-CD105 monoclonal antibody that binds to both human and murine CD105) positron emission tomography (PET) was used to assess the response to pravastatin treatment in a murine model of peripheral artery disease (PAD). Hindlimb ischemia was induced by ligation of the right femoral arteries in BALB/c mice under anesthesia, and the left hindlimb served as an internal control. Mice in the treatment group were given intraperitoneal pravastatin daily until the end of the study, whereas the animals in the control group were injected with 0.9% sodium chloride solution. Laser Doppler imaging showed that blood flow in the ischemic hindlimb plummeted to ~20% of the normal level after surgery, and gradually recovered to near normal level on day 10 in the treatment group and on day 20 in the control group. Angiogenesis was non-invasively monitored and quantified with (64)Cu-NOTA-TRC105 PET on postoperative days 3, 10, 17, and 24. Tracer uptake at 48 h post-injection in the ischemic hindlimb in the treatment group was significantly higher than that of the control group on day 10 (20.5 ± 1.9 %ID/g vs 11.4 ± 1.5 %ID/g), suggesting increased CD105 expression and higher level of angiogenesis upon pravastatin treatment, and gradually decreased to background levels in both groups (4.9 ± 0.8 %ID/g vs 3.4 ± 1.9 %ID/g on day 24). The in vivo PET data correlated well with ex vivo biodistribution studies performed on day 24. Increased CD105 expression on days 3 and 10 following ischemia was further confirmed by immunofluorescence staining. Taken together, our results indicated that (64)Cu-NOTA-TRC105 PET is a suitable and non-invasive method to monitor the angiogenesis and therapeutic response in PAD, which can also be utilized for non-invasive evaluation of other pro-angiogenic/anti-angiogenic drugs in other cardiovascular diseases and cancer.

Statins cause profound effects on gene expression in human cancer cells in vitro: the role of membrane microdomains.

PubMed

Garnett, David John; Greenhough, Trevor James

2012-01-01

There is increasing evidence that statin treatment can be beneficial in certain cancer patients. To determine if these benefits are a direct result of the cholesterol-lowering effects of statins or a result of secondary, protein transcription effects, the impacts of pravastatin and a cholesterol sequestrating agent methyl-beta-cyclodextrin (MbetaCD) on mRNA expression in the breast cancer cell MDA-MB-231 and the lung carcinoma cell Calu-1 have been compared by microarray techniques. The effects of these agents on cholesterol-rich rafts and caveolae, which have significance in cancer signaling, have also been examined. Both treatments caused a general downregulation of not only signal transduction including cancer pathway proteins, but also apoptosis and chemokine pathways, with statins impacting 35 genes by twofold or greater in MDA-MB-231 and > 300 genes in Calu-1. These manifold dysregulations could also explain the various side effects reportedly caused by statins. MbetaCD produced far fewer statistical events than pravastatin in the breast cancer line but many more in the lung cell line. Pravastatin increased expression of CAV1 but caveolae density decreased and overall raft density was unaffected. MbetaCD also caused an increase in CAV1 expression and reduced the prevalence of both rafts and caveolae. It is proposed that sequestration of cholesterol from the membrane by MbetaCD is not equivalent to blockade of the cholesterol pathway and causes different effects on microdomain-mediated signal transduction dependant on the cell line. The profound effects of statins on mRNA expression can be explained by the failure of caveolin-1 to properly complex with cholesterol in an altered sterol environment, with caveolae acting as the main loci for signaling directed towards those transcription processes unaffected by MbetaCD. Targeted inhibition of the postmevalonate pathway could offer an opportunity to specifically reduce caveolae-based signaling in cancer cells. The observed impact of pravastatin on gene expression may explain the pleiotropic effects of statins when they are used as adjuvants in chemotherapy and suggests impact on gene expression as a possible cause of side effects from statin use.

Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin

PubMed Central

Rose, R H; Neuhoff, S; Abduljalil, K; Chetty, M; Rostami-Hodjegan, A; Jamei, M

2014-01-01

Typically, pharmacokinetic–pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concentration. A physiologically based PK/PD model for rosuvastatin was developed that linked the predicted liver concentration to the PD response model. The model was then applied to predict the effect of genotype-dependent uptake by the organic anion-transporting polypeptide 1B1 (OATP1B1) transporter on the pharmacological response. The area under the plasma concentration–time curve (AUC0–∞) was increased by 63 and 111% for the c.521TC and c.521CC genotypes vs. the c.521TT genotype, while the PD response remained relatively unchanged (3.1 and 5.8% reduction). Using local concentration at the effect site to drive the PD response enabled us to explain the observed disconnect between the effect of the OATP1B1 c521T>C polymorphism on rosuvastatin plasma concentration and the cholesterol synthesis response. PMID:25006781

Pharmacokinetic Evaluation of a Drug Transporter Cocktail Consisting of Digoxin, Furosemide, Metformin, and Rosuvastatin

PubMed Central

Giessmann, T; Hohl, K; Sharma, A; Ishiguro, N; Taub, ME; Zimdahl‐Gelling, H; Gansser, D; Wein, M; Ebner, T; Müller, F

2016-01-01

This article reports the clinical investigation of a probe drug cocktail containing substrates of key drug transporters. Single oral doses of 0.25 mg digoxin (P‐gp), 5 mg furosemide (OAT1 and OAT3), 500 mg metformin (OCT2, MATE1, and MATE2‐K), and 10 mg rosuvastatin (OATP1B1, OATP1B3, and BCRP) were administered separately or as a cocktail in a randomized six‐period crossover trial in 24 healthy male volunteers. As a cocktail, relative bioavailabilities of digoxin and metformin and furosemide AUC0‐tz were similar to separate dosing. However, when administered as a cocktail the Cmax of furosemide was 19.1% lower and the Cmax and AUC0‐tz of rosuvastatin were 38.6% and 43.4% higher, respectively. In addition, the effects of increased doses of metformin or furosemide on the cocktail were investigated in 11 and 12 subjects, respectively. The cocktail explored in this trial has the potential to be used for the in vivo screening of transporter‐mediated drug–drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics PMID:27256812

Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome.

PubMed

Kargiotis, Konstantinos; Athyros, Vasilios G; Giouleme, Olga; Katsiki, Niki; Katsiki, Evangelia; Anagnostis, Panagiotis; Boutari, Chrysoula; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

2015-07-07

To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20(th), which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3(rd) treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6(th) treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3(rd) treatment month. No patient had MetS by the 9(th) treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed solely to rosuvastatin treatment. A limitation of the study is the absence of a control group. These findings suggest that rosuvastatin monotherapy could ameliorate biopsy proven NASH and resolve MetS within 12 mo. These effects and the reduction of fasting plasma glucose and SUA levels may reduce the risk of vascular and liver morbidity and mortality in NASH patients. These findings need confirmation in larger studies.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-06-01

[¹¹C]RAC; (18)F-Fluoromisonidazole; 89-12; 9-[¹⁸F]Fluoropropyl-(+)-dihydrotetrabenazine; Adalimumab, Adecatumumab, ADMVA, ADXS-11-001, Aflibercept, Agatolimod sodium, AGS-004, Alglucosidase alfa, Aliskiren fumarate, Alvocidib hydrochloride, AMG-108, AMG-853, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride; Bevacizumab, BioMatrix Flex drug eluting stent, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, Cediranib, Cetuximab, ChimeriVax-Dengue, Choriogonadotropin alfa, Cinacalcet hydrochloride, Cizolirtine citrate, Clofarabine, Cocaine conjugate vaccine, CX-717; Darbepoetin alfa, Dasatinib, Decitabine, Denosumab, Desvenlafaxine succinate, Dexamethasone sodium phosphate, Dienogest, Diphencyprone, Doripenem, DTaP-HepB-IPV, Dutasteride; E-7010, Ecallantide, Ecstasy, Eicosapentaenoic acid/docosahexaenoic acid, Emtricitabine, Enfuvirtide, Erlotinib hydrochloride, Eszopiclone, Etonogestrel/ethinyl estradiol, Etoricoxib, Everolimus, Everolimus-eluting coronary stent EVT-201, Ezetimibe, Ezetimibe/simvastatin; Ferumoxytol, Fesoterodine fumavate, Figitumumab, Filgrastim, Fingolimod hydrochloride, Fluticasone furoate, Fluval P, Fluzone, Fondaparinux sodium, Fulvestrant, Fungichromin; Gamma-hydroxybutyrate sodium, Gefitinib, GHB-01L1, GLY-230, GSK-1349572; Hib-MenCY-TT, Hib-TT, HPV-6/11/16/18, Hydrocodone bitartrate; IC-51, Icatibant acetate, Imatinib mesylate, Immunoglobulin intravenous (human), Indetanib, Influenza A (H1N1) 2009 Monovalent Vaccine, Inhalable human insulin, Insulin glargine, Insulin glulisine, Interferon-beta, Ispinesib mesylate, Ixabepilone; Laromustine, Latanoprost/timolol maleate, L-Citrulline, Lenalidomide, Lexatumumab, Linezolid, Lopinavir/ritonavir, Lutropin alfa; Mapatumumab, MDX-066, MDX-1388, Mepolizumab, Methoxy polyethylene glycol-epoetin-beta, Metreleptin, Micafungin sodium, Mometasone furoate/oxymetazoline hydrochloride, Mx-dnG1, Mycophenolic acid sodium salt; Nabiximols, Natalizumab, Nemonoxacin, Norelgestromin/ethinyl estradiol; Oblimersen sodium, Ocriplasmin, Olmesartan medoxomil, Omacetaxine mepesuccinate; Paclitaxel-eluting stent, Pagoclone, Paliperidone, Panitumumab, Pazopanib hydrochloride, PCV7, Pegaptanib octasodium, Peginterferon alfa-2a, Peginterferon alfa-2b/ ribavirin, Pegvisomant, Pemetrexed disodium, Perifosine, Pimecrolimus, Pitavastatin calcium, Plerixafor hydrochloride, Plitidepsin, Posaconazole, Pregabalin, Progesterone capriate; Raltegravir potassium, Ramucirumab, Ranelic acid distrontium salt, Rasburicase, Recombinant Bet V1, Recombinant human insulin, rhFSH, Rolofylline, Romidepsin, Romiplostim, Rosuvastatin calcium; Sapacitabine, Sevelamer carbonate, Sinecatechins, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, SN-29244, Sorafenib, Sugammadex sodium, Sunitinib malate; Tadalafil, Tafenoquine, Talnetant, Tanezumab, Tapentadol hydrochloride, Tasocitinib citrate, Technosphere/Insulin, Telcagepant, Tenofovir disoproxil fumarate, Teriparatide, Ticagrelor, Tigecycline, Tiotropium bromide, Tipifarnib, Tocilizumab, TS-041; Ulipristal acetate, Urtoxazumab, Ustekinumab; Vandetanib, Varenicline tartrate, Vicriviroc, Voriconazole, Vorinostat, VRC-HIVADV014-00-VP, VRC-HIVDNA016-00-VP; Zoledronic acid monohydrate. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Economic Evaluation of Lipid-Lowering Therapy in the Secondary Prevention Setting in the Philippines.

PubMed

Tumanan-Mendoza, Bernadette A; Mendoza, Victor L

2013-05-01

To determine the cost-effectiveness of lipid-lowering therapy in the secondary prevention of cardiovascular events in the Philippines. A cost-utility analysis was performed by using Markov modeling in the secondary prevention setting. The models incorporated efficacy of lipid-lowering therapy demonstrated in randomized controlled trials and mortality rates obtained from local life tables. Average and incremental cost-effectiveness ratios were obtained for simvastatin, atorvastatin, pravastatin, and gemfibrozil. The costs of the following were included: medications, laboratory examinations, consultation and related expenses, and production losses. The costs were expressed in current or nominal prices as of the first quarter of 2010 (Philippine peso). Utility was expressed in quality-adjusted life-years gained. Sensitivity analyses were performed by using variations in the cost centers, discount rates, starting age, and differences in utility weights for stroke. In the analysis using the lower-priced generic counterparts, therapy using 40 mg simvastatin daily was the most cost-effective option compared with the other therapies, while pravastatin 40 mg daily was the most cost-effective alternative if the higher-priced innovator drugs were used. In all sensitivity analyses, gemfibrozil was strongly dominated by the statins. In secondary prevention, simvastatin or pravastatin were the most cost-effective options compared with atorvastatin and gemfibrozil in the Philippines. Gemfibrozil was strongly dominated by the statins. Copyright © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Factors influencing dyslipidemia in statin-treated patients in Lebanon and Jordan: results of the Dyslipidemia International Study.

PubMed

Azar, Sami T; Hantash, Hadi Abu; Jambart, Selim; El-Zaheri, Mohamed M; Rachoin, Rachoin; Chalfoun, Amal; Lahoud, Layla; Okkeh, Osama; Bramlage, Peter; Brudi, Philippe; Ambegaonkar, Baishali M

2014-01-01

Cardiovascular disease is the leading cause of death and disability worldwide. Therefore, as part of the Dyslipidemia International Study (DYSIS), we have analyzed the prevalence of lipid abnormalities and risk factors for dyslipidemia in statin-treated patients in Lebanon and Jordan. This cross-sectional, multicenter study enrolled 617 patients at 13 hospitals in Lebanon and Jordan. Patients were at least 45 years old and had been treated with statins for at least 3 months. Multivariate logistic regression analysis was used to determine patient characteristics contributing to dyslipidemia during statin therapy. Our findings indicated that 55.9% of statin-treated patients (mean age 60.3 years, 47% female) in Lebanon and Jordan did not achieve goal levels for low-density lipoprotein cholesterol which were dependent on Systematic Coronary Risk Evaluation (SCORE) risk, and 70% of patients (76% men and 63.3% of women) were at very high cardiovascular risk. Low-density lipoprotein cholesterol goals were not achieved in 67.2% of those with very high cardiovascular risk. The most commonly prescribed statin was atorvastatin (44.6%), followed by simvastatin (27.7%), rosuvastatin (21.2%), fluvastatin (3.3%), pravastatin (3%), and lovastatin (0.2%). Approximately half of the population was treated with a statin dose potency of 4, equaling 40 mg of simvastatin. In Lebanon and Jordan, the strongest independent associations with low-density lipoprotein cholesterol not at goal were current smoking (odds ratio [OR] 1.96; 95% confidence [CI] 1.25-3.08), diabetes mellitus (OR 2.53; 95% CI 1.70-3.77), and ischemic heart disease (OR 2.26; 95% CI 1.45-3.53), while alcohol consumption was associated with reduced risk (OR 0.12; 95% CI 0.03-0.57). We observed that many patients in Lebanon and Jordan experienced persistent dyslipidemia during statin treatment, supporting the notion that novel lipid-lowering strategies need to be developed. Also, social programs aimed at combating the extremely high rates of tobacco use and obesity in Lebanon and Jordan are critical for combating cardiovascular disease in these countries.

Factors influencing dyslipidemia in statin-treated patients in Lebanon and Jordan: results of the Dyslipidemia International Study

PubMed Central

Azar, Sami T; Hantash, Hadi Abu; Jambart, Selim; El-Zaheri, Mohamed M; Rachoin, Rachoin; Chalfoun, Amal; Lahoud, Layla; Okkeh, Osama; Bramlage, Peter; Brudi, Philippe; Ambegaonkar, Baishali M

2014-01-01

Background Cardiovascular disease is the leading cause of death and disability worldwide. Therefore, as part of the Dyslipidemia International Study (DYSIS), we have analyzed the prevalence of lipid abnormalities and risk factors for dyslipidemia in statin-treated patients in Lebanon and Jordan. Methods This cross-sectional, multicenter study enrolled 617 patients at 13 hospitals in Lebanon and Jordan. Patients were at least 45 years old and had been treated with statins for at least 3 months. Multivariate logistic regression analysis was used to determine patient characteristics contributing to dyslipidemia during statin therapy. Results Our findings indicated that 55.9% of statin-treated patients (mean age 60.3 years, 47% female) in Lebanon and Jordan did not achieve goal levels for low-density lipoprotein cholesterol which were dependent on Systematic Coronary Risk Evaluation (SCORE) risk, and 70% of patients (76% men and 63.3% of women) were at very high cardiovascular risk. Low-density lipoprotein cholesterol goals were not achieved in 67.2% of those with very high cardiovascular risk. The most commonly prescribed statin was atorvastatin (44.6%), followed by simvastatin (27.7%), rosuvastatin (21.2%), fluvastatin (3.3%), pravastatin (3%), and lovastatin (0.2%). Approximately half of the population was treated with a statin dose potency of 4, equaling 40 mg of simvastatin. In Lebanon and Jordan, the strongest independent associations with low-density lipoprotein cholesterol not at goal were current smoking (odds ratio [OR] 1.96; 95% confidence [CI] 1.25–3.08), diabetes mellitus (OR 2.53; 95% CI 1.70–3.77), and ischemic heart disease (OR 2.26; 95% CI 1.45–3.53), while alcohol consumption was associated with reduced risk (OR 0.12; 95% CI 0.03–0.57). Conclusion We observed that many patients in Lebanon and Jordan experienced persistent dyslipidemia during statin treatment, supporting the notion that novel lipid-lowering strategies need to be developed. Also, social programs aimed at combating the extremely high rates of tobacco use and obesity in Lebanon and Jordan are critical for combating cardiovascular disease in these countries. PMID:24872710

Risk of adverse events among older adults following co-prescription of clarithromycin and statins not metabolized by cytochrome P450 3A4

PubMed Central

Li, Daniel Q.; Kim, Richard; McArthur, Eric; Fleet, Jamie L.; Bailey, David G.; Juurlink, David; Shariff, Salimah Z.; Gomes, Tara; Mamdani, Muhammad; Gandhi, Sonja; Dixon, Stephanie; Garg, Amit X.

2015-01-01

Background: The cytochrome P450 3A4 (CYP3A4) inhibitor clarithromycin may also inhibit liver-specific organic anion–transporting polypeptides (OATP1B1 and OATP1B3). We studied whether concurrent use of clarithromycin and a statin not metabolized by CYP3A4 was associated with an increased frequency of serious adverse events. Methods: Using large health care databases, we studied a population-based cohort of older adults (mean age 74 years) who were taking a statin not metabolized by CYP3A4 (rosuvastatin [76% of prescriptions], pravastatin [21%] or fluvastatin [3%]) between 2002 and 2013 and were newly prescribed clarithromycin (n = 51 523) or azithromycin (n = 52 518), the latter an antibiotic that inhibits neither CYP3A4 nor OATP1B1 and OATP1B3. Outcomes were hospital admission with a diagnostic code for rhabdomyolysis, acute kidney injury or hyperkalemia, and all-cause mortality. All outcomes were assessed within 30 days after co-prescription. Results: Compared with the control group, patients co-prescribed clarithromycin and a statin not metabolized by CYP3A4 were at increased risk of hospital admission with acute kidney injury (adjusted relative risk [RR] 1.65, 95% confidence interval [CI] 1.31 to 2.09), admission with hyperkalemia (adjusted RR 2.17, 95% CI 1.22 to 3.86) and all-cause mortality (adjusted RR 1.43, 95% CI 1.15 to 1.76). The adjusted RR for admission with rhabdomyolysis was 2.27 (95% CI 0.86 to 5.96). The absolute increase in risk for each outcome was small and likely below 1%, even after we considered the insensitivity of some hospital database codes. Interpretation: Among older adults taking a statin not metabolized by CYP3A4, co-prescription of clarithromycin versus azithromycin was associated with a modest but statistically significant increase in the 30-day absolute risk of adverse outcomes. PMID:25534598

National Drug Formulary review of statin therapeutic group using the multiattribute scoring tool

PubMed Central

Ramli, Azuana; Aljunid, Syed Mohamed; Sulong, Saperi; Md Yusof, Faridah Aryani

2013-01-01

Purpose HMG-CoA reductase inhibitors (statins) are extensively used in treating hypercholesterolemia. The statins available in Malaysia include atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and fluvastatin. Over the years, they have accumulated in the National Drug Formulary; hence, the need for review. Effective selection of the best drugs to remain in the formulary can become complex due to the multiple drug attributes involved, and is made worse by the limited time and resources available. The multiattribute scoring tool (MAST) systematizes the evaluation of the drug attributes to facilitate the drug selection process. In this study, a MAST framework was developed to rank the statins based on their utilities or benefits. Methods Published literature on multicriteria decision analysis (MCDA) were studied and five sessions of expert group discussions were conducted to build the MAST framework and to review the evidence. The attributes identified and selected for analysis were efficacy (clinical efficacy, clinical endpoints), safety (drug interactions, serious side effects and documentation), drug applicability (drug strength/formulation, indications, dose frequency, side effects, food–drug interactions, and dose adjustments), and cost. The average weights assigned by the members for efficacy, safety, drug applicability and cost were 32.6%, 26.2%, 24.1%, and 17.1%, respectively. The utility values of the attributes were scored based on the published evidence or/and agreements during the group discussions. The attribute scores were added up to provide the total utility score. Results Using the MAST, the six statins under review were successfully scored and ranked. Atorvastatin scored the highest total utility score (TUS) of 84.48, followed by simvastatin (83.11). Atorvastatin and simvastatin scored consistently high, even before drug costs were included. The low scores on the side effects for atorvastatin were compensated for by the higher scores on the clinical endpoints resulting in a higher TUS for atorvastatin. Fluvastatin recorded the lowest TUS. Conclusion The multiattribute scoring tool was successfully applied to organize decision variables in reviewing statins for the formulary. Based on the TUS, atorvastatin is recommended to remain in the formulary and be considered as first-line in the treatment of hypercholesterolemia. PMID:24353428

Statins and Cancer Prevention

MedlinePlus

... the United States, statins available by prescription include atorvastatin ( Lipitor ™ ), lovastatin ( Mevacor ™ ), pravastatin ( Pravachol ™), and simvastatin ( Zocor ™). ... 2006. The study will assess the efficacy of atorvastatin (and two other investigational agents, an anti-inflammatory , ...

Rosuvastatin and atorvastatin: comparative effects on glucose metabolism in non-diabetic patients with dyslipidaemia.

PubMed

Abbas, Ahmed; Milles, John; Ramachandran, Sudarshan

2012-01-01

The ever increasing interventional CVD outcome studies have resulted in statins being an essential factor of cardiovascular prevention strategies. The JUPITER study in 2008, despite reducing CVD and overall mortality, highlighted an increase in new onset diabetes in the rosuvastatin treated arm. Since then there have been many meta-analyses of the RCTs and the largest carried out by Sattar et al showed a significant increase in the incidence of diabetes during the trials. The findings from the individual studies when comparing the different statins were less clear. A higher statin dosage and risk factors associated with diabetes appeared to predict this phenomenon. There have been many studies investigating the effects of statins on glycaemic control, but again no clear conclusion is apparent. Despite the increase in new onset diabetes observed, the risk is clearly out-weighed by the CVD benefits observed in nearly all the statin trials. Thus, no change is required to any of the prevention guidelines regarding statins. However, it may be prudent to monitor glycaemic control after commencing statin therapy. This review will focus on atorvastatin which is the most widely used statin worldwide and rosuvastatin which is the most efficacious. This will be against a background of the effects of other statins on glucose metabolism in non-diabetic patients.

Rosuvastatin and Atorvastatin: Comparative Effects on Glucose Metabolism in Non-Diabetic Patients with Dyslipidaemia

PubMed Central

Abbas, Ahmed; Milles, John; Ramachandran, Sudarshan

2012-01-01

The ever increasing interventional CVD outcome studies have resulted in statins being an essential factor of cardiovascular prevention strategies. The JUPITER study in 2008, despite reducing CVD and overall mortality, highlighted an increase in new onset diabetes in the rosuvastatin treated arm. Since then there have been many meta-analyses of the RCTs and the largest carried out by Sattar et al showed a significant increase in the incidence of diabetes during the trials. The findings from the individual studies when comparing the different statins were less clear. A higher statin dosage and risk factors associated with diabetes appeared to predict this phenomenon. There have been many studies investigating the effects of statins on glycaemic control, but again no clear conclusion is apparent. Despite the increase in new onset diabetes observed, the risk is clearly out-weighed by the CVD benefits observed in nearly all the statin trials. Thus, no change is required to any of the prevention guidelines regarding statins. However, it may be prudent to monitor glycaemic control after commencing statin therapy. This review will focus on atorvastatin which is the most widely used statin worldwide and rosuvastatin which is the most efficacious. This will be against a background of the effects of other statins on glucose metabolism in non-diabetic patients. PMID:22879796

Preparation of biocompatible copolymeric micelles as a carrier of atorvastatin and rosuvastatin for potential anticancer activity study.

PubMed

Hamidreza Kheiri, Manjili; Alimohammadi, Niusha; Danafar, Hossein

2018-05-18

Statins are widely used for the treatment of hypercholesterolemia. However, their inhibitory action on HMG-CoA reductase also results in the depletion of intermediate biosynthetic products, which importantly contribute to cell proliferation. The aim of the present study was to compare the effects of the individual commercially available statins on investigational breast cancer. Thus, in this study, biodegradable polymeric micelles as carrier of statins were prepared using biodegradable copolymers (PCL-PEG-PCL). These nanoparticles were prepared with two statins (atorvastatin and rosuvastatin) and drug loading, release, kinetic release, and anti-cancer activity of these drugs were studied. The triblock copolymer PCL-PEG-PCL was synthesized by a ring opening polymerization of e-caprolactone in the presence of PEG as the initiator and Sn(oct) 2 as the catalyst. The synthesized copolymers and nanoparticles were characterized by FTIR, HNMR, GPC, DLS, and AFM analyses. The drug loading and release of drugs were studied by UV-Vis. Additionally, MTT assays on HFF-2 cell lines were performed for determination of biocompatibility of micelles. Finally, the anticancer activity of micelles was studied on MCF-7 breast cancer cell lines. The results showed that the average diameter of nanoparticles was less than 45 nm. The loading capacity of atorvastatin and rosuvastatin was 20.0 ± 1.01% and 13.21 ± 1.18%, respectively, and encapsulation efficiency of atorvastatin and rosuvastatin was 88.19 ± 1.11% and 69.32 ± 0.23%, respectively. The results showed strong and dose-dependent inhibition of cell (MCF-7line) growth by the nanoparticles compared with statins. The result of cell viability assay on the MCF-7 cell line verified that the bare nanoparticles showed little inherent cytotoxicity whereas the statins-loaded nanoparticles were cytotoxic.

Efficacy and safety of rosuvastatin every other day compared with once daily in patients with hypercholesterolemia.

PubMed

Wongwiwatthananukit, Supakit; Sansanayudh, Nakarin; Dhummauppakorn, Rawadee; Kitiyadisai, Chutiporn

2006-11-01

Although most patients with hypercholesterolemia require life-long therapy with statins, these drugs are underused due to high costs. Every-other-day therapy could be one strategy to resolve this problem. To compare the efficacy and safety of rosuvastatin 10 mg administered every other day versus once daily. An 8 week, randomized, open-label, parallel trial was conducted at the outpatient department of Phramongkutklao Hospital in Bangkok, Thailand. Eighty patients with primary hypercholesterolemia were equally randomized to receive rosuvastatin 10 mg once daily or every other day; 76 patients completed the study. Laboratory data were assessed at baseline and at the end of the study. Low-density lipoprotein cholesterol (LDL-C) levels were reduced by 48% and 39% in the once-daily and every-other-day groups, respectively (p = 0.011). The percentage of patients who achieved LDL-C goals according to National Cholesterol Education Program-Adult Treatment Panel III guidelines was not significantly different between the once-daily (85%) and every-other-day (70%) groups (p = 0.180). In addition, both regimens were well tolerated, with no patient developing an elevation of more than 3 times baseline levels of aspartate aminotransferase or alanine aminotransferase or 10 times that of creatine kinase. As expected, the monthly cost per percent LDL-C reduction of the once-daily (0.72 dollars) regimen was about 38% higher than that of the every-other-day (0.44 dollars) regimen. Every-other-day dosing of rosuvastatin may be an alternative regimen for cost savings, without a major decrease in therapeutic benefit or increase in adverse events, in patients with hypercholesterolemia. The number of patients achieving their LDL-C goal using the every-other-day regimen is comparable with the number using the once-daily regimen, especially in the low-risk patient category.

Optical Isomers of Atorvastatin, Rosuvastatin and Fluvastatin Enantiospecifically Activate Pregnane X Receptor PXR and Induce CYP2A6, CYP2B6 and CYP3A4 in Human Hepatocytes

PubMed Central

Korhonova, Martina; Doricakova, Aneta; Dvorak, Zdenek

2015-01-01

Atorvastatin, fluvastatin and rosuvastatin are drugs used for treatment of hypercholesterolemia. They cause numerous drug-drug interactions by inhibiting and inducing drug-metabolizing cytochromes P450. These three statins exist in four optical forms, but they are currently used as enantiopure drugs, i.e., only one single enantiomer. There are numerous evidences that efficacy, adverse effects and toxicity of drugs may be enantiospecific. Therefore, we investigated the effects of optical isomers of atorvastatin, fluvastatin and rosuvastatin on the expression of drug-metabolizing P450s in primary human hepatocytes, using western blots and RT-PCR for measurement of proteins and mRNAs, respectively. The activity of P450 transcriptional regulators, including pregnane X receptor (PXR), aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR), was assessed by gene reporter assays and EMSA. Transcriptional activity of AhR was not influenced by any statin tested. Basal transcriptional activity of GR was not affected by tested statins, but dexamethasone-inducible activity of GR was dose-dependently and enantioselectively inhibited by fluvastatin. Basal and ligand-inducible transcriptional activity of PXR was dose-dependently influenced by all tested statins, and the potency and efficacy between individual optical isomers varied depending on statin and optical isomer. The expression of CYP1A1 and CYP1A2 in human hepatocytes was not influenced by tested statins. All statins induced CYP2A6, CYP2B6 and CYP3A4, and the effects on CYP2C9 were rather modulatory. The effects varied between statins and enantiomers and induction potency decreased in order: atorvastatin (RR>RS = SR>SS) > fluvastatin (SR>RS = SS>RR) >> rosuvastatin (only RS active). The data presented here might be of toxicological and clinical importance. PMID:26366873

Rosuvastatin Slows Progression of Subclinical Atherosclerosis in Patients with Treated HIV Infection

PubMed Central

Longenecker, Chris T.; Sattar, Abdus; Gilkeson, Robert; Mccomsey, Grace A.

2016-01-01

Objective To determine the effect of statins on the progression of subclinical atherosclerosis in a population of HIV-infected adults on antiretroviral therapy. Design Double-blind, randomized clinical trial Methods SATURN-HIV was a 96-week double-blind, randomized clinical trial of 10 mg daily rosuvastatin (n=72) versus placebo (n=75) in a population of HIV-infected subjects on stable antiretroviral therapy with LDL-cholesterol ≤130mg/dL (≤3.36mmol/L) and evidence of heightened T-cell activation (CD8+CD38+HLA-DR+ ≥19%) or increased inflammation (high sensitivity C-reactive protein ≥2mg/L (≥19mmol/L)). Change in common carotid artery IMT (CCA-IMT) was the primary outcome. Secondary outcomes were changes in LDL and coronary artery calcium (CAC). Results Median (Q1, Q3) age was 46 (40, 53) years; 78% were male and 68% African American; 49% were on a protease inhibitor. Mean (95% CI) change in LDL was −21 (−27 to −15) mg/dL [−0.54 (−0.70 to −0.39) mmol/L] in the rosuvastatin arm. In a multivariable linear mixed-effects model, assignment to statin was associated with 0.019mm (95% CI: 0.002–0.037mm) less progression of CCA-IMT over 96 weeks. We did not find substantial effect modification by level of inflammation or immune activation biomarkers, except for a borderline statistically significant interaction for soluble vascular cell adhesion molecule (p=0.065). There was no difference in CAC change (p=0.61). Conclusions Rosuvastatin effectively lowers LDL and appears to substantially slow progression of CCA-IMT in patients with treated HIV infection. Future study is needed to determine whether subjects with higher levels of inflammation or immune activation derive greater cardiovascular benefit from statin therapy. PMID:27203715

Development of a Stability-Indicating Stereoselective Method for Quantification of the Enantiomer in the Drug Substance and Pharmaceutical Dosage Form of Rosuvastatin Calcium by an Enhanced Approach

PubMed Central

Rajendra Reddy, Gangireddy; Ravindra Reddy, Papammagari; Siva Jyothi, Polisetty

2015-01-01

A novel, simple, precise, and stability-indicating stereoselective method was developed and validated for the accurate quantification of the enantiomer in the drug substance and pharmaceutical dosage forms of Rosuvastatin Calcium. The method is capable of quantifying the enantiomer in the presence of other related substances. The chromatographic separation was achieved with an immobilized cellulose stationary phase (Chiralpak IB) 250 mm x 4.6 mm x 5.0 μm particle size column with a mobile phase containing a mixture of n-hexane, dichloromethane, 2-propanol, and trifluoroacetic acid in the ratio 82:10:8:0.2 (v/v/v/v). The eluted compounds were monitored at 243 nm and the run time was 18 min. Multivariate analysis and statistical tools were used to develop this highly robust method in a short span of time. The stability-indicating power of the method was established by subjecting Rosuvastatin Calcium to the stress conditions (forced degradation) of acid, base, oxidative, thermal, humidity, and photolytic degradation. Major degradation products were identified and found to be well-resolved from the enantiomer peak, proving the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to specificity, limit of detection and limit of quantification, precision, linearity, accuracy, and robustness. The method exhibited consistent, high-quality recoveries (100 ± 10%) with a high precision for the enantiomer. Linear regression analysis revealed an excellent correlation between the peak responses and concentrations (r2 value of 0.9977) for the enantiomer. The method is sensitive enough to quantify the enantiomer above 0.04% and detect the enantiomer above 0.015% in Rosuvastatin Calcium. The stability tests were also performed on the drug substances as per ICH norms. PMID:26839815

Platelet reactivity in response to loading dose of atorvastatin or rosuvastatin in patients with stable coronary disease before percutaneous coronary intervention: The STATIPLAT randomized study.

PubMed

Godino, Cosmo; Pavon, Anna Giulia; Mangieri, Antonio; Salerno, Anna; Cera, Michela; Monello, Alberto; Chieffo, Alaide; Magni, Valeria; Cappelletti, Alberto; Margonato, Alberto; Colombo, Antonio

2017-08-01

The acute effects of statin loading dose (LD) on platelet reactivity in patients with chronic stable angina (CSA) are not completely clear. We hypothesized that LDs of atorvastatin and rosuvastatin have different pharmacodynamic acute effects on platelet aggregability in CSA patients with baseline normal platelet reactivity while on dual antiplatelet therapy (DAPT). From September 2011 to February 2014, all consecutive CSA patients on chronic DAPT (aspirin and clopidogrel) were evaluated before elective percutaneous coronary intervention (PCI). An initial assessment of platelet reactivity in response to thrombin receptor agonist, ADP, and ASP (respectively, indicative of the response to clopidogrel and aspirin) was performed with impedance aggregometry. Patients with high platelet reactivity to ADP test (area under the curve >47) were excluded. The remaining patients were randomized into 3 treatment groups: Group A, atorvastatin LD 80 mg; Group B, rosuvastatin LD 40 mg; and Group C, no statin LD (control group). A second assessment of platelet reactivity was performed ≥12 hours after statin LD. 682 patients were screened and 145 were randomized into the 3 groups. At baseline and after statin LD, no significant difference was found in platelet reactivity in response to 3 different agonists between the 3 groups. Subgroup analysis showed that platelet reactivity to ADP test was significantly lower in patients chronically treated with low-dose statins (n = 94) compared with statin-naïve patients (n = 51; 15.32 ± 1.50 vs 18.59 ± 1.30; P = 0.007). Loading dose of atorvastatin (80 mg) or rosuvastatin (40 mg) did not induce significant variation in platelet reactivity in CSA patients with baseline reduced platelet reactivity as in chronic DAPT. Our data confirm that chronic concomitant treatment with low-dose statins and clopidogrel resulted in significantly lower platelet reactivity compared with clopidogrel alone. © 2017 Wiley Periodicals, Inc.

Understanding the Potential Interethnic Difference in Rosuvastatin Pharmacokinetics.

PubMed

Benet, Leslie Z; Wu, Hsin-Fang

2017-09-01

Here we address the potential difference in rosuvastatin pharmacokinetics in Asians vs. whites. Our prospective study, reported in this issue, shows no ethnic difference when all subjects are wild-type for OATP1B1 and BCRP. We argue that although our study may be under powered to prove no ethnic difference, and that further confirmatory study is required, the virtual clinical study analysis, also reported in this issue, does not contradict the results of our prospective clinical study and that previous retrospective analysis of clinical studies does not include enough relevant subjects to conclude that wild-type OATP1B1 and BCRP do still demonstrate ethnic differences. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Update of green tea interactions with cardiovascular drugs and putative mechanisms.

PubMed

Werba, José Pablo; Misaka, Shingen; Giroli, Monica Gianna; Shimomura, Kenju; Amato, Manuela; Simonelli, Niccolò; Vigo, Lorenzo; Tremoli, Elena

2018-04-01

Many patients treated with cardiovascular (CV) drugs drink green tea (GT), either as a cultural tradition or persuaded of its putative beneficial effects for health. Yet, GT may affect the pharmacokinetics and pharmacodynamics of CV compounds. Novel GT-CV drug interactions were reported for rosuvastatin, sildenafil and tacrolimus. Putative mechanisms involve inhibitory effects of GT catechins at the intestinal level on influx transporters OATP1A2 or OATP2B1 for rosuvastatin, on CYP3A for sildenafil and on both CYP3A and the efflux transporter p-glycoprotein for tacrolimus. These interactions, which add to those previously described with simvastatin, nadolol and warfarin, might lead, in some cases, to reduced drug efficacy or risk of drug toxicity. Oddly, available data on GT interaction with CV compounds with a narrow therapeutic index, such as warfarin and tacrolimus, derive from single case reports. Conversely, GT interactions with simvastatin, rosuvastatin, nadolol and sildenafil were documented through pharmacokinetic studies. In these, the effect of GT or GT derivatives on drug exposure was mild to moderate, but a high inter-individual variability was observed. Further investigations, including studies on the effect of the dose and the time of GT intake are necessary to understand more in depth the clinical relevance of GT-CV drug interactions. Copyright © 2018. Published by Elsevier B.V.

Effect of vildagliptin and pravastatin combination on cholesterol efflux in adipocytes.

PubMed

Mostafa, Ahmed M; Hamdy, Nadia M; Abdel-Rahman, Sherif Z; El-Mesallamy, Hala O

2016-07-01

Many reports suggested that some statins are almost ineffective in reducing triglycerides or enhancing HDL-C plasma levels, although statin treatment was still efficacious in reducing LDL-C. In diabetic dyslipidemic patients, it may therefore be necessary to use a combination therapy with other drugs to achieve either LDL-C- and triglyceride-lowering or HDL-C-enhancing goals. Such ineffectiveness of statins can be attributed to their effect on the liver X receptor (LXR) which regulates the expression of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. A decrease in the expression of these transporters eventually leads to decreased cholesterol efflux from peripheral tissues leading to low levels of HDL-C. Although manipulating the LXR pathway may complement the effects of statins, LXR synthetic ligands as T091317 have shown significant hypertriglyceridemic action which limits their use. We recently found that the antidiabetic drug vildagliptin stimulates LXR expression leading to increased ABCB1/ABCG1 expression which improves cholesterol efflux from adipocytes. Therefore, a combination of vildagliptin and statin may provide a solution without the hypertriglyceridemic action observed with LXR agonist. We hypothesize that a combination of vildagliptin and pravastatin will improve cholesterol efflux in adipocytes. Statin-treated 3T3-L1 adipocytes were treated with vildagliptin, and the expression of LXR-ABCA1/ABCG1 cascade and the cholesterol efflux were then determined. Our data indicate that a combination of vildagliptin and pravastatin significantly induces the expression of LXR-ABCA1/ABCG1 cascade and improves cholesterol efflux (P > 0.05) in adipocytes. Our data may explain, at least in part, the improvement in HDL-C levels observed in patients receiving both medications. © 2016 IUBMB Life, 68(7):535-543, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

Circulating N-Linked Glycoprotein Side-Chain Biomarker, Rosuvastatin Therapy, and Incident Cardiovascular Disease: An Analysis From the JUPITER Trial.

PubMed

Akinkuolie, Akintunde O; Glynn, Robert J; Padmanabhan, Latha; Ridker, Paul M; Mora, Samia

2016-07-13

GlycA, a novel protein glycan biomarker of N-acetyl side chains of acute-phase proteins, was recently associated with incident cardiovascular disease (CVD) in healthy women. Whether GlycA predicts CVD events in the setting of statin therapy in men and women without CVD but with evidence of chronic inflammation is unknown. In the Justfication for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681), participants with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L were randomized to rosuvastatin 20 mg/day or placebo. GlycA was quantified by nuclear magnetic resonance spectroscopy in 12 527 before randomization and 10 039 participants at 1 year. A total of 310 first primary CVD events occurred during maximum follow-up of 5.0 years (median, 1.9). GlycA changed minimally after 1 year on study treatment: 6.8% and 4.7% decrease in the rosuvastatin and placebo groups, respectively. Overall, baseline GlycA levels were associated with increased risk of CVD: multivariable-adjusted hazard ratio (HR) per SD increment, 1.20 (95% CI, 1.08-1.34; P=0.0006). After additionally adjusting for hsCRP, this was slightly attenuated (HR, 1.18; 95% CI, 1.04-1.35; P=0.01). On-treatment GlycA levels were also associated with CVD; corresponding multivariable-adjusted HRs per SD before and after additionally adjusting for hsCRP: 1.27 (95% CI, 1.13-1.42; P<0.0001) and 1.24 (95% CI, 1.07-1.44; P=0.004), respectively. Tests for heterogeneity by treatment arm were not significant (P for interaction, >0.20). In the JUPITER trial, increased levels of GlycA were associated with an increased risk of CVD events independent of traditional risk factors and hsCRP. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Statin therapy and plasma coenzyme Q10 concentrations--A systematic review and meta-analysis of placebo-controlled trials.

PubMed

Banach, Maciej; Serban, Corina; Ursoniu, Sorin; Rysz, Jacek; Muntner, Paul; Toth, Peter P; Jones, Steven R; Rizzo, Manfredi; Glasser, Stephen P; Watts, Gerald F; Blumenthal, Roger S; Lip, Gregory Y H; Mikhailidis, Dimitri P; Sahebkar, Amirhossein

2015-09-01

Statin therapy may lower plasma coenzyme Q10 (CoQ10) concentrations, but the evidence as to the significance of this effect is unclear. We assessed the impact of statin therapy on plasma CoQ10 concentrations through the meta-analysis of available RCTs. The literature search included selected databases up to April 30, 2015. The meta-analysis was performed using either a fixed-effects or random-effect model according to I(2) statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). The data from 8 placebo-controlled treatment arms suggested a significant reduction in plasma CoQ10 concentrations following treatment with statins (WMD: -0.44 μmol/L, 95%CI: -0.52, -0.37, p<0.001). The pooled effect size was robust and remained significant in the leave-one-out sensitivity analysis. Subgroup analysis suggested that the impact of statins on plasma CoQ10 concentrations is significant for all 4 types of statins studied i.e. atorvastatin (WMD: -0.41 μmol/L, 95%CI: -0.53, -0.29, p<0.001), simvastatin (WMD: -0.47 μmol/L, 95% CI: -0.61, -0.33, p<0.001), rosuvastatin (WMD: -0.49 μmol/L, 95%CI: -0.67, -0.31, p<0.001) and pravastatin (WMD: -0.43 μmol/L, 95%CI: -0.69, -0.16, p=0.001). Likewise, there was no differential effect of lipophilic (WMD: -0.43 μmol/L, 95%CI: -0.53, -0.34, p<0.001) and hydrophilic statins (WMD: -0.47 μmol/L, 95%CI: -0.62, -0.32, p<0.001). With respect to treatment duration, a significant effect was observed in both subsets of trials lasting <12 weeks (WMD: -0.51 μmol/L, 95%CI: -0.64, -0.39, p<0.001) and ≥12 weeks (WMD: -0.40 μmol/L, 95%CI: -0.50, -0.30, p<0.001). The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins. Further well-designed trials are required to confirm our findings and elucidate their clinical relevance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of a Rat Primary Cell-Based Blood-Brain Barrier Model With Epithelial and Brain Endothelial Cell Lines: Gene Expression and Drug Transport.

PubMed

Veszelka, Szilvia; Tóth, András; Walter, Fruzsina R; Tóth, Andrea E; Gróf, Ilona; Mészáros, Mária; Bocsik, Alexandra; Hellinger, Éva; Vastag, Monika; Rákhely, Gábor; Deli, Mária A

2018-01-01

Cell culture-based blood-brain barrier (BBB) models are useful tools for screening of CNS drug candidates. Cell sources for BBB models include primary brain endothelial cells or immortalized brain endothelial cell lines. Despite their well-known differences, epithelial cell lines are also used as surrogate models for testing neuropharmaceuticals. The aim of the present study was to compare the expression of selected BBB related genes including tight junction proteins, solute carriers (SLC), ABC transporters, metabolic enzymes and to describe the paracellular properties of nine different culture models. To establish a primary BBB model rat brain capillary endothelial cells were co-cultured with rat pericytes and astrocytes (EPA). As other BBB and surrogate models four brain endothelial cells lines, rat GP8 and RBE4 cells, and human hCMEC/D3 cells with or without lithium treatment (D3 and D3L), and four epithelial cell lines, native human intestinal Caco-2 and high P-glycoprotein expressing vinblastine-selected VB-Caco-2 cells, native MDCK and MDR1 transfected MDCK canine kidney cells were used. To test transporter functionality, the permeability of 12 molecules, glucopyranose, valproate, baclofen, gabapentin, probenecid, salicylate, rosuvastatin, pravastatin, atorvastatin, tacrine, donepezil, was also measured in the EPA and epithelial models. Among the junctional protein genes, the expression level of occludin was high in all models except the GP8 and RBE4 cells, and each model expressed a unique claudin pattern. Major BBB efflux (P-glycoprotein or ABCB1) and influx transporters (GLUT-1, LAT-1) were present in all models at mRNA levels. The transcript of BCRP (ABCG2) was not expressed in MDCK, GP8 and RBE4 cells. The absence of gene expression of important BBB efflux and influx transporters BCRP, MRP6, -9, MCT6, -8, PHT2, OATPs in one or both types of epithelial models suggests that Caco-2 or MDCK models are not suitable to test drug candidates which are substrates of these transporters. Brain endothelial cell lines GP8, RBE4, D3 and D3L did not form a restrictive paracellular barrier necessary for screening small molecular weight pharmacons. Therefore, among the tested culture models, the primary cell-based EPA model is suitable for the functional analysis of the BBB.

Association of Cognitive Impairment in Patients on 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitors.

PubMed

Roy, Satyajeet; Weinstock, Joshua Louis; Ishino, Allyse Sachiko; Benites, Jefferson Felix; Pop, Samantha Rachel; Perez, Christopher David; Gumbs, Edvard Adrian; Rosenbaum, Jennifer Ann; Roccato, Mary Kate; Shah, Hely; Contino, Gabriela; Hunter, Krystal

2017-07-01

Atherosclerotic cardiovascular diseases are the leading cause of death in the United States. A reduction in cholesterol with 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statin) significantly reduces mortality and morbidity. Statins may be associated with cognitive impairment or dementia. Our aim was to study the association of cognitive impairment or dementia in patients who were on a statin. Electronic medical records of 3,500 adult patients in our suburban internal medicine office were reviewed. There were 720 (20.6%) patients in the statin treatment group. Dementia or cognitive impairment was an associated comorbid condition in 7.9% patients in the statin treatment group compared to 3.1% patients in the non-statin group (P < 0.001). Analysis of all of the patients with cognitive impairment or dementia showed that among the age ranges of 51 years through 100 years, the patients in the statin treatment group had a higher prevalence of cognitive impairment or dementia compared to the non-statin group. In the statin treatment group, we found significantly higher prevalence of hyperlipidemia (86.3%), hypertension (69.6%), diabetes mellitus (36.0%), osteoarthritis (31.5%), coronary artery disease (26.1%), hypothyroidism (21.5%) and depression (19.3%) compared to the non-statin group (P < 0.001). About 39.9% of the patients with dementia or cognitive impairment were on statin therapy compared to 18.9% patients who had no dementia or cognitive impairment and were on statin therapy (P < 0.001). Among the patients with cognitive deficit or dementia in the statin treatment group, the majority of the patients were either on atorvastatin (43.9%) or simvastatin (35.1%), followed by rosuvastatin (12.2%) and pravastatin (8.8%). We found greater odds of dementia or cognitive impairment with each year increase in age (1.3 times), in women (2.2 times), African American race (2.7 times), non-consumption of moderate amount of alcohol (two times), diabetes mellitus (1.6 times), hypothyroidism (1.7 times), cerebrovascular accident (3.2 times), and other rheumatological diseases (1.8 times). The association of dementia or cognitive impairment was significantly higher in the patients who were on statin therapy compared to the patients who were not on a statin.

Rosuvastatin in Treating Women With Cardiovascular Complications Who Are Undergoing Chemotherapy For Breast Cancer

ClinicalTrials.gov

2017-05-25

Cardiovascular Complications; Recurrent Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

C-reactive protein and genetic variants and cognitive decline in old age: The PROSPER Study

USDA-ARS?s Scientific Manuscript database

Plasma concentrations of C-reactive protein (CRP), a marker of chronic inflammation, have been associated with cognitive impairment in old age. However, it is unknown whether CRP is causally linked to cognitive decline. Within the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) tri...

Finger millet (Eleusine coracana) - an economically viable source for antihypercholesterolemic metabolites production by Monascus purpureus.

PubMed

Venkateswaran, V; Vijayalakshmi, G

2010-08-01

Rice, parboiled rice, finger millet, germinated finger millet, broken wheat, njavara (medicinal rice), sorghum and maize were used as substrates for solid state fermentation of Monascus purpureus at 28°C for 7 days using 2% seed medium as inoculum for the production of its metabolites. The fungus exhibited good growth in all the substrates. The fermented substrates were dried at 45°C and analysed for antihypercholesterolemic metabolite statins by standardized HPLC method and dietary sterol contents by spectrophotometric method using reference standards of statin (pravastatin and lovastatin) and cholesterol, respectively. Germinated finger millet yielded higher total statin production of 5.2 g/kg dry wt with pravastatin and lovastatin content of 4.9 and 0.37 g/kg dry wt respectively than other substrates which range from 1.04-4.41 g/kg. In addition to statin, monascus fermented germinated finger millet yielded dietary sterol of 0.053 g/kg dry wt which is 7.6 folds higher than the control. The value addition of finger millet by germination and fermentation with Monascus purpureus provides scope for development of functional food.

High-dose rosuvastatin treatment for multifocal stroke in trauma-induced cerebral fat embolism syndrome: a case report.

PubMed

Whalen, Lesta D; Khot, Sandeep P; Standage, Stephen W

2014-09-01

Fat embolism syndrome is a life-threatening condition with treatment centering on the provision of excellent supportive care and early fracture fixation. No pharmacologic intervention has yet shown any clear benefit. We used high-dose rosuvastatin specifically for its anti-inflammatory effects to treat a patient with severe fat embolism syndrome. We also suggest that magnetic resonance imaging and transcranial Doppler studies are helpful in establishing the diagnosis and for monitoring the patient's course. A 17-year-old boy developed severe cerebral fat embolism syndrome with multifocal strokes after sustaining bilateral femur fractures. In spite of profound and prolonged neurological impairment, our patient experienced dramatic recovery by the time he was discharged from inpatient rehabilitation several weeks after his initial injury. Magnetic resonance imaging revealed the classic "starfield" pattern of infarcts on diffusion-weighted sequences early in the illness. Additionally, serial transcranial Doppler studies demonstrated dramatically elevated microembolic events that resolved completely during the course of treatment. We feel that the acute administration of high-dose rosuvastatin early in the development of our patient's illness may have contributed to his ultimate recovery. Therapeutic guidelines cannot be extrapolated from a single patient, but our experience suggests that statin therapy could be potentially beneficial for individuals with severe fat embolism syndrome, and this approach deserves further clinical evaluation. Additionally, the diagnosis and monitoring of cerebral involvement in fat embolism syndrome is facilitated by both magnetic resonance imaging and transcranial Doppler studies. Copyright © 2014 Elsevier Inc. All rights reserved.

The cardiovascular event reduction tool (CERT)--a simplified cardiac risk prediction model developed from the West of Scotland Coronary Prevention Study (WOSCOPS).

PubMed

L'Italien, G; Ford, I; Norrie, J; LaPuerta, P; Ehreth, J; Jackson, J; Shepherd, J

2000-03-15

The clinical decision to treat hypercholesterolemia is premised on an awareness of patient risk, and cardiac risk prediction models offer a practical means of determining such risk. However, these models are based on observational cohorts where estimates of the treatment benefit are largely inferred. The West of Scotland Coronary Prevention Study (WOSCOPS) provides an opportunity to develop a risk-benefit prediction model from the actual observed primary event reduction seen in the trial. Five-year Cox model risk estimates were derived from all WOSCOPS subjects (n = 6,595 men, aged 45 to 64 years old at baseline) using factors previously shown to be predictive of definite fatal coronary heart disease or nonfatal myocardial infarction. Model risk factors included age, diastolic blood pressure, total cholesterol/ high-density lipoprotein ratio (TC/HDL), current smoking, diabetes, family history of fatal coronary heart disease, nitrate use or angina, and treatment (placebo/ 40-mg pravastatin). All risk factors were expressed as categorical variables to facilitate risk assessment. Risk estimates were incorporated into a simple, hand-held slide rule or risk tool. Risk estimates were identified for 5-year age bands (45 to 65 years), 4 categories of TC/HDL ratio (<5.5, 5.5 to <6.5, 6.5 to <7.5, > or = 7.5), 2 levels of diastolic blood pressure (<90, > or = 90 mm Hg), from 0 to 3 additional risk factors (current smoking, diabetes, family history of premature fatal coronary heart disease, nitrate use or angina), and pravastatin treatment. Five-year risk estimates ranged from 2% in very low-risk subjects to 61% in the very high-risk subjects. Risk reduction due to pravastatin treatment averaged 31%. Thus, the Cardiovascular Event Reduction Tool (CERT) is a risk prediction model derived from the WOSCOPS trial. Its use will help physicians identify patients who will benefit from cholesterol reduction.

A Genetic and Pharmacological Analysis of Isoprenoid Pathway by LC-MS/MS in Fission Yeast

PubMed Central

Takami, Tomonori; Fang, Yue; Zhou, Xin; Jaiseng, Wurentuya; Ma, Yan; Kuno, Takayoshi

2012-01-01

Currently, statins are the only drugs acting on the mammalian isoprenoid pathway. The mammalian genes in this pathway are not easily amenable to genetic manipulation. Thus, it is difficult to study the effects of the inhibition of various enzymes on the intermediate and final products in the isoprenoid pathway. In fission yeast, antifungal compounds such as azoles and terbinafine are available as inhibitors of the pathway in addition to statins, and various isoprenoid pathway mutants are also available. Here in these mutants, treated with statins or antifungals, we quantified the final and intermediate products of the fission yeast isoprenoid pathway using liquid chromatography-mass spectrometry/mass spectrometry. In hmg1-1, a mutant of the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), ergosterol (a final sterol product), and squalene (an intermediate pathway product), were decreased to approximately 80% and 10%, respectively, compared with that of wild-type cells. Consistently in wild-type cells, pravastatin, an HMGR inhibitor decreased ergosterol and squalene, and the effect was more pronounced on squalene. In hmg1-1 mutant and in wild-type cells treated with pravastatin, the decrease in the levels of farnesyl pyrophosphate and geranylgeranyl pyrophosphate respectively was larger than that of ergosterol but was smaller than that of squalene. In Δerg6 or Δsts1 cells, mutants of the genes involved in the last step of the pathway, ergosterol was not detected, and the changes of intermediate product levels were distinct from that of hmg1-1 mutant. Notably, in wild-type cells miconazole and terbinafine only slightly decreased ergosterol level. Altogether, these studies suggest that the pleiotropic phenotypes caused by the hmg1-1 mutation and pravastatin might be due to decreased levels of isoprenoid pyrophosphates or other isoprenoid pathway intermediate products rather than due to a decreased ergosterol level. PMID:23145048

Protein engineering of CYP105s for their industrial uses.

PubMed

Yasuda, Kaori; Sugimoto, Hiroshi; Hayashi, Keiko; Takita, Teisuke; Yasukawa, Kiyoshi; Ohta, Miho; Kamakura, Masaki; Ikushiro, Shinichi; Shiro, Yoshitsugu; Sakaki, Toshiyuki

2018-01-01

Cytochrome P450 enzymes belonging to the CYP105 family are predominantly found in bacteria belonging to the phylum Actinobacteria and the order Actinomycetales. In this review, we focused on the protein engineering of P450s belonging to the CYP105 family for industrial use. Two Arg substitutions to Ala of CYP105A1 enhanced its vitamin D 3 25- and 1α-hydroxylation activities by 400 and 100-fold, respectively. The coupling efficiency between product formation and NADPH oxidation was largely improved by the R84A mutation. The quintuple mutant Q87W/T115A/H132L/R194W/G294D of CYP105AB3 showed a 20-fold higher activity than the wild-type enzyme. Amino acids at positions 87 and 191 were located at the substrate entrance channel, and that at position 294 was located close to the heme group. Semi-rational engineering of CYP105A3 selected the best performing mutant, T85F/T119S/V194N/N363Y, for producing pravastatin. The T119S and N363Y mutations synergistically had remarkable effects on the interaction between CYP105A3 and putidaredoxin. Although wild-type CYP105AS1 hydroxylated compactin to 6-epi-pravastatin, the quintuple mutant I95T/Q127R/A180V/L236I/A265N converted almost all compactin to pravastatin. Five amino acid substitutions by two rounds of mutagenesis almost completely changed the stereo-selectivity of CYP105AS1. These results strongly suggest that the protein engineering of CYP105 enzymes greatly increase their industrial utility. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. Copyright © 2017 Elsevier B.V. All rights reserved.

Response to comment on: Statin use and risk of diabetes mellitus

PubMed Central

Chogtu, Bharti; Magazine, Rahul; Bairy, Kurady Laxminarayana

2016-01-01

In letter to the editor “Comment on: Statin use and risk of diabetes mellitus” authors found the statement “pravastatin 40 mg/d reduced the risk of diabetes by 30% in West of Scotland Coronary Prevention study” erroneous. As per our opinion the statement is right but had been referenced incorrectly. PMID:27795822

The Cost-Benefit Balance of Statins in Hawai'i: A Moving Target.

PubMed

Lum, Corey J; Nakagawa, Kazuma; Shohet, Ralph V; Seto, Todd B; Taira, Deborah A

2017-04-01

Statins are lipid-lowering medications used for primary and secondary prevention of atherosclerotic disease and represent a substantial portion of drug costs in the United States. A better understanding of prescribing patterns and drug costs should lead to more rational utilization and help constrain health care expenditures in the United States. The 2013 Medicare Provider Utilization and Payment Data: Part D Prescriber Public Use File for the State of Hawai'i was analyzed. The number of prescriptions for statins, total annual cost, and daily cost were calculated by prescriber specialty and drug. Potential savings from substituting the highest-cost statin with lower-cost statins were calculated. Over 421,000 prescriptions for statins were provided to Medicare Part D beneficiaries in Hawai'i in 2013, which cost $17.6M. The three most commonly prescribed statins were simvastatin (33.4%), atorvastatin (33.4%), and lovastatin (13.9%). Although rosuvastatin comprised 5.4% of the total statin prescriptions, it represented 30.1% of the total cost of statins due to a higher daily cost ($5.53/day) compared to simvastatin ($0.25/day) and atorvastatin ($1.10/day). Cardiologists and general practitioners prescribed the highest percentage of rosuvastatin (8% each). Hypothetical substitution of rosuvastatin would have resulted in substantial annual cost savings (Simvastatin would have saved $1.3M for 25% substitution and $5.1M for 100% substitution, while atorvastatin would have saved $1.1M for 25% substitution and $4.3M for 100% substitution). Among Medicare Part D beneficiaries in Hawai'i, prescribing variation for statins between specialties were observed. Substitution of higher-cost with lower-cost statins may lead to substantial cost savings.

Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects.

PubMed

Edwards, Jeffrey E; Eliot, Lise; Parkinson, Andrew; Karan, Sharon; MacConell, Leigh

2017-09-01

Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin). OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max ) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs. In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin). Intercept Pharmaceuticals, Inc.

Antidepressant-selective gynecomastia.

PubMed

Kaufman, Kenneth R; Podolsky, Dina; Greenman, Danielle; Madraswala, Rehman

2013-01-01

To describe what we believe is the first reported case of synergistic gynecomastia during treatment of depressive and anxiety disorders when sertraline was added to a stable medication regimen including duloxetine, rosuvastatin, and amlodipine. A 67-year-old male with major depression, dysthymia, obsessive-compulsive disorder, social anxiety, hypertension, diabetes, and hyperlipidemia presented with new-onset gynecomastia and breast tenderness. Mammography revealed bilateral gynecomastia (fibroglandular tissue posterior to the nipples bilaterally) without suspicious mass, calcification, or other abnormalities. These new symptoms developed after sertraline was added to his stable medication regimen (duloxetine, alprazolam, rosuvastatin, metoprolol, amlodipine, hydrochlorothiazide/triamterene, metformin, and sitagliptin). These symptoms were dose-dependent, with gynecomastia and breast tenderness more severe as sertraline was titrated from 25 mg/day to 50 mg/day and then to 75 mg/day. When sertraline was discontinued, gynecomastia and breast tenderness rapidly resolved. Mammoplasia and gynecomastia are associated with altered dopamine neurotransmission and/or perturbations in sexual hormones. These adverse effects may be medication induced. Selective serotonin reuptake inhibitors (sertraline), serotonin-norepinephrine reuptake inhibitors (duloxetine), rosuvastatin, and amlodipine have been reported to cause these adverse effects. This case was unique, since the patient had been on both sertraline and duloxetine previously as independent psychotropics without the development of gynecomastia. In the context of an additive drug adverse effect, the probability of sertraline as the precipitant drug was determined by both the Naranjo probability scale and the Horn drug interaction probability scale as probable. Gynecomastia is associated with antidepressants and other medications but is rarely addressed. Gynecomastia may be antidepressant selective or may be the result of additive adverse effects. Clinicians are advised to question patients regarding this potential adverse effect. Further education of clinicians is indicated.

Effects of Rosuvastatin Versus Atorvastatin, Alone or in Combination, on Lipoprotein (a).

PubMed

Vavlukis, Marija; Mladenovska, Kristina; Daka, Arlinda; Dimovski, Aleksandar; Domazetovska, Saska; Kuzmanovska, Sonja; Kedev, Sasko

2016-08-01

There are little evidences about the therapeutic efficacy of different lipid-lowering agents in the reduction of elevated lipoprotein(a) [Lp(a)]. testing the effect of different lipid-lowering agents on elevated Lp(a). prospective interventional study performed in patients with CAD, or high CAD risk, with Lp(a), >50 mg/dL. Lp(a), total cholesterol (C), HDL-C, LDL-C, triglycerides (TGs), apolipoprotein (Apo) A1, Apo B, enzymes of myocyte and hepatic injury were comparatively analyzed between 4 lipid-lowering strategies: rosuvastatin (R group) 40 mg, atorvastatin (A group) 80 mg, atorvastatin 40 mg add-on micronized fenofibrate (A+F group), and atorvastatin 40 mg add-on 1 g extended-release niacin (A+ERN group). Comparison was made for their therapeutic efficacy on Lp(a), and safety. 87 patients with mean Lp(a) 94.6 ± 39.6 mg/dL were analyzed. Groups: 25 patients in the R, 22 in the A, 20 in the A+F and 20 in A+ERN group. Significant reduction in all lipid fractions in all treatment groups was reported after 6 months. The average reduction of Lp(a) was 15.9 ± 21.0 mg/dL, with: 18.2 ± 24.8 (P = 0.001) in the R group, 17.3 ± 10.4 (P = 0.001) in A+F, 19.5 ± 10.9 (P = 0.001) in A+ERN and the lowest in the A group (11.24 ± 22.91, P = 0.032). No adverse effects were observed in any of the treatment groups. When compared with atorvastatin, it seems that rosuvastatin can achieve more significant decrease of Lp(a).The efficacy of the second one can be increased by adding fibrate or ERN. © The Author(s) 2016.

Development of a high-throughput method for the determination of ethosuximide in human plasma by liquid chromatography mass spectrometry.

PubMed

Bhatt, Mitesh; Shah, Sanjay; Shivprakash

2010-06-01

A simple, rapid, sensitive and specific ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of ethosuximide in human plasma is described. Analyte was chromatographed on a Hypersil Gold C18 column (100 mm x 2.1 mm, i.d., 1.9 microm) with isocratic elution at a flow rate of 0.250 mL/min and pravastatin was used as the internal standard. The assay involves a simple solid-phase extraction procedure of 0.25 mL human plasma and the analysis was performed on a triple-quadrupole tandem mass spectrometer by MRM mode via electrospray ionization (ESI). The method was linear in the concentration range of 0.25-60.0 microg/mL. The lower limit of quantification (LLOQ) was 0.25 microg/mL. The within- and between-day precision and accuracy of the quality control samples were within 10.0%. The recovery was 95.1% and 94.4% for ethosuximide and pravastatin, respectively. The analysis time for each sample was 1.8 min. The method was highly reproducible and gave peaks with excellent chromatography properties. Copyright 2010 Elsevier B.V. All rights reserved.

Testing cognitive function in elderly populations: the PROSPER study. PROspective Study of Pravastatin in the Elderly at Risk.

PubMed

Houx, P J; Shepherd, J; Blauw, G-J; Murphy, M B; Ford, I; Bollen, E L; Buckley, B; Stott, D J; Jukema, W; Hyland, M; Gaw, A; Norrie, J; Kamper, A M; Perry, I J; MacFarlane, P W; Meinders, A Edo; Sweeney, B J; Packard, C J; Twomey, C; Cobbe, S M; Westendorp, R G

2002-10-01

For large scale follow up studies with non-demented patients in which cognition is an endpoint, there is a need for short, inexpensive, sensitive, and reliable neuropsychological tests that are suitable for repeated measurements. The commonly used Mini-Mental-State-Examination fulfils only the first two requirements. In the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), 5804 elderly subjects aged 70 to 82 years were examined using a learning test (memory), a coding test (general speed), and a short version of the Stroop test (attention). Data presented here were collected at dual baseline, before randomisation for active treatment. The tests proved to be reliable (with test/retest reliabilities ranging from acceptable (r=0.63) to high (r=0.88) and sensitive to detect small differences in subjects from different age categories. All tests showed significant practice effects: performance increased from the first measurement to the first follow up after two weeks. Normative data are provided that can be used for one time neuropsychological testing as well as for assessing individual and group change. Methods for analysing cognitive change are proposed.

Atorvastatin affects negatively respiratory function of isolated endothelial mitochondria.

PubMed

Broniarek, Izabela; Jarmuszkiewicz, Wieslawa

2018-01-01

The purpose of this research was to elucidate the direct effects of two popular blood cholesterol-lowering drugs used to treat cardiovascular diseases, atorvastatin and pravastatin, on respiratory function, membrane potential, and reactive oxygen species formation in mitochondria isolated from human umbilical vein endothelial cells (EA.hy926 cell line). Hydrophilic pravastatin did not significantly affect endothelial mitochondria function. In contrast, hydrophobic calcium-containing atorvastatin induced a loss of outer mitochondrial membrane integrity, an increase in hydrogen peroxide formation, and reductions in maximal (phosphorylating or uncoupled) respiratory rate, membrane potential and oxidative phosphorylation efficiency. The atorvastatin-induced changes indicate an impairment of mitochondrial function at the level of ATP synthesis and at the level of the respiratory chain, likely at complex I and complex III. The atorvastatin action on endothelial mitochondria was highly dependent on calcium ions and led to a disturbance in mitochondrial calcium homeostasis. Uptake of calcium ions included in atorvastatin molecule induced mitochondrial uncoupling that enhanced the inhibition of the mitochondrial respiratory chain by atorvastatin. Our results indicate that hydrophobic calcium-containing atorvastatin, widely used as anti-atherosclerotic agent, has a direct negative action on isolated endothelial mitochondria. Copyright © 2017. Published by Elsevier Inc.

Pravastatin chitosan nanogels-loaded erythrocytes as a new delivery strategy for targeting liver cancer.

PubMed

Harisa, Gamaleldin I; Badran, Mohamed M; AlQahtani, Saeed A; Alanazi, Fars K; Attia, Sabry M

2016-01-01

Chitosan nanogels (CNG) are developed as one of the most promising carriers for cancer targeting. However, these carriers are rapidly eliminated from circulation by reticuloendothelial system (RES), which limits their application. Therefore, erythrocytes (ER) loaded CNG as multifunctional carrier may overcome the massive elimination of nanocarriers by RES. In this study, erythrocytes loaded pravastatin-chitosan nanogels (PR-CNG-ER) were utilized as a novel drug carrier to target liver cancer. Thus, PR-CNG formula was developed in nanosize, with good entrapment efficiency, drug loading and sustained release over 48 h. Then, PR-CNG loaded into ER were prepared by hypotonic preswelling technique. The resulting PR-CNG-ER showed 36.85% of entrapment efficiency, 66.82% of cell recovery and release consistent to that of hemoglobin over 48 h. Moreover, PR-CNG-ER exhibited negative zeta potential, increasing of hemolysis percent, marked phosphatidylserine exposure and stomatocytes shape compared to control unloaded erythrocytes. PR-CNG-ER reduced cells viability of HepG2 cells line by 28% compared to unloaded erythrocytes (UER). These results concluded that PR-CNG-ER are promising drug carriers to target liver cancer.

HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial.

PubMed

Ridker, Paul M; Genest, Jacques; Boekholdt, S Matthijs; Libby, Peter; Gotto, Antonio M; Nordestgaard, Børge G; Mora, Samia; MacFadyen, Jean G; Glynn, Robert J; Kastelein, John J P

2010-07-31

HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events. We addressed, using the JUPITER trial cohort, whether this association remains when LDL-cholesterol concentrations are reduced to the very low ranges with high-dose statin treatment. Participants in the randomised placebo-controlled JUPITER trial were adults without diabetes or previous cardiovascular disease, and had baseline concentrations of LDL cholesterol of less than 3.37 mmol/L and high-sensitivity C-reactive protein of 2 mg/L or more. Participants were randomly allocated by a computer-generated sequence to receive rosuvastatin 20 mg per day or placebo, with participants and adjudicators masked to treatment assignment. In the present analysis, we divided the participants into quartiles of HDL-cholesterol or apolipoprotein A1 and sought evidence of association between these quartiles and the JUPITER primary endpoint of first non-fatal myocardial infarction or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT00239681. For 17,802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p<0.0001). In 8901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2.80 mmol/L [IQR 2.43-3.24]), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio [HR] 0.54, 95% CI 0.35-0.83, p=0.0039) and on-treatment (0.55, 0.35-0.87, p=0.0047). By contrast, among the 8900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1.42 mmol/L [IQR 1.14-1.86]), no significant relationships were noted between quartiles of HDL-cholesterol concentration and vascular risk either at baseline (1.12, 0.62-2.03, p=0.82) or on-treatment (1.03, 0.57-1.87, p=0.97). Our analyses for apolipoprotein A1 showed an equivalent strong relation to frequency of primary outcomes in the placebo group but little association in the rosuvastatin group. Although measurement of HDL-cholesterol concentration is useful as part of initial cardiovascular risk assessment, HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL cholesterol. AstraZeneca. Copyright 2010 Elsevier Ltd. All rights reserved.

The differences in the incidence of diabetes mellitus and prediabetes according to the type of HMG-CoA reductase inhibitors prescribed in Korean patients.

PubMed

Kim, Tong Min; Kim, Hyunah; Jeong, Yoo Jin; Baik, Sun Jung; Yang, So Jung; Lee, Seung-Hwan; Cho, Jae-Hyoung; Lee, Hyunyong; Yim, Hyeon Woo; Choi, In Young; Yoon, Kun-Ho; Kim, Hun-Sung

2017-10-01

Very few studies conducted in Korea have investigated the relationship between statins and the incidence of diabetes. Therefore, we analyzed the progression from normal blood glucose to prediabetes and then to diabetes mellitus (DM) according to the type, intensity, and dose of statin prescribed. Data of patients who were first prescribed statins between 2009 and 2011 were extracted from electronic medical records. Patients with normal blood glucose or prediabetes were observed for 4 years after initiation of statin therapy. A total of 2890 patients were included in our study and analyzed on the basis of the first statin they were prescribed. The incidence rate of DM in patients with prediabetes was 1.72 times that of patients with normal glucose levels (odds ratio = 1.72, 95% confidence interval = 1.41-2.10, P < .001). Regarding progression from normal blood glucose to prediabetes, the incidence rate of prediabetes was significantly lower in patients prescribed pitavastatin (odds ratio = 0.62, 95% confidence interval = 0.40-0.96, P = .031) compared to that in patients prescribed atorvastatin. Regarding the progression from normal blood glucose or prediabetes to DM, there were no significant differences among all statins. Lower DM incidence in patients prescribed pitavastatin appears to be primarily because of the lower rate of progression from normal blood glucose to prediabetes. These findings indicate that avoiding statins because of DM risk is unjustified and that clinicians should prescribe statins from the appropriate potency group. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of background statin therapy on glycemic response and cardiovascular events following initiation of insulin therapy in type 2 diabetes: a large UK cohort study.

PubMed

Anyanwagu, Uchenna; Mamza, Jil; Donnelly, Richard; Idris, Iskandar

2017-08-22

Statins may increase the risk of new-onset diabetes and adversely affect glycaemic control, but their effects on the glycemic response and mortality outcomes following commencement of insulin therapy in patients with Type 2 Diabetes (T2D) are unclear. A retrospective cohort study was conducted in 12,725 insulin initiators with T2D using The Health Improvement Network (THIN) UK database. Changes in HbA1c at 6, 12, 24 and 36 months, and the 5-year risk of mortality and (3-point) major adverse cardiovascular events (MACE), were compared between prior users (n = 10,682) and non-users (n = 2043) of statin therapy who were newly commenced on insulin treatment. Cox proportional hazard models were used to estimate the hazard ratios of the different outcomes. Mean age of the cohort was 58.7 ± 14.0 years (51% male) and mean baseline HbA1c was 8.7 ± 1.8%. A greater initial reduction in HbA1c was observed following insulin initiation in the non-users of statins compared with the users, which was significant in the short term (-0.34% vs -0.26% at 6 months; mean diff = -0.09%, p = 0.004) but not in the long term: -0.31% versus -0.35% at 3 years (mean diff = 0.05%, p = 0.344). CV events (3-point MACE) were 878 versus 217 in statin users versus non-users (20.7 vs 30.9 per 1000 person-years; adjusted Hazard Ratio (aHR) 1.36 (95% CI 1.15-1.62; p < 0.0001). In a subgroup analysis of individual statins, HbA1c was higher throughout the study duration with all statins relative to non-users of statin therapy (p < 0.05). The aHRs for 3-point MACE for atorvastatin, simvastatin, rosuvastatin and pravastatin were 0.82 (95% CI 0.68-0.98), 0.67 (0.55-0.82), 0.56 (0.39-0.81) and 0.78 (0.60-1.01), respectively. Following initiation of insulin therapy in patients with T2D in routine care, concurrent use of a statin was associated with less good glycaemic control in the short-term but a much lower risk of major adverse CV events.

Evaluation of the possible nephroprotective effects of vitamin E and rosuvastatin in amikacin-induced renal injury in rats.

PubMed

Selim, Ahmed; Khalaf, Marwa M; Gad, Amany M; Abd El-Raouf, Ola M

2017-11-01

Amikacin (AMIK) is an aminoglycoside antibiotic that possesses considerable nephrotoxic adverse effects. This study examined the protective effects of vitamin E (VIT. E) or rosuvastatin (ROSU) against AMIK-induced nephrotoxicity. For this purpose, eight groups of rats were used. Two control groups received saline and vehicle, AMIK group (1.2 g/kg, i.p.), VIT. E group (1000 mg/kg; p.o.), ROSU group (10 mg/kg; p.o.), AMIK + VIT. E group, AMIK + ROSU group, and combination group. The results showed that AMIK significantly increased serum levels of urea and creatinine. Meanwhile, serum levels of total protein and albumin were decreased. The kidney content of malondialdehyde was increased, whereas glutathione content and catalase activity were decreased. Tumor necrosis factor-α and nuclear transcriptional factor levels were increased. Conversely, administration of VIT. E and/or ROSU with AMIK ameliorated such damage and reduced DNA fragmentation, apoptosis, and necrosis. In conclusion, co-administration of VIT. E, ROSU, or their combination alleviated AMIK-induced nephrotoxicity. © 2017 Wiley Periodicals, Inc.

High HbA1c levels correlate with reduced plaque regression during statin treatment in patients with stable coronary artery disease: results of the coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS).

PubMed

Daida, Hiroyuki; Takayama, Tadateru; Hiro, Takafumi; Yamagishi, Masakazu; Hirayama, Atsushi; Saito, Satoshi; Yamaguchi, Tetsu; Matsuzaki, Masunori

2012-07-25

The incidence of cardiac events is higher in patients with diabetes than in people without diabetes. The Coronary Atherosclerosis Study Measuring Effects of Rosuvastatin Using Intravascular Ultrasound in Japanese Subjects (COSMOS) demonstrated significant plaque regression in Japanese patients with chronic coronary disease after 76 weeks of rosuvastatin (2.5 mg once daily, up-titrated to a maximum of 20 mg/day to achieve LDL cholesterol <80 mg/dl). In this subanalysis of COSMOS, we examined the association between HbA1c and plaque regression in 40 patients with HbA1c ≥6.5% (high group) and 86 patients with HbA1c <6.5% (low group). In multivariate analyses, HbA1c and plaque volume at baseline were major determinants of plaque regression. LDL cholesterol decreased by 37% and 39% in the high and low groups, respectively, while HDL cholesterol increased by 16% and 22%, respectively. The reduction in plaque volume was significantly (p = 0.04) greater in the low group (from 71.0 ± 39.9 to 64.7 ± 34.7 mm(3)) than in the high group (from 74.3 ± 34.2 to 71.4 ± 32.3 mm(3)). Vessel volume increased in the high group but not in the low group (change from baseline: +4.2% vs -0.8%, p = 0.02). Change in plaque volume was significantly correlated with baseline HbA1c. Despite similar improvements in lipid levels, plaque regression was less pronounced in patients with high HbA1c levels compared with those with low levels. Tight glucose control during statin therapy may enhance plaque regression in patients with stable coronary disease. ClinicalTrials.gov, Identifier NCT00329160.

Current statins show calcium channel blocking activity through voltage gated channels.

PubMed

Ali, Niaz; Begum, Robina; Faisal, Muhammad Saleh; Khan, Aslam; Nabi, Muhammad; Shehzadi, Gulfam; Ullah, Shakir; Ali, Waqar

2016-09-21

Statins are used for treatment of hypercholestremia. Common adverse reports associated with use of statins are generalized bodyache, rhabdomyolysis, muscles weakness and gastrointestinal disorders. The current work is an attempt to explain how smooth muscles of gastrointestinal tissues are affected by the current statins (Simvastatin, atorvastatin, fluvastatin and rosuvastatin). Effects of the current statins were studied on spontaneous activity of isolated rabbits' jejunal preparations. Different molar concentrations (10(-12)-10(-2)M) of the statins were applied on spontaneously contracting rabbits' jejunal preparations. As statins relaxed spontaneous activity, so we tested the statins on KCl (80 mM) induced contractions in similar test concentrations. Positive relaxant statins were tested again through construction of Calcium Concentration Response Curves (CCRCs) in the absence and presence of the statins using verapamil, a standard calcium channel blocker. CCRCs of statins were compared with CCRCs of verapamil. Simvastatin, atorvastatin, fluvastatin and rosuvastatin relaxed the spontaneous and KCl-induced contractions. IC50 for simvastatin on spontaneous rabbit's jejunal preparations is -5.08 ± 0.1 Log 10 M. Similarly, IC50 for KCl-induced contractions is -4.25 ± 0.01 Log 10 M. Mean IC50 (Log 10 M) for atorvastatin on spontaneous rabbit's jejunal preparations and KCl-induced contractions are -5.19 ± 0.07 and -4.37 ± 0.09, respectively. Fluvastatin relaxed spontaneous activity of rabbits' jejunal preparations with an IC50 (Log 10 M) -4.5 ± 0.03. Rosuvastatin relaxed spontaneous as well as KCl (80 mM) induced contractions with respective IC50 (Log 10 M) -3.62 ± 0.04 and -4.57 ± 0.06. In case of CCRCs, tissues pre-treated with 4.6 μg/ml of simvastatin, have IC50 = -1.84 ± 0.03 [log (Ca(++)) M] vs control IC50 = -2.54 ± 0.04 [log (Ca(++)) M]. Similarly, atorvastatin, fluvastatin and rosuvastatin produced significant right shift in IC50 for CCRCs (P ≤ 0.05). In case of verapamil, IC50 for control curves is -2.45 ± 0.06 [log (Ca (++)) M], while IC50 in presence of verapamil (0.1 μM) is -1.69 ± 0.05 [log (Ca (++)) M]. Statins produced right shift in the IC50 of CCRCs. The effects of statins are like that of effects of verapamil, a standard calcium channel blocker. Our findings suggest that current statins have calcium antagonistic effects that act on voltage gated calcium channels that may provide a rationale for cause muscle weakness and gastrointestinal disorders.

Effect of Aggressive lipid-lowering treatment with Rosuvastatin on vascular endoTHelium function: evaluation of vascular endothelium function (EARTH study).

PubMed

Takayama, Tadateru; Hiro, Takafumi; Yoda, Shunichi; Fukamachi, Daisuke; Haruta, Hironori; Kogo, Takaaki; Mineki, Takashi; Murata, Hironobu; Oshima, Toru; Hirayama, Atsushi

2018-06-01

Vascular endothelial dysfunction plays an important role in the process of atherosclerosis up to the final stage of plaque rupture. Vascular endothelial dysfunction is reversible, and can be recovered by medications and life-style changes. Improvement in endothelial function may reduce cardiovascular events and improve long-term prognosis. A total of 50 patients with stable angina and dyslipidemia were enrolled, including patients who had not received prior treatment with statins and had serum LDL-C levels ≥ 100 mg/dL, and patients who had previously received statin treatment. All agreed to register regardless of their LDL-C level. Rosuvastatin was initially administered at a dose of 2.5 mg and appropriately titrated up to the maximum dose of 20 mg or until LDL-C levels lower than 80 mg/dL were achieved, for 24 weeks. Endothelial function was assessed by the reactive hyperemia peripheral arterial tonometry (RH-PAT) index in the radial artery by Endo-PAT ® 2000 (Endo-PAT ® 2000, software version 3.0.4, Itamar Medical Ltd., Caesarea, Israel). RH-PAT data were digitally analyzed online by Endo-PAT ® 2000 at baseline and at 24 weeks. LDL-C and MDA-LDL-C decreased from 112.6 ± 23.3 to 85.5 ± 20.2 mg/dL and from 135.1 ± 36.4 to 113.9 ± 23.5 mg/dL respectively (p < 0.0001). However, HDL-C, hs-CRP and TG did not change significantly after treatment. RH-PAT index levels significantly improved, from 1.60 ± 0.31 to 1.77 ± 0.57 (p = 0.04) after treatment, and the percent change of the RH-PAT index was 12.8 ± 36.9%. Results of multivariate analysis show that serum LDL-C levels over 24 weeks did not act as a predictor of improvement of the RH-PAT index. However, HbA1c at baseline was an independent predictor which influenced the 24-week RH-PAT index level. The RH-PAT index of patients with high HbA1c at baseline did not improve after administration of rosuvastatin but it did improve in patients with low HbA1c at baseline. Aggressive lowering of LDL-C with rosuvastatin significantly improved the RH-PAT index, suggesting that it may improve endothelial function in patients with coronary artery disease.Clinical Trial Registration No: UMIN-CTR, UMIN000010040.

High speed clinical data retrieval system with event time sequence feature: with 10 years of clinical data of Hamamatsu University Hospital CPOE.

PubMed

Kimura, M; Tani, S; Watanabe, H; Naito, Y; Sakusabe, T; Watanabe, H; Nakaya, J; Sasaki, F; Numano, T; Furuta, T; Furuta, T

2008-01-01

This paper illustrates a high speed clinical data retrieving system, from 10 years of data of operating hospital information system for the purposes of research, evidence creation, patient safety, etc., even incorporating time sequence of causal relations. Total of 73,709,298 records of 10 years at Hamamatsu University Hospital (as of June 2008) are sent from HIS to retrieval system in HL7 v2.5 format. Hierarchical variable length database is used to install them. A search for "listing patients who were prescribed Pravastatin (Mevalotin and generic drugs, any titer)" took 1.92 seconds. "Pravastatin (any) prescribed and recorded AST >150 within two weeks" took 112.22 seconds. Searching conditions can be set to be more complex, connected by Boolean operator and/or. This system called D*D is in operation at Hamamatsu University Hospital since August 2002. It is used for 48,518 times (monthly average of 703 searches). Neither searching, nor background export of data from HIS caused delay of routine operating CPOE. Search database outside of routine operating CPOE, with daily export of order data in HL7 v2.5 format, is proved to provide excellent search environment without causing trouble. Hierarchical representation gives high-speed search response, especially with time sequence of events.

Severity of statin-induced adverse effects on muscle and associated conditions: data from the DAMA study.

PubMed

Pedro-Botet, Juan; Millán Núñez-Cortés, Jesús; Chillarón, Juan J; Flores-Le Roux, Juana A; Rius, Joan

2016-12-01

Statins are generally well tolerated, but muscular adverse effects appear to be the most common obstacle limiting their use. Our objective was to describe the severity of muscle injury (myalgia, myositis and rhabdomyolysis) and associated conditions related to statin therapy that may be clinically significant. A cross-sectional one-visit, non-interventional, national multicenter study including patients of both sexes over 18 years of age referred for past or present muscle symptoms associated with statin therapy was conducted. Clinical, biochemical and drug therapy characteristics were obtained at the initial evaluation. 3,845 patients were recruited from a one-day record from 2,001 physicians. Myalgia was present in 78.2% of patients, myositis in 19.3% and rhabdomyolysis in 2.5%. The prevalence of different comorbidities such as diabetes, hypertension, atrial fibrillation, and coronary heart disease increased as the severity of myopathy rose. High-intensity statin therapy was used in 33.4% of patients. Concomitant drugs metabolized by the CYP450 3A4 pathway were taken by 9.3% of patients, and statins with this metabolic route by 75%. Independent variables associated with myositis or rhabdomyolysis compared with myalgia alone in the multivariate model were excessive alcohol consumption and pravastatin therapy. Myalgia was the most common muscle adverse effect associated with statin therapy. Excessive alcohol consumption and pravastatin were independently associated with myositis or rhabdomyolysis.

Cholesterol Efflux Capacity, High-Density Lipoprotein Particle Number, and Incident Cardiovascular Events: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin).

PubMed

Khera, Amit V; Demler, Olga V; Adelman, Steven J; Collins, Heidi L; Glynn, Robert J; Ridker, Paul M; Rader, Daniel J; Mora, Samia

2017-06-20

Recent failures of drugs that raised high-density lipoprotein (HDL) cholesterol levels to reduce cardiovascular events in clinical trials have led to increased interest in alternative indices of HDL quality, such as cholesterol efflux capacity, and HDL quantity, such as HDL particle number. However, no studies have directly compared these metrics in a contemporary population that includes potent statin therapy and low low-density lipoprotein cholesterol. HDL cholesterol levels, apolipoprotein A-I, cholesterol efflux capacity, and HDL particle number were assessed at baseline and 12 months in a nested case-control study of the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), a randomized primary prevention trial that compared rosuvastatin treatment to placebo in individuals with normal low-density lipoprotein cholesterol but increased C-reactive protein levels. In total, 314 cases of incident cardiovascular disease (CVD) (myocardial infarction, unstable angina, arterial revascularization, stroke, or cardiovascular death) were compared to age- and gender-matched controls. Conditional logistic regression models adjusting for risk factors evaluated associations between HDL-related biomarkers and incident CVD. Cholesterol efflux capacity was moderately correlated with HDL cholesterol, apolipoprotein A-I, and HDL particle number (Spearman r = 0.39, 0.48, and 0.39 respectively; P <0.001). Baseline HDL particle number was inversely associated with incident CVD (adjusted odds ratio per SD increment [OR/SD], 0.69; 95% confidence interval [CI], 0.56-0.86; P <0.001), whereas no significant association was found for baseline cholesterol efflux capacity (OR/SD, 0.89; 95% CI, 0.72-1.10; P =0.28), HDL cholesterol (OR/SD, 0.82; 95% CI, 0.66-1.02; P =0.08), or apolipoprotein A-I (OR/SD, 0.83; 95% CI, 0.67-1.03; P =0.08). Twelve months of rosuvastatin (20 mg/day) did not change cholesterol efflux capacity (average percentage change -1.5%, 95% CI, -13.3 to +10.2; P =0.80), but increased HDL cholesterol (+7.7%), apolipoprotein A-I (+4.3%), and HDL particle number (+5.2%). On-statin cholesterol efflux capacity was inversely associated with incident CVD (OR/SD, 0.62; 95% CI, 0.42-0.92; P =0.02), although HDL particle number again emerged as the strongest predictor (OR/SD, 0.51; 95% CI, 0.33-0.77; P <0.001). In JUPITER, cholesterol efflux capacity was associated with incident CVD in individuals on potent statin therapy but not at baseline. For both baseline and on-statin analyses, HDL particle number was the strongest of 4 HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681. © 2017 American Heart Association, Inc.

High HbA1c levels correlate with reduced plaque regression during statin treatment in patients with stable coronary artery disease: Results of the coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS)

PubMed Central

2012-01-01

Background The incidence of cardiac events is higher in patients with diabetes than in people without diabetes. The Coronary Atherosclerosis Study Measuring Effects of Rosuvastatin Using Intravascular Ultrasound in Japanese Subjects (COSMOS) demonstrated significant plaque regression in Japanese patients with chronic coronary disease after 76 weeks of rosuvastatin (2.5 mg once daily, up-titrated to a maximum of 20 mg/day to achieve LDL cholesterol <80 mg/dl). Methods In this subanalysis of COSMOS, we examined the association between HbA1c and plaque regression in 40 patients with HbA1c ≥6.5% (high group) and 86 patients with HbA1c <6.5% (low group). Results In multivariate analyses, HbA1c and plaque volume at baseline were major determinants of plaque regression. LDL cholesterol decreased by 37% and 39% in the high and low groups, respectively, while HDL cholesterol increased by 16% and 22%, respectively. The reduction in plaque volume was significantly (p = 0.04) greater in the low group (from 71.0 ± 39.9 to 64.7 ± 34.7 mm3) than in the high group (from 74.3 ± 34.2 to 71.4 ± 32.3 mm3). Vessel volume increased in the high group but not in the low group (change from baseline: +4.2% vs −0.8%, p = 0.02). Change in plaque volume was significantly correlated with baseline HbA1c. Conclusions Despite similar improvements in lipid levels, plaque regression was less pronounced in patients with high HbA1c levels compared with those with low levels. Tight glucose control during statin therapy may enhance plaque regression in patients with stable coronary disease. Trial registration ClinicalTrials.gov, Identifier NCT00329160 PMID:22831708

Statin-associated muscle symptoms and SLCO1B1 rs4149056 genotype in patients with familial hypercholesterolemia.

PubMed

Khine, Htet; Yuet, Wei Cheng; Adams-Huet, Beverley; Ahmad, Zahid

2016-09-01

Patients with familial hypercholesterolemia (FH) may be at increased risk for statin-associated muscle symptoms because they require long-term treatment with high-intensity statin therapy. We sought to determine (1) whether other predisposing factors, including the well-known genetic variant associated with statin-associated muscle symptoms-solute carrier organic anion transporter family, member 1B1 (SLCO1B1) rs4149056-also increase the risk of statin-associated muscle symptoms in FH patients, and (2) the natural history and management for FH patients with statin-associated muscle symptoms. We queried electronic records (2004-2014) of 278 genetically screened FH patients (113 men, 165 women; mean [SD] pretreatment low-density lipoprotein cholesterol [LDL-C] 259 [72] mg/dL) recruited from lipid clinics in the Dallas, TX, area from 2004 to 2014. Statin-associated muscle symptoms were defined as muscle symptoms arising while taking a statin and interrupting therapy. The risk of muscle symptoms was associated with age (odds ratio 1.6 [95% CI 1.2-2.2]), body mass index in non-African Americans (0.90 [0.83-0.97]), and hypertension (0.4 [0.2-0.9]). Simvastatin was the most commonly used statin, and it was the statin most associated with muscle symptoms. Among FH patients with muscle symptoms, 41% (n = 40) reestablished statin therapy ("eventually tolerant") and 29% (n = 28) never reestablished statin therapy ("never tolerant"). Rosuvastatin (43%) and pravastatin (30%) were the most common eventually tolerated statins, and eventually tolerant patients achieved lower treated LDL-C levels (eventually tolerant 127 vs never tolerant 192 mg/dL, P < .001). Never tolerant patients also developed muscle symptoms on nonstatins (16% vs 50%, P = .003). SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). SLCO1B1 genotype was not associated with the risk of statin-associated muscle symptoms (odds ratio 1.40 [95% CI 0.74-2.64]). Age, not SLCO1B1 rs4149056 genotype, was the strongest risk factor for statin-associated muscle symptoms in FH patients. After developing muscle symptoms, many patients reestablished statin therapy and achieved significant LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never reestablished statin therapy. Such patients developed muscle symptoms even on nonstatin lipid-lowering drugs and continued to have elevations in LDL-C. Further insight is needed into the relationship between FH and statin-associated muscle symptoms so all FH patients can be adequately treated. Copyright © 2016 Elsevier Inc. All rights reserved.

Statin-associated Muscle Symptoms and SLCO1B1 rs4149056 Genotype in Patients with Familial Hypercholesterolemia

PubMed Central

Khine, Htet; Yuet, Wei Cheng; Adams-Huet, Beverley; Ahmad, Zahid

2016-01-01

Background and Aims Patients with familial hypercholesterolemia (FH) may be at increased risk of statin-associated muscle symptoms since they require long-term treatment with high-intensity statin therapy. We sought to determine 1) whether other predisposing factors, including the well-known genetic variant associated with statin-associated muscle symptoms - solute carrier organic anion transporter family, member 1B1 (SLCO1B1) rs4149056 – also increase the risk of statin-associated muscle symptoms in FH patients, and 2) the natural history and management for FH patients with statin-associated muscle symptoms. Methods We queried electronic records (2004–2014) of 278 genetically screened FH patients (113 men, 165 women; mean [SD] pretreatment LDL-C 259 [72] mg/dL) recruited from lipid clinics in the Dallas, TX area from 2004 to 2014. Statin-associated muscle symptoms were defined as muscle symptoms arising while taking a statin and interrupting therapy. Results The risk of muscle symptoms was associated with age (OR 1.6, [95% CI 1.2, 2.2]), BMI in non-African-Americans (0.90 [0.83, 0.97]), and hypertension (0.4, [0.2, 0.9]). Simvastatin most commonly employed and most associated with muscle symptoms. Among FH patients with muscle symptoms, 41% (n = 40) reestablished statin therapy (“eventually tolerant”) and 29% (n = 28) never reestablished statin therapy (“never tolerant”). Rosuvastatin (43%) and pravastatin (30%) were the most common eventually-tolerated statins, and “eventually tolerant” patients achieved lower treated LDL-C levels (“eventually tolerant” 127 vs “never tolerant” 192 mg/dL, p < 0.001). “Never tolerant” patients also developed muscle symptoms on non-statins (16% vs. 50%, p = 0.003). SLCO1B1 rs4149056 genotyping revealed 224 wild-type patients (TT) and 49 heterozygotes (TC). SLCO1B1 genotype was not associated with the risk of statin-associated muscle symptoms (OR 1.40, [95% CI 0.74–2.64]). Conclusion Age, not SLCO1B1 rs4149056 genotype, was the strongest risk factor for statin-associated muscle symptoms in FH patients. After developing muscle symptoms, many patients reestablished statin therapy and achieved significant LDL-C reductions. Overall, 10% of all FH patients had statin-associated muscle symptoms and never re-established statin therapy. Such patients developed muscle symptoms even on non-statin lipid lowering drugs and continued to have elevations in LDL-C. Further insight is needed into the relationship of FH and statin-associated muscle symptoms so all FH patients can be adequately treated. PMID:27595674

Facile Fabrication of Microparticles with pH-responsive Macropores for Small Intestine Targeted Drug Formulation.

PubMed

Homayun, Bahman; Sun, Chengmeng; Kumar, Ankit; Montemagno, Carlo; Choi, Hyo-Jick

2018-05-10

Oral drugs present the most convenient, economical, and painless route for self-administration. Despite commercialization of multiple technologies relying on micro- and nanocrystalline drugs, research on microparticles (MPs) based oral biopharmaceuticals delivery systems has still not culminated well enough in commercial products. This is largely due to the drugs being exposed to the destabilizing environment during MP synthesis process, and partly because of complicated process conditions. Hence, we developed a solvent swelling-evaporation method of producing pH-responsive MPs with micron-sized macropores using poly(methacrylic acid-co-ethyl acrylate) in 1:1 ratio (commercial name: Eudragit ® L100-55 polymer). We investigated the effects of temperature and evaporation time on pore formation, freeze-drying induced pore closure, and the release profile of model drugs (fluorescent beads, lactase, and pravastatin sodium) encapsulated MPs in simulated gastrointestinal tract conditions. Encapsulated lactase/pravastatin maintained > 60% of their activity due to the preservation of pore closure, which proved the potential of this proof-of-concept microencapsulation system. Importantly, the presence of macropores on MPs can be beneficial for easy drug loading, and solve the problem of bioactivity loss during the conventional MP fabrication-drug encapsulation steps. Therefore, pH-sensing MPs with macropores can contribute to the development of oral drug formulations for a wide variety of drugs and bio-macromolecules, having a various size ranging from genes to micron-sized ingredients with high therapeutic efficacy. Copyright © 2018. Published by Elsevier B.V.

The forgotten majority: unfinished business in cardiovascular risk reduction.

PubMed

Libby, Peter

2005-10-04

Despite meaningful progress in the identification of risk factors and the development of highly effective clinical tools, deaths from cardiovascular disease continue to increase worldwide. Sparked by an obesity epidemic, the metabolic syndrome and the rising incidence of type 2 diabetes have led to an upsurge of cardiovascular risk. Although pharmacologic treatments with the statin class of drugs have reduced cholesterol levels and lowered mortality rates, several large controlled clinical trials, including the Scandinavian Simvastatin Survival Study, the Cholesterol and Recurrent Events trial, the Air Force/Texas Coronary Atherosclerosis Prevention studies, and Long-term Intervention with Pravastatin in Ischemic Disease study, have indicated that cardiovascular events continue to occur in two thirds of all patients. Follow-up studies, such as the Heart Protection Study and the Pravastatin or Atorvastatin Evaluation and Infection Therapy/Thrombolysis In Myocardial Infarction-22 trials, reinforced these earlier results. Although therapy with gemfibrozil, a fibric acid derivative, showed reduced occurrence of cardiovascular events in the Helsinki Heart Study and the Veterans Affairs HDL Intervention Trial, results of other studies, e.g., the Bezafibrate Intervention Program and the Diabetes Atherosclerosis Intervention study, showed less encouraging results. Although lifestyle modifications, such as improved diet and increased exercise levels, benefit general health and the metabolic syndrome and insulin resistance in particular, most people continue to resist changes in their daily routines. Thus, physicians must continue to educate their patients regarding an optimal balance of drug therapy and personal behavior.

Anger, Hostility, and Re-hospitalizations in Patients with Heart Failure

DTIC Science & Technology

2015-04-08

Discharge Survey (NHDS), capturing years 1979 to 2004, approximately 80% of individuals who were hospitalized due to heart failure were ~65...Rosuvastatin Multinational Trial In Heart Failure ( CORONA ). Circulation. Heart failure 2. Azevedo FB, Wang YP, Goulart AC, Lotufo PA, Bensenor IM. 2010...from the National Hospital Discharge Surveys 1980-2006. International journal of cardiology 149:39-45 33 . Luttik ML, Jaarsma T, Moser DK, Sanderman R

Surviving the Storm : Expanding Public Health’s Capabilities in Response to the Increasing Threats Posed by Novel Viruses

DTIC Science & Technology

2013-12-01

Therapy Citations Uses Pros Cons Medical Efficacy Mono-Therapy: Class: Statins Atorvastatin (Lipitor) Rosuvastatin (Crestor) Simvastatin...Considerations Citations Good Choice for a State Stockpile? Yes or No Mono-Therapy: Statins Atorvastatin (Lipitor) ↓ Virus Rep: No ↓ Imm...www.goodrx.com/lipitor/price#/?distance=13&filter-location=&coords=&label= atorvastatin &formtablet &strength=40mg&quantity=custom&qty-custom=18450&language

Development of β-cyclodextrin-based hydrogel microparticles for solubility enhancement of rosuvastatin: an in vitro and in vivo evaluation

PubMed Central

Sarfraz, Rai Muhammad; Ahmad, Mahmood; Mahmood, Asif; Akram, Muhammad Rouf; Abrar, Asad

2017-01-01

The aim of this study was to enhance the solubility of rosuvastatin (RST) calcium by developing β-cyclodextrin-g-poly(2-acrylamido-2-methylpropane sulfonic acid [AMPS]) hydrogel microparticles through aqueous free-radical polymerization technique. Prepared hydrogel microparticles were characterized for percent entrapment efficiency, solubility studies, Fourier transform infrared spectroscopy, differential scanning calorimetry, thermal gravimetric analysis, powder X-ray diffraction, scanning electron microscopy, zeta size and potential, swelling and release studies. Formulations (HS1–HS9) have shown entrapment efficiency between 83.50%±0.30% and 88.50%±0.25%, and optimum release was offered by formulation HS7 at both pH levels, ie, 1.2 (89%) and 7.4 (92%). The majority of microparticles had a particle size of less than 500 µm and zeta potential of −37 mV. Similarly, optimum solubility, ie, 10.66-fold, was determined at pH 6.8 as compared to pure RST calcium, ie, 7.30-fold. In vivo studies on fabricated hydrogel microparticulate system in comparison to pure drug were carried out, and better results regarding pharmacokinetic parameters were seen in the case of hydrogel microparticles. A potential approach for solubility enhancement of RST calcium and other hydrophobic moieties was successfully developed. PMID:29123380

Evaluation of topical application and systemic administration of rosuvastatin in preventing epidural fibrosis in rats.

PubMed

Gürer, Bora; Kahveci, Ramazan; Gökçe, Emre Cemal; Ozevren, Huseyin; Turkoglu, Erhan; Gökçe, Aysun

2015-03-01

Epidural fibrosis is a major challenge in spine surgery, with some patients having recurrent symptoms secondary to excessive formation of scar tissue resulting in neurologic compression. One of the most important factors initiating the epidural fibrosis is assumed to be the transforming growth factor-1β (TGF-1β). Rosuvastatin (ROS) has shown to demonstrate preventive effects over fibrosis via inhibiting the TGF-1β. We hypothesized that ROS might have preventive effects over epidural fibrosis through the inhibition of TGF-1β pathways. Experimental animal study. Forty-eight adult male Wistar Albino rats were equally and randomly divided into four groups (laminectomy, spongostan, topical ROS, and systemic ROS). Laminectomy was performed at the L3 level in all rats. Four weeks later, the extent of epidural fibrosis was assessed both macroscopically and histopathologically. Our data revealed that topical application and systemic administration of ROS both were effective in reducing epidural fibrosis formation. Furthermore, the systemic administration of ROS yielded better results than topical application. Both topical application and systemic administration of ROS show meaningful preventive effects over epidural fibrosis through multiple mechanisms. The results of our study provide the first experimental evidence of the preventive effects of ROS over epidural fibrosis. Copyright © 2015 Elsevier Inc. All rights reserved.

Analysis of the Impact of Rosuvastatin on Bacterial Mevalonate Production Using a UPLC-Mass Spectrometry Approach.

PubMed

Nolan, J A; Kinsella, M; Hill, C; Joyce, S A; Gahan, C G M

2016-07-01

Statins are widely prescribed cholesterol-lowering medications and act through inhibition of the human enzyme 3-methylglutaryl coenzyme A reductase (HMG-R) which produces mevalonate (MVAL), a key substrate for cholesterol biosynthesis. Some important microbial species also express an isoform of HMG-R; however, the nature of the interaction between statins and bacteria is currently unclear and studies would benefit from protocols to quantify MVAL in complex microbial environments. The objective of this study was to develop a protocol for the analytical quantification of MVAL in bacterial systems and to utilise this approach to analyse the effects of Rosuvastatin (RSV) on bacterial MVAL formation. To determine the effective concentration range of RSV, we examined the dose-dependent inhibition of growth in the HMG-R(+) bacterial pathogens Listeria monocytogenes, Staphylococcus aureus and Enterococcus faecium at various concentrations of pure RSV. Growth inhibition generally correlated with a reduction in bacterial MVAL levels, particularly in culture supernatants at high RSV concentrations, as determined using our ultra-performance liquid chromatography mass spectrometry protocol. This work therefore outlines a refined protocol for the analysis of MVAL in microbial cultures and provides evidence for statin-mediated inhibition of bacterial HMG-R. Furthermore, we show that MVAL is readily transported and secreted from bacterial cells into the growth media.

Improved pharmacokinetics and antihyperlipidemic efficacy of rosuvastatin-loaded nanostructured lipid carriers.

PubMed

Rizwanullah, Md; Amin, Saima; Ahmad, Javed

2017-01-01

In the present study, rosuvastatin calcium-loaded nanostructured lipid carriers were developed and optimized for improved efficacy. The ROS-Ca-loaded NLC was prepared using melt emulsification ultrasonication technique and optimized by Box-Behnken statistical design. The optimized NLC composed of glyceryl monostearate (solid lipid) and capmul MCM EP (liquid lipid) as lipid phase (3% w/v), poloxamer 188 (1%) and tween 80 (1%) as surfactant. The mean particle size, polydispersity index (PDI), zeta potential (ζ) and entrapment efficiency (%) of optimized NLC formulation was observed to be 150.3 ± 4.67 nm, 0.175 ± 0.022, -32.9 ± 1.36 mV and 84.95 ± 5.63%, respectively. NLC formulation showed better in vitro release in simulated intestinal fluid (pH 6.8) than API suspension. Confocal laser scanning showed deeper permeation of formulation across rat intestine compared to rhodamine B dye solution. Pharmacokinetic study on female albino Wistar rats showed 5.4-fold increase in relative bioavailability with NLC compared to API suspension. Optimized NLC formulation also showed significant (p < 0.01) lipid lowering effect in hyperlipidemic rats. Therefore, NLC represents a great potential for improved efficacy of ROS-Ca after oral administration.

A method for the direct injection and analysis of small volume human blood spots and plasma extracts containing high concentrations of organic solvents using revered-phase 2D UPLC/MS.

PubMed

Rainville, Paul D; Simeone, Jennifer L; Root, Dan S; Mallet, Claude R; Wilson, Ian D; Plumb, Robert S

2015-03-21

The emergence of micro sampling techniques holds great potential to improve pharmacokinetic data quality, reduce animal usage, and save costs in safety assessment studies. The analysis of these samples presents new challenges for bioanalytical scientists, both in terms of sample processing and analytical sensitivity. The use of two dimensional LC/MS with, at-column-dilution for the direct analysis of highly organic extracts prepared from biological fluids such as dried blood spots and plasma is demonstrated. This technique negated the need to dry down and reconstitute, or dilute samples with water/aqueous buffer solutions, prior to injection onto a reversed-phase LC system. A mixture of model drugs, including bromhexine, triprolidine, enrofloxacin, and procaine were used to test the feasibility of the method. Finally an LC/MS assay for the probe pharmaceutical rosuvastatin was developed from dried blood spots and protein-precipitated plasma. The assays showed acceptable recovery, accuracy and precision according to US FDA guidelines. The resulting analytical method showed an increase in assay sensitivity of up to forty fold as compared to conventional methods by maximizing the amount loaded onto the system and the MS response for the probe pharmaceutical rosuvastatin from small volume samples.

The effect of superdisintegrants on the properties and dissolution profiles of liquisolid tablets containing rosuvastatin.

PubMed

Vraníková, Barbora; Gajdziok, Jan; Doležel, Petr

2017-03-01

The preparation of liquisolid systems (LSS) represents a promising method for enhancing a dissolution rate and bioavailability of poorly soluble drugs. The release of the drug from LSS tablets is affected by many factors, including the disintegration time. The evaluation of differences among LSS containing varying amounts and types of commercially used superdisintegrants (Kollidon® CL-F, Vivasol® and Explotab®). LSS were prepared by spraying rosuvastatin solution onto Neusilin® US2 and further processing into tablets. Varying amounts of superdisintegrants were used and the differences among LSS were evaluated. The multiple scatter plot method was used to visualize the relationships within the obtained data. All disintegrants do not showed negative effect on the flow properties of powder blends. The type and concentration of superdisintegrant had an impact on the disintegration time and dissolution profiles of tablets. Tablets with Explotab® showed the longest disintegration time and the smallest amount of released drug. Fastest disintegration and dissolution rate were observed in tablets containing Kollidon® CL-F (≥2.5% w/w). Also tablets with Vivasol® (2.5-4.0% w/w) showed fast disintegration and complete drug release. Kollidon® CL-F and Vivasol® in concentration ≥2.5% are suitable superdisintegrants for LSS with enhanced release of drug.

Matrix Conditions and KLF2-Dependent Induction of Heme Oxygenase-1 Modulate Inhibition of HCV Replication by Fluvastatin

PubMed Central

Singethan, Katrin; Sirma, Hüseyin; Keller, Amelie Dorothea; Rosal, Sergio René Perez; Schrader, Jörg; Loscher, Christine; Volz, Tassilo; Bartenschlager, Ralf; Lohmann, Volker; Protzer, Ulrike; Dandri, Maura; Lohse, Ansgar W.; Tiegs, Gisa; Sass, Gabriele

2014-01-01

Background & Aims HMG-CoA-reductase-inhibitors (statins) have been shown to interfere with HCV replication in vitro. We investigated the mechanism, requirements and contribution of heme oxygenase-1(HO-1)-induction by statins to interference with HCV replication. Methods HO-1-induction by fluva-, simva-, rosuva-, atorva- or pravastatin was correlated to HCV replication, using non-infectious replicon systems as well as the infectious cell culture system. The mechanism of HO-1-induction by statins as well as its relevance for interference with HCV replication was investigated using transient or permanent knockdown cell lines. Polyacrylamide(PAA) gels of different density degrees or the Rho-kinase-inhibitor Hydroxyfasudil were used in order to mimic matrix conditions corresponding to normal versus fibrotic liver tissue. Results All statins used, except pravastatin, decreased HCV replication and induced HO-1 expression, as well as interferon response in vitro. HO-1-induction was mediated by reduction of Bach1 expression and induction of the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) cofactor Krueppel-like factor 2 (KLF2). Knockdown of KLF2 or HO-1 abrogated effects of statins on HCV replication. HO-1-induction and anti-viral effects of statins were more pronounced under cell culture conditions mimicking advanced stages of liver disease. Conclusions Statin-mediated effects on HCV replication seem to require HO-1-induction, which is more pronounced in a microenvironment resembling fibrotic liver tissue. This implicates that certain statins might be especially useful to support HCV therapy of patients at advanced stages of liver disease. PMID:24801208

Society already achieves economic benefits from generic substitution but fails to do the same for therapeutic substitution.

PubMed

Gumbs, Pearl D; Verschuren, W M Monique; Souverein, Patrick C; Mantel-Teeuwisse, Aukje K; de Wit, G Ardine; de Boer, Anthonius; Klungel, Olaf H

2007-11-01

To assess the potential annual savings due to generic and therapeutic substitution of statin therapy for the general Dutch population, taking the patients medical history into account. We conducted a population-based costing study using the PHARMO Record Linkage System (RLS). PHARMO RLS contains drug dispensing records from a representative sample of pharmacies located in more than 50 regions in the Netherlands. We selected all statin users in the database since 2003. The cost-savings of generic substitution of statin therapy for all simvastatin and pravastatin users, and of therapeutic substitution of statin therapy for other statin users were calculated. Substituting current users and new users of statins were considered separately. Therapeutic substitution was based on the medical history of the individual patient. Patients were only substituted if there was an appropriate substitute available. The appropriateness of substitution was based on drug-drug interactions between statins and possible comedication and the availability of an equipotent alternative. Substituting (generic and therapeutic) statin therapy for all current users would lead to potential annual savings of approximately 87 million euros. Substituting (generic and therapeutic) all starters on statin therapy would lead to potential annual savings of around 51 million euros. In the case of generic substitution only, the potential annual savings for all current simvastatin and pravastatin users would be 2.4 million euros and for the new users about 1.8 million euros. From an economic point of view, society could gain a lot from substituting statin therapy, especially from therapeutic substitution.

A new mouse model to explore therapies for preeclampsia.

PubMed

Ahmed, Abdulwahab; Singh, Jameel; Khan, Ysodra; Seshan, Surya V; Girardi, Guillermina

2010-10-27

Pre-eclampsia, a pregnancy-specific multisystemic disorder is a leading cause of maternal and perinatal mortality and morbidity. This syndrome has been known to medical science since ancient times. However, despite considerable research, the cause/s of preeclampsia remain unclear, and there is no effective treatment. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment. Here we show that the CBA/J x DBA/2 mouse model of recurrent miscarriage is also a model of immunologically-mediated preeclampsia (PE). DBA/J mated CBA/J females spontaneously develop many features of human PE (primigravidity, albuminuria, endotheliosis, increased sensitivity to angiotensin II and increased plasma leptin levels) that correlates with bad pregnancy outcomes. We previously reported that antagonism of vascular endothelial growth factor (VEGF) signaling by soluble VEGF receptor 1 (sFlt-1) is involved in placental and fetal injury in CBA/J x DBA/2 mice. Using this animal model that recapitulates many of the features of preeclampsia in women, we found that pravastatin restores angiogenic balance, ameliorates glomerular injury, diminishes hypersensitivity to angiotensin II and protects pregnancies. We described a new mouse model of PE, were the relevant key features of human preeclampsia develop spontaneously. The CBA/J x DBA/2 model, that recapitulates this complex disorder, helped us identify pravastatin as a candidate therapy to prevent preeclampsia and its related complications. We recognize that these studies were conducted in mice and that clinical trials are needed to confirm its application to humans.

Statin and Its Association With Delirium in the Medical ICU.

PubMed

Mather, Jeffrey F; Corradi, John P; Waszynski, Christine; Noyes, Adam; Duan, Yinghui; Grady, James; Dicks, Robert

2017-09-01

To examine the association between statin use and the risk of delirium in hospitalized patients with an admission to the medical ICU. Retrospective propensity-matched cohort analysis with accrual from September 1, 2012, to September 30, 2015. Hartford Hospital, Hartford, CT. An initial population of patients with an admission to a medical ICU totaling 10,216 visits were screened for delirium by means of the Confusion Assessment Method. After exclusions, a population of 6,664 was used to match statin users and nonstatin users. The propensity-matched cohort resulted in a sample of 1,475 patients receiving statin matched 1:1 with control patients not using statin. None. Delirium defined as a positive Confusion Assessment Method assessment was the primary end point. The prevalence of delirium was 22.3% in the unmatched cohort and 22.8% in the propensity-matched cohort. Statin use was associated with a significant decrease in the risk of delirium (odds ratio, 0.47; 95% CI, 0.38-0.56). Considering the type of statin used, atorvastatin (0.51; 0.41-0.64), pravastatin (0.40; 0.28-0.58), and simvastatin (0.33; 0.21-0.52) were all significantly associated with a reduced frequency of delirium. The use of statins was independently associated with a reduction in the risk of delirium in hospitalized patients. When considering types of statins used, this reduction was significant in patients using atorvastatin, pravastatin, and simvastatin. Randomized trials of various statin types in hospitalized patients prone to delirium should validate their use in protection from delirium.

Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons.

PubMed

Karten, Barbara; Vance, Dennis E; Campenot, Robert B; Vance, Jean E

2003-02-07

Niemann Pick type C (NPC) disease is a progressive neurodegenerative disorder. In cells lacking functional NPC1 protein, endocytosed cholesterol accumulates in late endosomes/lysosomes. We utilized primary neuronal cultures in which cell bodies and distal axons reside in separate compartments to investigate the requirement of NPC1 protein for transport of cholesterol from cell bodies to distal axons. We have recently observed that in NPC1-deficient neurons compared with wild-type neurons, cholesterol accumulates in cell bodies but is reduced in distal axons (Karten, B., Vance, D. E., Campenot, R. B., and Vance, J. E. (2002) J. Neurochem. 83, 1154-1163). We now show that NPC1 protein is expressed in both cell bodies and distal axons. In NPC1-deficient neurons, cholesterol delivered to cell bodies from low density lipoproteins (LDLs), high density lipoproteins, or cyclodextrin complexes was transported into axons in normal amounts, whereas transport of endogenously synthesized cholesterol was impaired. Inhibition of cholesterol synthesis with pravastatin in wild-type and NPC1-deficient neurons reduced axonal growth. However, LDLs restored a normal rate of growth to wild-type but not NPC1-deficient neurons treated with pravastatin. Thus, although LDL cholesterol is transported into axons of NPC1-deficient neurons, this source of cholesterol does not sustain normal axonal growth. Over the lifespan of NPC1-deficient neurons, these defects in cholesterol transport might be responsible for the observed altered distribution of cholesterol between cell bodies and axons and, consequently, might contribute to the neurological dysfunction in NPC disease.

The impact of the time of drug administration on the effectiveness of combined treatment of hypercholesterolemia with Rosuvastatin and Ezetimibe (RosEze): study protocol for a randomized controlled trial.

PubMed

Obońska, Karolina; Kasprzak, Michał; Sikora, Joanna; Obońska, Ewa; Racki, Krzysztof; Goździkiewicz, Natalia; Krintus, Magdalena; Kubica, Jacek

2017-07-11

Hypercholesterolemia is one of the main risk factors for cardiovascular disease. The first line treatment for hypercholesterolemia is statin therapy. When the expected low-density lipoprotein cholesterol (LDL-C) concentration is not achieved, the pharmacotherapy may be extended by combining the statin with the cholesterol absorption inhibitor ezetimibe. The study is designed as a randomized, open-label, single-center, crossover study evaluating the effectiveness of combined therapy with rosuvastatin and ezetimibe for hypercholesterolemia. The study is planned to include 200 patients with hypercholesterolemia ineffectively treated with statins for at least 6 weeks. After enrollment participants are randomized into one of two arms receiving rosuvastatin and ezetimibe. In the first arm the study drug is administered in the morning (8:00 am) for 6 weeks and then in the evening for the next 6 weeks; in the second arm the study drug is administered at first in the evening (8:00 pm) for the first 6 weeks and then in the morning for the following 6 weeks. In order to minimize non-adherence to the treatment, all patients will receive the study drug free of charge. The primary outcome of the study is change in LDL-C at 6 and 12 weeks of the treatment, depending on the time of day of study drug administration. The secondary endpoints include change in total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins ApoB and Apo AI, non-HDL cholesterol, small, dense (sd)-LDL cholesterol, lipoprotein(a), glucose, glycated hemoglobin, high-sensitivity C-reactive protein, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, and creatine kinase at 6 and 12 weeks of the study drug treatment, as well as assessment of plasma fluorescence using stationary and time-resolved fluorescence spectroscopy at baseline and at 6 and 12 weeks of the therapy. The RosEze trial is expected to demonstrate whether there is a significant difference in the effectiveness of the lipid-lowering therapy in reducing the concentration of cholesterol when the medications are taken in the morning compared with the evening time of day. ClinicalTrials.gov, NCT02772640 . Registered on 28 March 2016.

Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial.

PubMed

Mora, Samia; Caulfield, Michael P; Wohlgemuth, Jay; Chen, Zhihong; Superko, H Robert; Rowland, Charles M; Glynn, Robert J; Ridker, Paul M; Krauss, Ronald M

2015-12-08

Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo. In 11 186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88-1.21). In contrast, associations with CVD events were observed for baseline non-high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01-1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11-1.48), and ion mobility-measured non-HDL particles (HR, 1.19; 95% CI, 1.05-1.35) and LDL particles (HR, 1.21; 95% CI, 1.07-1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility-measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk. In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility-measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681. © 2015 American Heart Association, Inc.

Protective effects of rosuvastatin and vitamin E against fipronil-mediated oxidative damage and apoptosis in rat liver and kidney.

PubMed

Abdel-Daim, Mohamed M; Abdeen, Ahmed

2018-04-01

Fipronil (FPN) is a phenylpyrazole insecticide that is extensively used in agriculture and veterinary applications. However, FPN is also a potent environmental toxicant to animals and humans. Therefore, the current study aimed to investigate the protective role of rosuvastatin (ROSU) and vitamin E (Vit E) against FPN-induced hepatorenal toxicity in albino rats. Seven groups with eight rats each were used for this purpose; these groups included the control vehicle group that received corn oil, the Vit E group (1000 mg/kg, orally), the ROSU group (10 mg/kg, orally), the FPN group (20 mg/kg, orally), the FPN-ROSU group, the FPN-Vit E group, and the FPN-Vit E-ROSU group. The results revealed that FPN significantly increased serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, cholesterol, urea, and creatinine. In addition, there were substantial increases in the liver and kidney contents of malondialdehyde and nitric oxide, along with significant decreases in glutathione, superoxide dismutase, catalase, and glutathione peroxidase. FPN also caused histological changes and increased the expression of caspase-3 in the liver and kidney tissues. However, administration of ROSU and Vit E alone or in combination ameliorated the FPN-induced oxidative damage and apoptosis, possibly through their antioxidant properties. Copyright © 2018 Elsevier Ltd. All rights reserved.

Solid super saturated self-nanoemulsifying drug delivery system (sat-SNEDDS) as a promising alternative to conventional SNEDDS for improvement rosuvastatin calcium oral bioavailability.

PubMed

Abo Enin, Hadel A; Abdel-Bar, Hend Mohamed

2016-11-01

This study aims to illustrate the applicability of solid supersaturated self-nanoemulsifying drug delivery system (sat-SNEDDS) for the improvement of rosuvastatin calcium (RC) oral bioavailability. Different sat-SNEDDS were prepared by incorporating different ratios of RC into SNEDDS using tween80/PEG400 (77.2%) as surfactant/cosurfactant mixture and garlic /olive oil (22.8%) as oil phase. The prepared systems were characterized viz; size, zeta potential, TEM and stability. Various hydrophilic and hydrophobic carriers were employed to solidify the optimized RC sat-SNEDDS. The influence of the carrier was investigated by SEM, XRPD, DSC, flow properties, in vitro precipitation, drug release and oral bioavailability study. The adsorption of the stable positively charged nanocarrier RC sat-SNEDDS onto solid carriers provided free flowing amorphous powder. The carrier could amend the morphological architecture and in vitro release of the RC solid sat-SNEDDS. Hydrophobic carriers as microcrystalline cellulose 102 (MCC) showed superior physical characters and higher dissolution rate over hydrophilic carriers as maltodextrin with respective T 100% 30 min and 45 min. The rapid spontaneous emulsification, the positively nanosized MCC-sat-SNEDDS improved oral bioavailability of RC by 2.1-fold over commercial tablets. Solid MCC-sat-SNEDDS combined dual benefits of sat-SNEDDS and solid dosage form was successfully optimized to improve RC oral bioavailability.

Self-nanoemulsifying drug-delivery system for improved oral bioavailability of rosuvastatin using natural oil antihyperlipdemic.

PubMed

Abo Enin, Hadel A

2015-01-01

The aim is improving the antihyperlipidemic activity of Rosuvastatin Calcium (Rs) through improving its solubility using self-nanoemulsifying drug delivery system (SNEDDS) containing natural oil full of unsaturated fatty acid and omega 3. A 7 × 3(2) full factorial design was adopted for optimization of oil ratio, Surfactant: Co-surfactant (S:CoS) ratio and oil:S/CoS ratio. Ternary phase diagrams were constructed for optimizing the system with drug loading (10 and 20%). The optimized SNEDD systems were evaluated according to their physical evaluation and drug release. Furthermore, the anti-hyperlipidemia efficacy was compared with commercially marketed product on rates followed by clinical study. The system containing Tween 80:PEG 400 (3:1) and olive oil:garlic oil (1:1) as an oily phase has droplet size less than 100 nm, ZP (+23.43 ± 2.58 mV), PDI (<0.02) and cloud point (>90 °C). In vitro drug release studies showed remarkable enhancement of the Rs release from Rs-SNEDDS. The antihyperlipidemic effect of Rs-SNEDDS is greater than that of the commercial tablets and the pure drug on rates and in hyperlipidemic patients. Rs-SNEDDS is a promising drug delivery system for improving the drug solubility and antihyperlipidemic effect using natural oils as (olive oil and garlic oil).

Non-every day statin administration--a literature review.

PubMed

Elis, Avishay; Lishner, Michael

2012-07-01

Statins are the treatment of choice for lowering LDL-C levels and reducing cardiovascular events. They have a remarkable safety profile, although some patients do not tolerate them. The aim of the study was to summarize the existing data on non-every day statin administration regimens. We searched the MEDLINE databases to identify articles on non-every day statin administration, published between 1990 and January 2010. All publications regardless of methodology, design, size, or language were included. Data extracted included study design, duration and aims, type of statin, therapeutic regimen, patient characteristics, effectiveness, tolerability, and costs. The 21 retrieved articles were characterized by small sample size, short follow up period, and a preponderance of males and "primary" prevention cases. Several lacked randomization or a control group. The heterogeneity of the study groups, medications, doses, design and aims precluded a pooled or meta-analysis. The most reported and effective regimens were atorvastatin and rosuvastatin on alternate days. These regimens, with or without other lipid lowering agents, were well tolerated even among subjects with previous statin intolerance, and produced meaningful cost savings. Nevertheless, the effectiveness of these regimens on cardiovascular events was not clarified. Atorvastatin or rosuvastatin on alternate days might be considered for patients who are intolerant to statin therapy. Further studies are needed to evaluate the effect of these regimens on cardiovascular events. Copyright © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Effects of hypercholesterolemia of renal hemodynamics: study in patients with nephrotic syndrome.

PubMed

Fuiano, G; Esposito, C; Sepe, V; Colucci, G; Bovino, M; Rosa, M; Balletta, M; Bellinghieri, G; Conte, G; Cianciaruso, B; Dal Canton, A

1996-01-01

Experimental and clinical studies have demonstrated a positive relationship between hyperlipidemia and rate of progression of renal disease, suggesting that lipids can induce or aggravate glomerular injury mainly by interacting with mesangial cells. Nevertheless, recently has been demonstrated that increased cholesterol levels can also induce endothelial cell dysfunction. Thus, since endothelium is known to play a major role in modulating the vascular tone, we have tested the possibility that hypercholesterolemia impairs the renal hemodynamics in patients with active nephrotic syndrome and elevated serum cholesterol levels. In this single-blind, nonrandom study, 12 patients were treated with pravastatin (group T, treated, n = 12) and 8 with placebo (group C, controls, n = 8). The controls were studied after the pravastatin group had been completed. Before starting the treatment the patients underwent basal determinations including routine laboratory investigations and PAH and inulin clearances. The same determinations were repeated after 48 h, and 6 and 12 weeks from the beginning of the treatment. The study at 48 h was performed to see if pravastatin had a direct, cholesterol-independent effect on renal function. The following basal results were reported (mean +/- SEM; group T vs. group C): serum cholesterol (mmol/l) 9.7 +/- 0.4 vs. 9.1 +/- 0.3 (NS); proteinuria (g/24 h): 6.2 +/- 0.2 vs. 7.0 +/- 0.7 (NS); PAH clearance (ml/min): 353 +/- 21 vs. 385 +/- 31 (NS); inulin clearance (ml/min): 62.5 +/- 7.7 vs. 67 +/- 9.3 (NS). After 48 h, no changes were observed in both groups. Subsequently, in group T, the following percentage changes of basal levels were observed: serum cholesterol -21.4 +/- 3.2% at 6 weeks (p < 0.05) and -34.9 +/- 3.2% at 12 weeks (p < 0.01); inulin clearance +3 +/- 3.7% at 6 weeks (NS) and +9.3 +/- 2.9% at 12 weeks (p < 0.05); PAH clearance +7 +/- 3.1% at 6 weeks (p < 0.05) and +21.2 +/- 5.5% at 12 weeks (p < 0.01). By contrast, no significant changes of these parameters occurred in group C at any time, so that the percent changes of baseline values of CPAH were significantly greater in group T (at 6 weeks: p < 0.05; at 12 weeks p < 0.005). These results indicate that the reduction of cholesterol is associated with a significant increase in renal plasma flow, thus, suggesting that hypercholesterolemia may actually impair the renal hemodynamics. We speculate that this effect may contribute to increase the risk of ischemic acute renal failure in nephrotic patients and, along with changes induced in the mesangium by other mechanisms, to contribute to the progression of renal disease.

Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease.

PubMed

Zissimopoulos, Julie M; Barthold, Douglas; Brinton, Roberta Diaz; Joyce, Geoffrey

2017-02-01

To our knowledge, no effective treatments exist for Alzheimer disease, and new molecules are years away. However, several drugs prescribed for other conditions have been associated with reducing its risk. To analyze the association between statin exposure and Alzheimer disease incidence among Medicare beneficiaries. We examined the medical and pharmacy claims of a 20% sample of Medicare beneficiaries from 2006 to 2013 and compared rates of Alzheimer disease diagnosis for 399 979 statin users 65 years of age or older with high or low exposure to statins and with drug molecules for black, Hispanic, and non-Hispanic white people, and men and women of Asian, Native American, or unkown race/ethnicity who are referred to as "other." The main outcome was incident diagnosis of Alzheimer disease based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We used Cox proportional hazard models to analyze the association between statin exposure and Alzheimer disease diagnosis for different sexes, races and ethnicities, and statin molecules. The 399 979 study participants included 7794 (1.95%) black men, 24 484 (6.12%) black women, 11 200 (2.80%) Hispanic men, 21 458 (5.36%) Hispanic women, 115 059 (28.77%) white men, and 195 181 (48.80%) white women. High exposure to statins was associated with a lower risk of Alzheimer disease diagnosis for women (hazard ratio [HR], 0.85; 95% CI, 0.82-0.89; P<.001) and men (HR, 0.88; 95% CI, 0.83-0.93; P<.001). Simvastatin was associated with lower Alzheimer disease risk for white women (HR, 0.86; 95% CI, 0.81-0.92; P<.001), white men (HR, 0.90; 95% CI, 0.82-0.99; P=.02), Hispanic women (HR, 0.82; 95% CI, 0.68-0.99; P=.04), Hispanic men (HR, 0.67; 95% CI, 0.50-0.91; P=.01), and black women (HR, 0.78; 95% CI, 0.66-0.93; P=.005). Atorvastatin was associated with a reduced risk of incident Alzheimer disease diagnosis for white women (HR, 0.84, 95% CI, 0.78-0.89), black women (HR, 0.81, 95% CI, 0.67-0.98), and Hispanic men (HR, 0.61, 95% CI, 0.42-0.89) and women (HR, 0.76, 95% CI, 0.60-0.97). Pravastatin and rosuvastatin were associated with reduced Alzheimer disease risk for white women only (HR, 0.82, 95% CI, 0.70-0.95 and HR, 0.81, 95% CI, 0.67-0.98, respectively). High statin exposure was not associated with a statistically significant lower Alzheimer disease risk among black men. The reduction in Alzheimer disease risk varied across statin molecules, sex, and race/ethnicity. Clinical trials that include racial and ethnic groups need to confirm these findings. Because statins may affect Alzheimer disease risk, physicians should consider which statin is prescribed to each patient.

Localization of the Placental BCRP/ABCG2 Transporter to Lipid Rafts: Role for Cholesterol in Mediating Efflux Activity

PubMed Central

Szilagyi, John T.; Vetrano, Anna M.; Laskin, Jeffrey D.; Aleksunes, Lauren M.

2017-01-01

Introduction The breast cancer resistance protein (BCRP/ABCG2) is an efflux transporter in the placental barrier. By transporting chemicals from the fetal to the maternal circulation, BCRP limits fetal exposure to a range of drugs, toxicants, and endobiotics such as bile acids and hormones. The purpose of the present studies was to 1) determine whether BCRP localizes to highly-ordered, cholesterol-rich lipid raft microdomains in placenta microvillous membranes, and 2) determine the impact of cholesterol on BCRP-mediated placental transport in vitro. Methods BCRP expression was analyzed in lipid rafts isolated from placentas from healthy, term pregnancies and BeWo trophoblasts by density gradient ultracentrifugation. BeWo cells were also tested for their ability to efflux BCRP substrates after treatment with the cholesterol sequestrant methyl-β-cyclodextrin (MβCD, 5mM, 1 h) or the cholesterol synthesis inhibitor pravastatin (200μM, 48 h). Results and Discussion BCRP was found to co-localize with lipid raft proteins in detergent-resistant, lipid raft-containing fractions from placental microvillous membranes and BeWo cells. Treatment of BeWo cells with MβCD redistributed BCRP protein into higher density non-lipid raft fractions. Repletion of the cells with cholesterol restored BCRP localization to lipid raft-containing fractions. Treatment of BeWo cells with MβCD or pravastatin increased cellular retention of two BCRP substrates, the fluorescent dye Hoechst 33342 and the mycotoxin zearalenone. Repletion with cholesterol restored BCRP transporter activity. Taken together, these data demonstrate that cholesterol may play a critical role in the post-translational regulation of BCRP in placental lipid rafts. PMID:28623970

Green analytical method development for statin analysis.

PubMed

Assassi, Amira Louiza; Roy, Claude-Eric; Perovitch, Philippe; Auzerie, Jack; Hamon, Tiphaine; Gaudin, Karen

2015-02-06

Green analytical chemistry method was developed for pravastatin, fluvastatin and atorvastatin analysis. HPLC/DAD method using ethanol-based mobile phase with octadecyl-grafted silica with various grafting and related-column parameters such as particle sizes, core-shell and monolith was studied. Retention, efficiency and detector linearity were optimized. Even for column with particle size under 2 μm, the benefit of keeping efficiency within a large range of flow rate was not obtained with ethanol based mobile phase compared to acetonitrile one. Therefore the strategy to shorten analysis by increasing the flow rate induced decrease of efficiency with ethanol based mobile phase. An ODS-AQ YMC column, 50 mm × 4.6 mm, 3 μm was selected which showed the best compromise between analysis time, statin separation, and efficiency. HPLC conditions were at 1 mL/min, ethanol/formic acid (pH 2.5, 25 mM) (50:50, v/v) and thermostated at 40°C. To reduce solvent consumption for sample preparation, 0.5mg/mL concentration of each statin was found the highest which respected detector linearity. These conditions were validated for each statin for content determination in high concentrated hydro-alcoholic solutions. Solubility higher than 100mg/mL was found for pravastatin and fluvastatin, whereas for atorvastatin calcium salt the maximum concentration was 2mg/mL for hydro-alcoholic binary mixtures between 35% and 55% of ethanol in water. Using atorvastatin instead of its calcium salt, solubility was improved. Highly concentrated solution of statins offered potential fluid for per Buccal Per-Mucous(®) administration with the advantages of rapid and easy passage of drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Impact of HMG-CoA reductase inhibitors on the incidence of polyomavirus-associated nephropathy in renal transplant recipients with human BK polyomavirus viremia.

PubMed

Gabardi, S; Ramasamy, S; Kim, M; Klasek, R; Carter, D; Mackenzie, M R; Chandraker, A; Tan, C S

2015-08-01

Up to 20% of renal transplant recipients (RTR) will develop human BK polyomavirus (BKPyV) viremia. BKPyV viremia is a pre-requisite of polyomavirus-associated nephropathy (PyVAN). Risk of BKPyV infections increases with immunosuppression. Currently, the only effective therapy against PyVAN is reductions in immunosuppression, but this may increase the risk of rejection. In vitro data have shown that pravastatin dramatically decreased caveolin-1 expression in human renal proximal tubular epithelial cells (HRPTEC) and suppressed BKPyV infection in these cells. Based on these data, we postulated that statin therapy may prevent the progression of BKPyV viremia to PyVAN. A multicenter, retrospective study was conducted in adult RTR transplanted between July 2005 and March 2012. All patients with documented BKPyV viremia (viral load >500 copies/mL on 2 consecutive tests) were included. Group I consisted of patients taking a statin before the BKPyV viremia diagnosis (n = 32), and Group II had no statin exposure before or after the BKPyV viremia diagnosis (n = 36). The primary endpoint was the incidence of PyVAN. Demographic data, transplant characteristics, and the degree of immunosuppression (i.e., induction/maintenance therapies, rejection treatment) were similar between the groups, with the exception of more diabetics in Group I. The incidence of PyVAN was comparable between the 2 groups (Group I = 28.1% vs. Group II = 41.7%; P = 0.312). Despite the proven in vitro effectiveness of pravastatin preventing BKPyV infection in HRPTEC, statins at doses maximized for cholesterol lowering, in RTR with BKPyV viremia, did not prevent progression to PyVAN. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Impact of HMG-CoA reductase inhibitors on the incidence of polyomavirus-associated nephropathy in renal transplant recipients with human BK polyomavirus viremia

PubMed Central

Gabardi, S.; Ramasamy, S.; Kim, M.; Klasek, R.; Carter, D.; Mackenzie, M.R.; Chandraker, A.; Tan, C.S.

2015-01-01

Introduction Up to 20% of renal transplant recipients (RTR) will develop human BK polyomavirus (BKPyV) viremia. BKPyV viremia is a pre-requisite of polyomavirus-associated nephropathy (PyVAN). Risk of BKPyV infections increases with immunosuppression. Currently, the only effective therapy against PyVAN is reductions in immunosuppression; but this may increase the risk of rejection. In vitro data have shown that pravastatin dramatically decreased caveolin-1 expression in human renal proximal tubular epithelial cells (HRPTEC) and suppressed BKPyV infection in these cells. Based on these data, we postulated that statin therapy may prevent the progression of BKPyV viremia to PyVAN. Patients and methods A multicenter, retrospective study was conducted in adult RTR transplanted between July 2005 and March 2012. All patients with documented BKPyV viremia (viral load >500 copies/mL on 2 consecutive tests) were included. Group I consisted of patients taking a statin before the BKPyV viremia diagnosis (n = 32), and Group II had no statin exposure before or after the BKPyV viremia diagnosis (n = 36). The primary endpoint was the incidence of PyVAN. Results Demographic data, transplant characteristics, and the degree of immunosuppression (i.e., induction/maintenance therapies, rejection treatment) were similar between the groups, with the exception of more diabetics in Group I. The incidence of PyVAN was comparable between the 2 groups (Group I = 28.1% vs. Group II = 41.7%; P = 0.312). Conclusions Despite the proven in vitro effectiveness of pravastatin preventing BKPyV infection in HRPTEC, statins at doses maximized for cholesterol lowering, in RTR with BKPyV viremia, did not prevent progression to PyVAN. PMID:25989423

Biliary excretion of pravastatin and taurocholate in rats with bile salt export pump (Bsep) impairment.

PubMed

Cheng, Yaofeng; Freeden, Chris; Zhang, Yueping; Abraham, Pamela; Shen, Hong; Wescott, Debra; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong

2016-07-01

The bile salt export pump (BSEP) is expressed on the canalicular membrane of hepatocytes regulating liver bile salt excretion, and impairment of BSEP function may lead to cholestasis in humans. This study explored drug biliary excretion, as well as serum chemistry, individual bile acid concentrations and liver transporter expressions, in the SAGE Bsep knockout (KO) rat model. It was observed that the Bsep protein in KO rats was decreased to 15% of that in the wild type (WT), as quantified using LC-MS/MS. While the levels of Ntcp and Mrp2 were not significantly altered, Mrp3 expression increased and Oatp1a1 decreased in KO animals. Compared with the WT rats, the KO rats had similar serum chemistry and showed normal liver transaminases. Although the total plasma bile salts and bile flow were not significantly changed in Bsep KO rats, individual bile acids in plasma and liver demonstrated variable changes, indicating the impact of Bsep KO. Following an intravenous dose of deuterium labeled taurocholic acid (D4-TCA, 2 mg/kg), the D4-TCA plasma exposure was higher and bile excretion was delayed by approximately 0.5 h in the KO rats. No differences were observed for the pravastatin plasma concentration-time profile or the biliary excretion after intravenous administration (1 mg/kg). Collectively, the results revealed that these rats have significantly lower Bsep expression, therefore affecting the biliary excretion of endogenous bile acids and Bsep substrates. However, these rats are able to maintain a relatively normal liver function through the remaining Bsep protein and via the regulation of other transporters. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Recommendation to Exclude Bile-Duct-Cannulated Rats with Hyperbilirubinemia for Proper Conduct of Biliary Drug Excretion Studies.

PubMed

Kato, Koji; Hasegawa, Yoshitaka; Iwata, Katsuya; Ichikawa, Takuya; Yahara, Tohru; Tsuji, Satoshi; Sugiura, Masayuki; Yamaguchi, Jun-Ichi

2016-08-01

Hyperbilirubinemia (HB) is sometimes encountered following bile-duct cannulation in rats. It possibly originates from the reduced functioning of multidrug resistance-associated protein 2 (Mrp2) and subsequent adaptive alterations in the expression of Mrp3 and the organic anion transporting polypeptides (Oatps). Our aim was to clarify the importance of excluding bile-duct-cannulated (BDC) rats with HB for proper conduct of drug excretion studies. We detected HB [serum total bilirubin concentration (TBIL) ≥0.20 mg/dl] in 16% of all BDC rats prepared. The serum activities of aspartate aminotransferase, alanine aminotransferase, leucine aminopeptidase, and alkaline phosphatase were within the respective normal ranges in the BDC rats with mild HB (TBIL, 0.20-0.79 mg/dl), indicating the absence of hepatic failure. In the pharmacokinetics of pravastatin, an Oatps/Mrp2 probe drug in the BDC rats, the apparent volume of distribution and the clearance were smaller in the mild HB group as compared with the normal group, suggesting the reduction of apparent hepatic uptake and hepatobiliary elimination. The biliary excretion (percentage of dose) was significantly reduced by 54%, suggesting that the biliary efflux activity via Mrp2 was reduced to a greater extent relative to metabolic activity in hepatocytes. The serum γ-glutamyltransferase (GGT) activity correlated with TBIL and inversely correlated with biliary excretion of pravastatin, a finding which could serve as a clue to uncover the regulatory system involving cooperation between GGT and Mrp2. In conclusion, BDC rats with HB, however mild, should be excluded from drug excretion studies to avoid the risk of underestimation of the biliary excretion of drugs. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Studies on the Antibacterial Effects of Statins - In Vitro and In Vivo

PubMed Central

Bergman, Peter; Linde, Charlotte; Pütsep, Katrin; Pohanka, Anton; Normark, Staffan; Henriques-Normark, Birgitta; Andersson, Jan; Björkhem-Bergman, Linda

2011-01-01

Background Statin treatment has been associated with a beneficial outcome on respiratory tract infections. In addition, previous in vitro and in vivo experiments have indicated favorable effects of statins in bacterial infections. Aim The aim of the present study was to elucidate possible antibacterial effects of statins against primary pathogens of the respiratory tract. Methods MIC-values for simvastatin, fluvastatin and pravastatin against S. pneumoniae, M. catarrhalis and H. influenzae were determined by traditional antibacterial assays. A BioScreen instrument was used to monitor effects of statins on bacterial growth and to assess possible synergistic effects with penicillin. Bacterial growth in whole blood and serum from healthy volunteers before and after a single dose of simvastatin, fluvastatin and penicillin (positive control) was determined using a blood culture system (BactAlert). Findings The MIC-value for simvastatin against S pneumoniae and M catarrhalis was 15 µg/mL (36 mmol/L). Fluvastatin and Pravastatin showed no antibacterial effect in concentrations up to 100 µg/mL (230 µmol/L). Statins did not affect growth or viability of H influenzae. Single doses of statins given to healthy volunteers did not affect growth of pneumococci, whereas penicillin efficiently killed all bacteria. Conclusions Simvastatin at high concentrations 15 µg/mL (36 µmol/L) rapidly kills S pneumoniae and M catarrhalis. However, these concentrations by far exceed the concentrations detected in human blood during simvastatin therapy (1–15 nmol/L) and single doses of statins given to healthy volunteers did not improve antibacterial effects of whole blood. Thus, a direct bactericidal effect of statins in vivo is probably not the mechanism behind the observed beneficial effect of statins against various infections. PMID:21912631

Localization of the placental BCRP/ABCG2 transporter to lipid rafts: Role for cholesterol in mediating efflux activity.

PubMed

Szilagyi, John T; Vetrano, Anna M; Laskin, Jeffrey D; Aleksunes, Lauren M

2017-07-01

The breast cancer resistance protein (BCRP/ABCG2) is an efflux transporter in the placental barrier. By transporting chemicals from the fetal to the maternal circulation, BCRP limits fetal exposure to a range of drugs, toxicants, and endobiotics such as bile acids and hormones. The purpose of the present studies was to 1) determine whether BCRP localizes to highly-ordered, cholesterol-rich lipid raft microdomains in placenta microvillous membranes, and 2) determine the impact of cholesterol on BCRP-mediated placental transport in vitro. BCRP expression was analyzed in lipid rafts isolated from placentas from healthy, term pregnancies and BeWo trophoblasts by density gradient ultracentrifugation. BeWo cells were also tested for their ability to efflux BCRP substrates after treatment with the cholesterol sequestrant methyl-β-cyclodextrin (MβCD, 5 mM, 1 h) or the cholesterol synthesis inhibitor pravastatin (200 μM, 48 h). BCRP was found to co-localize with lipid raft proteins in detergent-resistant, lipid raft-containing fractions from placental microvillous membranes and BeWo cells. Treatment of BeWo cells with MβCD redistributed BCRP protein into higher density non-lipid raft fractions. Repletion of the cells with cholesterol restored BCRP localization to lipid raft-containing fractions. Treatment of BeWo cells with MβCD or pravastatin increased cellular retention of two BCRP substrates, the fluorescent dye Hoechst 33342 and the mycotoxin zearalenone. Repletion with cholesterol restored BCRP transporter activity. Taken together, these data demonstrate that cholesterol may play a critical role in the post-translational regulation of BCRP in placental lipid rafts. Copyright © 2017 Elsevier Ltd. All rights reserved.

Estimating the extent of reporting to FDA: a case study of statin-associated rhabdomyolysis.

PubMed

McAdams, Mara; Staffa, Judy; Dal Pan, Gerald

2008-03-01

To estimate the extent of reporting to FDA through statin-associated rhabdomyolysis data. Data included incidence rates (IRs) of hospitalized rhabdomyolysis among statin users from a population-based study, and comparable reported AERS cases and national estimates of statin use from an AERS analysis. Using IRs, national estimates of statin use and average days supply per prescription, we estimated the number of US statin-associated cases of hospitalized rhabdomyolysis. We compared this estimate to the observed number of cases reported to FDA to evaluate the extent of reporting. We repeated this method for atorvastatin, cerivastatin, pravastatin, and simvastatin and statin combinations. We performed sensitivity analyses to check for biases such as misclassification of statin use and cohort selection bias. We evaluated potential time-dependent cerivastatin reporting by a "Dear Health Care Provider (DHCP)" letter. The estimated extent of reporting to FDA varied by statin (atorvastatin, 5.0%; cerivastatin, 31.2%; simvastatin, 14.2%; all four combined, 17.7%; and non-cerivastatin statins combined, 9.9%). No pravastatin-associated cohort cases occurred. Across a reasonable value range, sensitivity analyses did not significantly alter the results; overall the cohort was similar to national statin-users. There was a large increase in AERS reports after the cerivastatin DHCP letter and the estimated extent of reporting increased from 14.8 to 35.0%. The extent of reporting of adverse events to FDA varied by statin and may be influenced by publicity. For statins-associated rhabdomyolysis, the estimated extent of reporting appears to range from 5 to 30% but in the absence of stimulated reporting appears to be 5-15%. Copyright 2008 John Wiley & Sons, Ltd.

Statins Increase Plasminogen Activator Inhibitor Type 1 Gene Transcription through a Pregnane X Receptor Regulated Element

PubMed Central

Stanley, Frederick M.; Linder, Kathryn M.; Cardozo, Timothy J.

2015-01-01

Plasminogen activator inhibitor type 1 (PAI-1) is a multifunctional protein that has important roles in inflammation and wound healing. Its aberrant regulation may contribute to many disease processes such as heart disease. The PAI-1 promoter is responsive to multiple inputs including cytokines, growth factors, steroids and oxidative stress. The statin drugs, atorvastatin, mevastatin and rosuvastatin, increased basal and stimulated expression of the PAI-1 promoter 3-fold. A statin-responsive, nuclear hormone response element was previously identified in the PAI-1 promoter, but it was incompletely characterized. We characterized this direct repeat (DR) of AGGTCA with a 3-nucleotide spacer at -269/-255 using deletion and directed mutagenesis. Deletion or mutation of this element increased basal transcription from the promoter suggesting that it repressed PAI-1 transcription in the unliganded state. The half-site spacing and the ligand specificity suggested that this might be a pregnane X receptor (PXR) responsive element. Computational molecular docking showed that atorvastatin, mevastatin and rosuvastatin were structurally compatible with the PXR ligand-binding pocket in its agonist conformation. Experiments with Gal4 DNA binding domain fusion proteins showed that Gal4-PXR was activated by statins while other DR + 3 binding nuclear receptor fusions were not. Overexpression of PXR further enhanced PAI-1 transcription in response to statins. Finally, ChIP experiments using Halo-tagged PXR and RXR demonstrated that both components of the PXR-RXR heterodimer bound to this region of the PAI-1 promoter. PMID:26379245

Rosuvastatin ameliorates cognitive impairment in rats fed with high-salt and cholesterol diet via inhibiting acetylcholinesterase activity and amyloid beta peptide aggregation.

PubMed

Husain, I; Akhtar, M; Abdin, M Zainul; Islamuddin, M; Shaharyar, M; Najmi, A K

2018-04-01

Amyloid beta (Aβ) peptide aggregation and cholinergic neurodegeneration are involved in the development of cognitive impairment. Therefore, in this article, we examined rosuvastatin (RSV), an oral hypolipidemic drug, to determine its potential as a dual inhibitor of acetylcholinesterase (AChE) and Aβ peptide aggregation for the treatment of cognitive impairment. Molecular docking study was done to examine the affinity of RSV with Aβ 1-42 and AChE in silico. We also employed neurobehavioral activity tests, biochemical estimation, and histopathology to study the anti-Aβ 1-42 aggregation capability of RSV in vivo. Molecular docking study provided evidence that RSV has the best binding conformer at its receptor site or active site of an enzyme. The cognitive impairment in female Wistar rats was induced by high-salt and cholesterol diet (HSCD) ad libitum for 8 weeks. RSV ameliorated serum cholesterol level, AChE activity, and Aβ 1-42 peptide aggregations in HSCD induced cognitive impairment. In addition, RSV-treated rats showed greater scores in the open field (locomotor activity) test. Moreover, the histopathological studies in the hippocampus and cortex of rat brain also supported that RSV markedly reduced the cognitive impairment and preserved the normal histoarchitectural pattern of the hippocampus and cortex. Taken together, these data indicate that RSV may act as a dual inhibitor of AChE and Aβ 1-42 peptide aggregation, therefore suggesting a therapeutic strategy for cognitive impairment treatment.

Improved anti-hyperlipidemic activity of Rosuvastatin Calcium via lipid nanoparticles: Pharmacokinetic and pharmacodynamic evaluation.

PubMed

Dudhipala, Narendar; Veerabrahma, Kishan

2017-01-01

The intent of this investigation was to improve pharmacokinetic (PK) and pharmacodynamic (PD) effects of Rosuvastatin calcium (RC) by solid lipid nanoparticles (SLNs). RC is anti-hyperlipidemic drug with low oral bioavailability (20%) due to first-pass metabolism. Hot homogenization followed by ultrasonication method was used to prepare RC-SLNs with stearic acid, glyceryl behenate and glyceryl trilaurate as lipid matrices, egg lecithin and poloxamer 188 as surfactants. The prepared SLNs were tested for particle size, PDI, zeta potential (ZP), entrapment efficiency (EE), drug content and in vitro release. Further, PK and PD studies were conducted on selected SLNs. No changes in physical stability of the optimized SLN were observed at refrigerated and room temperature for 90days. SLNs prepared with glyceryl trilaurate having average size of 67.21±1.71nm, PDI of 0.25±0.01, ZP of -28.93±0.84mV with 93.51±0.34% EE was considered as optimized. DSC and XRD studies revealed that no interaction occurred between the drug and lipid. SEM and TEM studies revealed that SLNs were nearly spherical in shape. PK studies showed improvement in the oral bioavailability (extent of absorption) of SLNs by 4.6-fold when compared to that of suspension. PD study of SLNs in hyperlipidemic rats exhibited a decrease in lipid profile for 36h, while a suspension exhibited for 24h. Copyright © 2016 Elsevier B.V. All rights reserved.

Extreme all-cause mortality in JUPITER requires reexamination of vital records.

PubMed

Serebruany, Victor L

2011-01-01

To compare all-cause mortality in JUPITER with other statin trials at 21 months of follow-up. Outcome advantages including all-cause mortality reduction yielded from the JUPITER trial support aggressive use of rosuvastatin and, perhaps by extension, other statins for primary prevention. Despite enrolling apparently healthy subjects and early trial termination at 21 months of mean follow-up, JUPITER revealed very high all-cause mortality in both the placebo (2.8%) and rosuvastatin (2.2%) arms. Comparison of all-cause mortality prorated for 21 months in 10 primary prevention studies and 1 acute coronary syndromes statin trial. The all-cause mortality in JUPITER was more than twice that of the average of primary prevention studies, matching well only with specific trials designed in diabetics (ASPEN or CARDS), early hypertension studies (ALLHAT-LLT) or a trial in patients with acute coronary syndromes (PROVE IT). Since the 'play of chance' is unlikely to explain these discrepancies due to excellent baseline match, excess death rates and all-cause mortality rates in both JUPITER arms must be questioned. It may be important that the study sponsor self-monitored sites. Excess all-cause mortality rates in the apparently relatively healthy JUPITER population are alarming and require independent verification. If, indeed, the surprising outcomes in JUPITER are successfully challenged, and considering established harm of statins with regard to rhabdomyolysis as well as, potentially, diabetes, millions of patients may find better and safer options for primary prevention of vascular events. Copyright © 2011 S. Karger AG, Basel.

Therapeutic neovascularization by nanotechnology-mediated cell-selective delivery of pitavastatin into the vascular endothelium.

PubMed

Kubo, Mitsuki; Egashira, Kensuke; Inoue, Takahiro; Koga, Jun-ichiro; Oda, Shinichiro; Chen, Ling; Nakano, Kaku; Matoba, Tetsuya; Kawashima, Yoshiaki; Hara, Kaori; Tsujimoto, Hiroyuki; Sueishi, Katsuo; Tominaga, Ryuji; Sunagawa, Kenji

2009-06-01

Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization. In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice. NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.

Pharmaceutical Industry-Sponsored Meals and Physician Prescribing Patterns for Medicare Beneficiaries.

PubMed

DeJong, Colette; Aguilar, Thomas; Tseng, Chien-Wen; Lin, Grace A; Boscardin, W John; Dudley, R Adams

2016-08-01

The association between industry payments to physicians and prescribing rates of the brand-name medications that are being promoted is controversial. In the United States, industry payment data and Medicare prescribing records recently became publicly available. To study the association between physicians' receipt of industry-sponsored meals, which account for roughly 80% of the total number of industry payments, and rates of prescribing the promoted drug to Medicare beneficiaries. Cross-sectional analysis of industry payment data from the federal Open Payments Program for August 1 through December 31, 2013, and prescribing data for individual physicians from Medicare Part D, for all of 2013. Participants were physicians who wrote Medicare prescriptions in any of 4 drug classes: statins, cardioselective β-blockers, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers (ACE inhibitors and ARBs), and selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs). We identified physicians who received industry-sponsored meals promoting the most-prescribed brand-name drug in each class (rosuvastatin, nebivolol, olmesartan, and desvenlafaxine, respectively). Data analysis was performed from August 20, 2015, to December 15, 2015. Receipt of an industry-sponsored meal promoting the drug of interest. Prescribing rates of promoted drugs compared with alternatives in the same class, after adjustment for physician prescribing volume, demographic characteristics, specialty, and practice setting. A total of 279 669 physicians received 63 524 payments associated with the 4 target drugs. Ninety-five percent of payments were meals, with a mean value of less than $20. Rosuvastatin represented 8.8% (SD, 9.9%) of statin prescriptions; nebivolol represented 3.3% (7.4%) of cardioselective β-blocker prescriptions; olmesartan represented 1.6% (3.9%) of ACE inhibitor and ARB prescriptions; and desvenlafaxine represented 0.6% (2.6%) of SSRI and SNRI prescriptions. Physicians who received a single meal promoting the drug of interest had higher rates of prescribing rosuvastatin over other statins (odds ratio [OR], 1.18; 95% CI, 1.17-1.18), nebivolol over other β-blockers (OR, 1.70; 95% CI, 1.69-1.72), olmesartan over other ACE inhibitors and ARBs (OR, 1.52; 95% CI, 1.51-1.53), and desvenlafaxine over other SSRIs and SNRIs (OR, 2.18; 95% CI, 2.13-2.23). Receipt of additional meals and receipt of meals costing more than $20 were associated with higher relative prescribing rates. Receipt of industry-sponsored meals was associated with an increased rate of prescribing the brand-name medication that was being promoted. The findings represent an association, not a cause-and-effect relationship.

A tale of three labels: translating the JUPITER trial data into regulatory claims.

PubMed

Ridker, Paul M

2011-08-01

Whether a pivotal randomized trial will be interpreted in a similar and consistent manner by different regulatory agencies is uncertain as policy perspectives may play a role in data interpretation and the translation of trial results into clinical practice. Using a contemporary example, to compare and contrast regulatory claims in the United States, Europe, and Canada that derive from a pivotal clinical trial. The recently completed JUPITER trial of rosuvastatin as compared to placebo conducted among 17,802 men and women with LDL-C <130 mg/dL and hsCRP ≥ 2 mg/L, provides the only available data on rosuvastatin for primary prevention of cardiovascular disease. Thus, the JUPITER trial provides an opportunity to compare and contrast how regulatory agencies in the United States, Canada, and Europe chose to interpret an identical database. Labeling indications based on earlier statin trials of primary and secondary prevention were also reviewed. JUPITER demonstrated a 44% reduction (p < 0.000001) in the trial pre-specified primary endpoint (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, coronary revascularization, or cardiovascular death) with no evidence of heterogeneity across geographic regions. In response to these data, the US Food and Drug Administration label for rosuvastatin in primary prevention came closest to the actual JUPITER trial population by stipulating that those eligible for treatment should be older men and women with hsCRP >2 mg/L, plus one additional risk factor for heart disease. The Canadian label is silent on age and hsCRP (the major trial inclusion criterion), stipulating instead that treatment can be considered for those with 'at least two conventional risk factors for cardiovascular disease,' a group more inclusive than that studied. In contrast, the European Medicines Agency label limits treatment only to 'high risk individuals' ignoring hsCRP and using instead a post hoc definition of 'high risk' that comprised a subgroup of less than 10% of the study population who contributed but 67 events to the study total and did not show statistical significance when compared to placebo. None of the regulatory labels included the trial primary endpoint; instead, each focused on separate and different components of the primary endpoint. Similar discrepancies were found between European and North American regulatory agencies with regard to earlier pivotal trials of statins for primary prevention, but not for secondary prevention. The JUPITER experience represents a case study and is not a systematic review of the regulatory decision process. Labeling indications can vary widely in different regulatory environments even when based on the same trial data.

Resolution of Graves' disease after renal transplantation.

PubMed

Lee, Yvonne; Butani, Lavjay; Glaser, Nicole; Nguyen, Stephanie

2016-06-01

We report a case of an adolescent boy with Down's syndrome and ESRD on hemodialysis who developed mild Graves' disease that was not amenable to radioablation, surgery, or ATDs. After 14 months of observation without resolution of Graves' disease, he successfully received a DDRT with a steroid minimization protocol. Thymoglobulin and a three-day course of steroids were used for induction and he was started on tacrolimus, MMF, and pravastatin for maintenance transplant immunosuppression. One month after transplantation, all biochemical markers and antibody profiling for Graves' disease had resolved and remain normal one yr later. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Assay of lovastatin containing dietary supplement by LC-MS/MS under MRM condition.

PubMed

Di Donna, Leonardo; Bartella, Lucia; Napoli, Anna; Sindona, Giovanni; Mazzotti, Fabio

2018-05-16

Monacolin K, the active ingredient present in dietary supplement, is a nutraceutical whose health benefits have been widely documented. A fast approach for the assay of lovastatin in both form, lactone and acid, by mass spectrometry is presented. The quantitative assay is carried out by HPLC-MS/MS using the multiple reaction monitoring (MRM) mode and simvastatin and pravastatin as internal standards. The accuracy values ranged from 97 to 101%; the analytical parameters values of LOQ, LOD, recovery and reproducibility, were calculated analyzing fortified samples, confirming the reliability of the proposed approach. This article is protected by copyright. All rights reserved.

Statin Effects on Aggression: Results from the UCSD Statin Study, a Randomized Control Trial

PubMed Central

Golomb, Beatrice A.; Dimsdale, Joel E.; Koslik, Hayley J.; Evans, Marcella A.; Lu, Xun; Rossi, Steven; Mills, Paul J.; Criqui, Michael H.

2015-01-01

Background Low/ered cholesterol is linked to aggression in some study designs. Cases/series have reported reproducible aggression increases on statins, but statins also bear mechanisms that could reduce aggression. Usual statin effects on aggression have not been characterized. Methods 1016 adults (692 men, 324 postmenopausal women) underwent double-blind sex-stratified randomization to placebo, simvastatin 20mg, or pravastatin 40mg (6 months). The Overt-Aggression-Scale-Modified–Aggression-Subscale (OASMa) assessed behavioral aggression. A significant sex-statin interaction was deemed to dictate sex-stratified analysis. Exploratory analyses assessed the influence of baseline-aggression, testosterone-change (men), sleep and age. Results The sex-statin interaction was significant (P=0.008). In men, statins tended to decrease aggression, significantly so on pravastatin: difference=-1.0(SE=0.49)P=0.038. Three marked outliers (OASMa-change ≥40 points) offset otherwise strong significance-vs-placebo: statins:-1.3(SE=0.38)P=0.0007; simvastatin:-1.4(SE=0.43)P=0.0011; pravastatin:-1.2(SE=0.45)P=0.0083. Age≤40 predicted greater aggression-decline on statins: difference=-1.4(SE=0.64)P=0.026. Aggression-protection was emphasized in those with low baseline aggression: age<40-and-low-baseline-aggression (N=40) statin-difference-vs-placebo=-2.4(SE=0.71)P=0.0016. Statins (especially simvastatin) lowered testosterone, and increased sleep problems. Testosterone-drop on statins predicted aggression-decline: β=0.64(SE=0.30)P=0.034, particularly on simvastatin: β=1.29(SE=0.49)P=0.009. Sleep-worsening on statins significantly predicted aggression-increase: β=2.2(SE=0.55)P<0.001, particularly on simvastatin (potentially explaining two of the outliers): β=3.3(SE=0.83)P<0.001. Among (postmenopausal) women, a borderline aggression-increase on statins became significant with exclusion of one younger, surgically-menopausal woman (N=310) β=0.70(SE=0.34)P=0.039. The increase was significant, without exclusions, for women of more typical postmenopausal age (≥45): (N=304) β=0.68(SE=0.34)P=0.048 – retaining significance with modified age-cutoffs (≥50 or ≥55). Significance was observed separately for simvastatin. The aggression-increase in women on statins was stronger in those with low baseline aggression (N=175) β=0.84(SE=0.30)P=0.006. No statin effect on whole blood serotonin was observed; and serotonin-change did not predict aggression-change. Conclusion Statin effects on aggression differed by sex and age: Statins generally decreased aggression in men; and generally increased aggression in women. Both findings were selectively prominent in participants with low baseline aggression – bearing lower change-variance, rendering an effect more readily evident. Trial Registration Clinicaltrials.gov NCT00330980 PMID:26132393

Effect of resveratrol and rosuvastatin on experimental diabetic nephropathy in rats.

PubMed

Hussein, Mohamed M A; Mahfouz, Mohamed K

2016-08-01

The development of diabetic nephropathy (DN) relays mainly on control of blood glucose and restrains hyperglycemic-induced oxidative stress. Hence, the effect administration of resveratrol (RSV) (5mg/kg) alone or in combination with rosuvastatin (RSU) (10mg/kg) on development and progression of diabetic nephropathy (DN) was evaluated. Oral treatment of diabetic rats with RSV alone or co-administered with RSU improved renal dysfunction indicated by a significant decrease in serum creatinine, urinary protein and urinary TGF-β1 when compared with diabetic control rats. Also, a significant increase in body weight, relative kidney weight with a significant decrease in serum glucose and glycated hemoglobin in diabetic treated groups when compared with diabetic control group. Hyperglycemic-induced oxidative stress in diabetic control rats indicated by a significant decrease in renal activities of catalase, superoxide dismutase, glutathione peroxidase and reduced glutathione level with a significant increase in malondialdehyde levels. However, oral treatment of diabetic rats with RSV alone or co-administered with RSU improved the antioxidant status back to control values. Similarly, mRNA analysis of quantitative real time-PCR substantiated that RSV with RSU notably normalizes the renal expression of TGF-β1, fibronectin, NF-κB/p65, Nrf2, Sirt1 and FoxO1 in the diabetic group of rats. The histopathological observations of the combined treated diabetic rats effectively protect the kidneys from hyperglycemic-induced oxidative damage. These findings confirmed the renoprotective effects of RSV with RSU treatment through improving glycemic control and attenuating oxidative stress damage in renal tissues of diabetic rats. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Generic atorvastatin, the Belgian statin market and the cost-effectiveness of statin therapy.

PubMed

Simoens, Steven; Sinnaeve, Peter R

2013-02-01

This study examines how the market entry of generic atorvastatin influences the Belgian statin market and the cost-effectiveness of statin therapy. Using IMS Health data, the Belgian 2000-2011 statin market was analyzed in terms of total expenditure, annual price of statin treatment, and patient numbers. A simulation analysis projected statin market shares from 2012 to 2015 following market entry of generic atorvastatin. This analysis was based on three scenarios regarding the number of patients taking specific statins. Savings associated with an atorvastatin price reduction of 50-70 % were calculated. A literature review of economic evaluations assessed the cost-effectiveness of generic atorvastatin. Statin expenditure increased from €113 million in 2000 to €285 million in 2011 due to higher expenditure on atorvastatin and rosuvastatin. Although the number of patients treated with simvastatin increased by nearly 800 %, the resulting increase in expenditure was partially offset by price reductions. Atorvastatin is projected to become the dominant product in the Belgian statin market (market share of 47-66 % by 2015). Annual savings would attain €108.6-€153.7 million for a 50 % reduction in the atorvastatin price and €152.0-€215.2 million for a 70 % price reduction. The literature suggests that generic atorvastatin is cost-effective as compared to simvastatin. The limited evidence about the cost-effectiveness of rosuvastatin as compared with generic atorvastatin is inconclusive. Generic atorvastatin is cost-effective as compared to simvastatin, is projected to become the dominant product in the Belgian statin market and is expected to generate substantial savings to health care payers.

Preparation and optimization of tablets containing a self-nano-emulsifying drug delivery system loaded with rosuvastatin.

PubMed

Salem, Heba F; Kharshoum, Rasha M; Halawa, Abdel Khalek A; Naguib, Demiana M

2018-06-01

Rosuvastatin (ROS) calcium is the latest synthetic drug in the statin group that has an anti-hyperlipidemic activity. It is available as tablets, and its poor aqueous solubility, slow dissolution rate and low-absorption extent result in less than 20% bioavailability and about 80% being excreted unchanged in the feces without absorption. To utilize nanotechnology to reformulate ROS as a self-nano-emulsifying drug delivery system (SNEDDS), and utilizing design optimization to fabricate the SNEDDS as a tablet. The solubility of ROS in different oils, surfactants and co-surfactants was tested. Pseudo-ternary phase diagrams were developed and various SNEDDS formulations were prepared and evaluated regarding globule size, self-emulsification, viscosity and transmittance. The optimized system was examined using transmission electron microscopy. The self-nano-emulsifying tablets were prepared using two types of nano-silica and different percentages of Avicel as a binder and Ac-Di-Sol as a disintegrant. The prepared tablets were evaluated for their physicochemical properties. Bioavailability in human volunteers was assessed. A SNEDDS system was successfully developed with a droplet size range of 15 nm and a composition of 10% Labrafac, 80% Cremophore RH40 and 10% Propylene glycol. The optimized tablet formula contained: hydrophilic nano-silica, 3% Ac-Di-Sol and 30% Avicel. The pharmacokinetic study revealed that the bioavailability was enhanced by more than 2.4-fold compared with the commercially available tablet. Tablets containing SNEDDS loaded with ROS represent a promising novel formula that has higher gastrointestinal absorption and enhanced systemic bioavailability.

Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism

PubMed Central

Gu, Mingxia; Mordwinkin, Nicholas M.; Kooreman, Nigel G.; Lee, Jaecheol; Wu, Haodi; Hu, Shijun; Churko, Jared M.; Diecke, Sebastian; Burridge, Paul W.; He, Chunjiang; Barron, Frances E.; Ong, Sang-Ging; Gold, Joseph D.; Wu, Joseph C.

2015-01-01

Aims High-fat diet-induced obesity (DIO) is a major contributor to type II diabetes and micro- and macro-vascular complications leading to peripheral vascular disease (PVD). Metabolic abnormalities of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from obese individuals could potentially limit their therapeutic efficacy for PVD. The aim of this study was to compare the function of iPSC-ECs from normal and DIO mice using comprehensive in vitro and in vivo assays. Methods and results Six-week-old C57Bl/6 mice were fed with a normal or high-fat diet. At 24 weeks, iPSCs were generated from tail tip fibroblasts and differentiated into iPSC-ECs using a directed monolayer approach. In vitro functional analysis revealed that iPSC-ECs from DIO mice had significantly decreased capacity to form capillary-like networks, diminished migration, and lower proliferation. Microarray and ELISA confirmed elevated apoptotic, inflammatory, and oxidative stress pathways in DIO iPSC-ECs. Following hindlimb ischaemia, mice receiving intramuscular injections of DIO iPSC-ECs had significantly decreased reperfusion compared with mice injected with control healthy iPSC-ECs. Hindlimb sections revealed increased muscle atrophy and presence of inflammatory cells in mice receiving DIO iPSC-ECs. When pravastatin was co-administered to mice receiving DIO iPSC-ECs, a significant increase in reperfusion was observed; however, this beneficial effect was blunted by co-administration of the nitric oxide synthase inhibitor, Nω-nitro-l-arginine methyl ester. Conclusion This is the first study to provide evidence that iPSC-ECs from DIO mice exhibit signs of endothelial dysfunction and have suboptimal efficacy following transplantation in a hindlimb ischaemia model. These findings may have important implications for future treatment of PVD using iPSC-ECs in the obese population. PMID:25368203

Efficacy, safety and tolerability of ongoing statin plus ezetimibe versus doubling the ongoing statin dose in hypercholesterolemic Taiwanese patients: an open-label, randomized clinical trial

PubMed Central

2012-01-01

Background Reducing low-density lipoprotein cholesterol (LDL-C) is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia. Methods This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83) to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg) or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg) for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks. Results At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026) and total cholesterol (20.8% vs 12.2%, p = 0.0003). Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6%) vs doubling statin (41.2%), but the difference was not statistically significant (p = 0.1675). The safety and tolerability profiles were similar between treatments. Conclusion Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing. Trial registration Registered at ClinicalTrials.gov: NCT00652327 PMID:22621316

Effectiveness of statins for secondary prevention in elderly patients after acute myocardial infarction: an evaluation of class effect

PubMed Central

Zhou, Zheng; Rahme, Elham; Abrahamowicz, Michal; Tu, Jack V.; Eisenberg, Mark J.; Humphries, Karin; Austin, Peter C.; Pilote, Louise

2005-01-01

Background Clinical trials have shown the benefits of statins after acute myocardial infarction (AMI). However, it is unclear whether different statins exert a similar effect in reducing the incidence of recurrent AMI and death when used in clinical practice. Methods We conducted a retrospective cohort study (1997–2002) to compare 5 statins using data from medical administrative databases in 3 provinces (Quebec, Ontario and British Columbia). We included patients aged 65 years and over who were discharged alive after their first AMI-related hospital stay and who began statin treatment within 90 days after discharge. The primary end point was the combined outcome of recurrent AMI or death from any cause. The secondary end point was death from any cause. Adjusted hazard ratios (HRs) for each statin compared with atorvastatin as the reference drug were estimated using Cox proportional hazards regression analysis. Results A total of 18 637 patients were prescribed atorvastatin (n = 6420), pravastatin (n = 4480), simvastatin (n = 5518), lovastatin (n = 1736) or fluvastatin (n = 483). Users of different statins showed similar baseline characteristics and patterns of statin use. The adjusted HRs (and 95% confidence intervals) for the combined outcome of AMI or death showed that each statin had similar effects when compared with atorvastatin: pravastatin 1.00 (0.90–1.11), simvastatin 1.01 (0.91– 1.12), lovastatin 1.09 (0.95–1.24) and fluvastatin 1.01 (0.80– 1.27). The results did not change when death alone was the end point, nor did they change after adjustment for initial daily dose or after censoring of patients who switched or stopped the initial statin treatment. Interpretation Our results suggest that, under current usage, statins are equally effective for secocondary prevention in elderly patients after AMI. PMID:15851712

Attenuation of NADPH oxidase activation and glomerular filtration barrier remodeling with statin treatment.

PubMed

Whaley-Connell, Adam; Habibi, Javad; Nistala, Ravi; Cooper, Shawna A; Karuparthi, Poorna R; Hayden, Melvin R; Rehmer, Nathan; DeMarco, Vincent G; Andresen, Bradley T; Wei, Yongzhong; Ferrario, Carlos; Sowers, James R

2008-02-01

Activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase by angiotensin II is integral to the formation of oxidative stress in the vasculature and the kidney. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibition is associated with reductions of oxidative stress in the vasculature and kidney and associated decreases in albuminuria. Effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition on oxidative stress in the kidney and filtration barrier integrity are poorly understood. To investigate, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and renin-angiotensin system activation, and an immortalized murine podocyte cell line. We treated young, male Ren2 and Sprague-Dawley rats with rosuvastatin (20 mg/kg IP) or placebo for 21 days. Compared with controls, we observed increases in systolic blood pressure, albuminuria, renal NADPH oxidase activity, and 3-nitrotryosine staining, with reductions in the rosuvastatin-treated Ren2. Structural changes on light and transmission electron microscopy, consistent with periarteriolar fibrosis and podocyte foot-process effacement, were attenuated with statin treatment. Nephrin expression was diminished in the Ren2 kidney and trended to normalize with statin treatment. Angiotensin II-dependent increases in podocyte NADPH oxidase activity and subunit expression (NOX2, NOX4, Rac, and p22(phox)) and reactive oxygen species generation were decreased after in vitro statin treatment. These data support a role for increased NADPH oxidase activity and subunit expression with resultant reactive oxygen species formation in the kidney and podocyte. Furthermore, statin attenuation of NADPH oxidase activation and reactive oxygen species formation in the kidney/podocyte seems to play roles in the abrogation of oxidative stress-induced filtration barrier injury and consequent albuminuria.

Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations.

PubMed

Pan, Wei; Song, Im-Sook; Shin, Ho-Jung; Kim, Min-Hye; Choi, Yeong-Lim; Lim, Su-Jeong; Kim, Woo-Young; Lee, Sang-Seop; Shin, Jae-Gook

2011-06-01

Genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP; SLC10A1) and ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2), which greatly contribute to bile acid homeostasis, were extensively explored in the Korean population and functional variants of NTCP were compared among Asian populations. From direct DNA sequencing, six SNPs were identified in the SLC10A1 gene and 14 SNPs in the SLC10A2 gene. Three of seven coding variants were non-synonymous SNPs: two variants from SLC10A1 (A64T, S267F) and one from SLC10A2 (A171S). No linkage was analysed in the SLC10A1 gene because of low frequencies of genetic variants, and the SLC10A2 gene was composed of two separated linkage disequilibrium blocks contrary to the white population. The stably transfected NTCP-A64T variant showed significantly decreased uptakes of taurocholate and rosuvastatin compared with wild-type NTCP. The decreased taurocholate uptake and increased rosuvastatin uptake were shown in the NTCP-S267F variant. The allele frequencies of these functional variants were 1.0% and 3.1%, respectively, in a Korean population. However, NTCP-A64T was not found in Chinese and Vietnamese subjects. The frequency distribution of NTCP-S267F in Koreans was significantly lower than those in Chinese and Vietnamese populations. Our data suggest that NTCP-A64T and -S267F variants cause substrate-dependent functional change in vitro, and show ethnic difference in their allelic frequencies among Asian populations although the clinical relevance of these variants is remained to be evaluated.

A Peculiar Formula of Essential Amino Acids Prevents Rosuvastatin Myopathy in Mice

PubMed Central

D'Antona, Giuseppe; Tedesco, Laura; Ruocco, Chiara; Corsetti, Giovanni; Ragni, Maurizio; Fossati, Andrea; Saba, Elisa; Fenaroli, Francesca; Montinaro, Mery; Carruba, Michele O.; Valerio, Alessandra

2016-01-01

Abstract Aims: Myopathy, characterized by mitochondrial oxidative stress, occurs in ∼10% of statin-treated patients, and a major risk exists with potent statins such as rosuvastatin (Rvs). We sought to determine whether a peculiar branched-chain amino acid-enriched mixture (BCAAem), found to improve mitochondrial function and reduce oxidative stress in muscle of middle-aged mice, was able to prevent Rvs myopathy. Results: Dietary supplementation of BCAAem was able to prevent the structural and functional alterations of muscle induced by Rvs in young mice. Rvs-increased plasma 3-methylhistidine (a marker of muscular protein degradation) was prevented by BCAAem. This was obtained without changes of Rvs ability to reduce cholesterol and triglyceride levels in blood. Rather, BCAAem promotes de novo protein synthesis and reduces proteolysis in cultured myotubes. Morphological alterations of C2C12 cells induced by statin were counteracted by amino acids, as were the Rvs-increased atrogin-1 mRNA and protein levels. Moreover, BCAAem maintained mitochondrial mass and density and citrate synthase activity in skeletal muscle of Rvs-treated mice beside oxygen consumption and ATP levels in C2C12 cells exposed to statin. Notably, BCAAem assisted Rvs to reduce oxidative stress and to increase the anti-reactive oxygen species (ROS) defense system in skeletal muscle. Innovation and Conclusions: The complex interplay between proteostasis and antioxidant properties may underlie the mechanism by which a specific amino acid formula preserves mitochondrial efficiency and muscle health in Rvs-treated mice. Strategies aimed at promoting protein balance and controlling mitochondrial ROS level may be used as therapeutics for the treatment of muscular diseases involving mitochondrial dysfunction, such as statin myopathy. Antioxid. Redox Signal. 25, 595–608. PMID:27245589

Relationship between angina pectoris and outcomes in patients with heart failure and reduced ejection fraction: an analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).

PubMed

Badar, Athar A; Perez-Moreno, Ana Cristina; Jhund, Pardeep S; Wong, Chih M; Hawkins, Nathaniel M; Cleland, John G F; van Veldhuisen, Dirk J; Wikstrand, John; Kjekshus, John; Wedel, Hans; Watkins, Stuart; Gardner, Roy S; Petrie, Mark C; McMurray, John J V

2014-12-21

Angina pectoris is common in patients with heart failure and reduced ejection fraction (HF-REF) but its relationship with outcomes has not been well defined. This relationship was investigated further in a retrospective analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Four thousand, eight hundred and seventy-eight patients were divided into three categories: no history of angina and no chest pain at baseline (Group A; n = 1240), past history of angina but no chest pain at baseline (Group B; n = 1353) and both a history of angina and chest pain at baseline (Group C; n = 2285). Outcomes were examined using Kaplan-Meier and Cox regression survival analysis. Compared with Group A, Group C had a higher risk of non-fatal myocardial infarction or unstable angina (HR: 2.36, 1.54-3.61; P < 0.001), this composite plus coronary revascularization (HR: 2.54, 1.76-3.68; P < 0.001), as well as HF hospitalization (HR: 1.35, 1.13-1.63; P = 0.001), over a median follow-up period of 33 months. There was no difference in cardiovascular or all-cause mortality. Group B had a smaller increase in risk of coronary events but not of heart failure hospitalization. Patients with HF-REF and ongoing angina are at an increased risk of acute coronary syndrome and HF hospitalization. Whether these patients would benefit from more aggressive medical therapy or percutaneous revascularization is not known and merits further investigation. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Predictors and outcomes of increases in creatine phosphokinase concentrations or rhabdomyolysis risk during statin treatment

PubMed Central

van Staa, Tjeerd P; Carr, Daniel F; O’Meara, Helen; McCann, Gerry; Pirmohamed, Munir

2014-01-01

Aim The aim was to evaluate clinical risk factors associated with myotoxicity in statin users. Methods This was a cohort study of patients prescribed a statin in UK primary care practices contributing to the Clinical Practice Research Datalink. Outcomes of interest were creatine phosphokinase (CPK) concentrations and clinical records of rhabdomyolysis. Results The cohort comprised 641 703 statin users. Simvastatin was most frequently prescribed (66.3%), followed by atorvastatin (24.4%). CPK was measured in 127 209 patients: 81.4% within normal range and 0.7% above four times ULN CPK compared with normal CPK (OR 1.28, 95% CI 1.01, 1.60). Rosuvastatin users had higher risk of >four times ULN CPK (OR 1.62, 95% CI 1.22, 2.15) as did patients with larger daily doses of other statin types. A recent clinical record of myalgia was associated with an increased OR of >four times ULN CPK (OR 1.73, 95% CI 1.37, 2.18). In patients who were rechallenged to statins and had repeat CPK measurements after >four times ULN CPK abnormalities, 54.8% of the repeat CPK values were within normal range, 32.1% between one to three times and 13.0% >four times ULN. Conclusions The frequencies of substantive CPK increases and rhabdomyolysis during statin treatment were low, with highest risks seen in those on large daily doses or interacting drugs and on rosuvastatin. CPK measurements appeared to have been done in a haphazard manner and better guidance is needed. PMID:24602118

Rosuvastatin Attenuates CD40L-Induced Downregulation of Extracellular Matrix Production in Human Aortic Smooth Muscle Cells via TRAF6-JNK-NF-κB Pathway

PubMed Central

Wang, Xiao-Lin; Zhou, Yuan-Li; Sun, Wei; Li, Li

2016-01-01

CD40L and statins exhibit pro-inflammatory and anti-inflammatory effects, respectively. They are both pleiotropic and can regulate extracellular matrix (ECM) degeneration in an atherosclerotic plaque. Statins can decrease both the CD40 expression and the resulting inflammation. However, the effects of CD40L and stains on atherosclerotic plaque ECM production and the underlying mechanisms are not well established. Moreover, prolyl-4-hydroxylase α1 (P4Hα1) is involved in collagen synthesis but its correlations with CD40L and statins are unknown. In the present study, CD40L suppressed P4Hα1 expression in human aortic smooth muscle cells (HASMCs) in a dose- and time-dependent manner, with insignificant changes in MMP2 expression and negative enzymatic activity of MMP9. CD40L increased TRAF6 expression, JNK phosphorylation, NF-κB nuclear translocation as well as DNA binding. Furthermore, silencing TRAF6, JNK or NF-κB genes abolished CD40L-induced suppression of P4Hα1. Lower NF-κB nuclear import rates were observed when JNK or TRAF6 silenced HASMCs were stimulated with CD40L compared to HASMCs with active JNK or TRAF6. Together, these results indicate that CD40L suppresses P4Hα1 expression in HASMCs by activating the TRAF6-JNK- NF-κB pathway. We also found that rosuvastatin inhibits CD40L-induced activation of the TRAF6-JNK- NF-κB pathway, thereby significantly rescuing the CD40L stimulated P4Hα1 inhibition. The results from this study will help find potential targets for stabilizing vulnerable atherosclerotic plaques. PMID:27120457

Effect of Prescription Drug Coupons on Statin Utilization and Expenditures: A Retrospective Cohort Study.

PubMed

Daubresse, Matthew; Andersen, Martin; Riggs, Kevin R; Alexander, G Caleb

2017-01-01

Drug coupons are widely used, but their effects are not well understood. To quantify the effect of coupons on statin use and expenditures. Retrospective cohort analysis of IMS Health LRx LifeLink database. U.S. retail pharmacy transactions. Incident statin users who initiated branded atorvastatin or rosuvastatin between June 2006 and February 2013. Monthly statin utilization (pill-days of therapy), switching (filling a different statin), termination (failure to refill statin for 6 mo), and out-of-pocket and total costs. Of 1.1 million incident atorvastatin and rosuvastatin users, 2% used a coupon for at least one statin fill. At 1 year, compared with noncoupon users, those who used a statin coupon on their first fill were dispensed an equal number of monthly pill-days (23.7 vs 23.8), were less likely to switch statins (14.4% vs 16.3%), and were less likely to have terminated statin therapy (31.3% vs 39.2%). At 4 years, coupon users were more likely to have switched (45.5% vs 40.8%) and less likely to have terminated statin therapy (50.6% vs 61.1%) compared with noncoupon users. Those who used greater numbers of coupons were substantially less likely to switch and terminate statin therapies. Monthly out-of-pocket costs were lower among coupon than noncoupon users at 1 year ($9.7 vs $15.1), but total monthly costs were qualitatively similar ($115.5 vs $116.9). At 4 years, monthly out-of-pocket costs among coupon users remained lower ($14.3 vs $16.6) compared with noncoupon users. Sensitivity analyses supported the main results. Coupons for branded statins are associated with higher utilization and lower rates of discontinuation and short-term switching to other statin products. © 2016 Pharmacotherapy Publications, Inc.

JUPITER and satellites: Clinical implications of the JUPITER study and its secondary analyses.

PubMed

Kostapanos, Michael S; Elisaf, Moses S

2011-07-26

THE JUSTIFICATION FOR THE USE OF STATINS IN PREVENTION: an intervention trial evaluating rosuvastatin (JUPITER) study was a real breakthrough in primary cardiovascular disease prevention with statins, since it was conducted in apparently healthy individuals with normal levels of low-density lipoprotein cholesterol (LDL-C < 130 mg/dL) and increased inflammatory state, reflected by a high concentration of high-sensitivity C-reactive protein (hs-CRP ≥ 2 mg/L). These individuals would not have qualified for statin treatment according to current treatment guidelines. In JUPITER, rosuvastatin was associated with significant reductions in cardiovascular outcomes as well as in overall mortality compared with placebo. In this paper the most important secondary analyses of the JUPITER trial are discussed, by focusing on their novel findings regarding the role of statins in primary prevention. Also, the characteristics of otherwise healthy normocholesterolemic subjects who are anticipated to benefit more from statin treatment in the clinical setting are discussed. Subjects at "intermediate" or "high" 10-year risk according to the Framingham score, those who exhibit low post-treatment levels of both LDL-C (< 70 mg/dL) and hs-CRP (< 1 mg/L), who are 70 years of age or older, as well as those with moderate chronic kidney disease (estimated glomerular filtration rate < 60 mL/min every 1.73 m(2)) are anticipated to benefit more from statin treatment. Unlikely other statin primary prevention trials, JUPITER added to our knowledge that statins may be effective drugs in the primary prevention of cardiovascular disease in normocholesterolemic individuals at moderate-to-high risk. Also, statin treatment may reduce the risk of venous thromboembolism and preserve renal function. An increase in physician-reported diabetes represents a major safety concern associated with the use of the most potent statins.

A systematic review and economic evaluation of statins for the prevention of coronary events.

PubMed

Ward, S; Lloyd Jones, M; Pandor, A; Holmes, M; Ara, R; Ryan, A; Yeo, W; Payne, N

2007-04-01

To evaluate the clinical effectiveness and cost-effectiveness of statins for the primary and secondary prevention of cardiovascular events in adults with, or at risk of, coronary heart disease (CHD). Electronic databases were searched between November 2003 and April 2004. A review was undertaken to identify and evaluate all literature relating to the clinical and cost effectiveness of statins in the primary and secondary prevention of CHD and cardiovascular disease (CVD) in the UK. A Markov model was developed to explore the costs and health outcomes associated with a lifetime of statin treatment using a UK NHS perspective. Thirty-one randomised studies were identified that compared a statin with placebo or with another statin, and reported clinical outcomes. Meta-analysis of the available data from the placebo-controlled studies indicates that, in patients with, or at risk of, CVD, statin therapy is associated with a reduced relative risk of all cause mortality, cardiovascular mortality, CHD mortality and fatal myocardial infarction (MI), but not of fatal stroke. It is also associated with a reduced relative risk of morbidity [non-fatal stroke, non-fatal MI, transient ischaemic attack (TIA), unstable angina] and of coronary revascularisation. It is hardly possible, on the evidence available from the placebo-controlled trials, to differentiate between the clinical efficacy of atorvastatin, fluvastatin, pravastatin and simvastatin. However, there is some evidence from direct comparisons between statins to suggest that atorvastatin may be more effective than pravastatin in patients with symptomatic CHD. There is limited evidence for the effectiveness of statins in different subgroups. Statins are generally considered to be well tolerated and to have a good safety profile. This view is generally supported both by the evidence of the trials included in this review and by postmarketing surveillance data. Increases in creatine kinase and myopathy have been reported, but rhabdomyolysis and hepatotoxicity are rare. However, some patients may receive lipid-lowering therapy for as long as 50 years, and long-term safety over such a timespan remains unknown. In secondary prevention of CHD, the incremental cost-effectiveness ratios (ICERs) increase with age varying between pound 10,000 and pound 17,000 per quality adjusted life year (QALY) for ages 45 and 85 respectively. Sensitivity analyses show these results are robust. In primary prevention of CHD there is substantial variation in ICERs by age and risk. The average ICERs weighted by risk range from pound 20,000 to pound 27,500 for men and from pound 21,000 to pound 57,000 for women. The results are sensitive to the cost of statins, discount rates and the modelling time frame. In the CVD analyses, which take into account the benefits of statins on reductions in stroke and TIA events, the average ICER weighted by risk level remains below pound 20,000 at CHD risk levels down to 0.5%. Limitations of the analyses include the requirement to extrapolate well beyond the timeframe of the trial period, and to extrapolate effectiveness results from higher risk primary prevention populations to the treatment of populations at much lower risk. Consequently, the results for the lower age bands and lower risks are subject to greater uncertainty and need to be treated with caution. There is evidence to suggest that statin therapy is associated with a statistically significant reduction in the risk of primary and secondary cardiovascular events. As the confidence intervals for each outcome in each prevention category overlap, it is not possible to differentiate, in terms of relative risk, between the effectiveness of statins in primary and secondary prevention. However, the absolute risk of CHD death/non-fatal MI is higher, and the number needed to treat to avoid such an event is consequently lower, in secondary than in primary prevention. The generalisability of these results is limited by the exclusion, in some studies, of patients who were hypersensitive to, intolerant of, or known to be unresponsive to, statins, or who were not adequately compliant with study medication during a placebo run-in phase. Consequently, the treatment effect may be reduced when statins are used in an unselected population. The results of the economic modelling show that statin therapy in secondary prevention is likely to be considered cost-effective. In primary prevention, the cost-effectiveness ratios are dependent on the level of CHD risk and age, but the results for the CVD analyses offer support for the more aggressive treatment recommendation issued by recent guidelines in UK. Evidence on clinical endpoints for rosuvastatin is awaited from on-going trials. The potential targeting of statins at low-risk populations is however associated with major uncertainties, particularly the likely uptake and long-term compliance to lifelong medication by asymptomatic younger patients. The targeting, assessment and monitoring of low-risk patients in primary care would be a major resource implication for the NHS. These areas require further research.

Predicting transporter-mediated drug interactions: Commentary on: "Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin and rosuvastatin" and "Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A".

PubMed

Zhang, L; Sparreboom, A

2017-04-01

Transporters, expressed in various tissues, govern the absorption, distribution, metabolism, and excretion of drugs, and consequently their inherent safety and efficacy profiles. Drugs may interact with a transporter as a substrate and/or an inhibitor. Understanding transporter-mediated drug-drug interactions (DDIs), in addition to enzyme-mediated DDIs, is an integral part of risk assessment in drug development and regulatory review because the concomitant use of more than one medication in patients is common. © 2016 ASCPT.

Cyclosporine, Pravastatin Sodium, Etoposide, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

ClinicalTrials.gov

2017-06-27

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia

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

PubMed

Kamada, Tomohito; Hayashi, Mutsuharu; Yokoi, Hiroatsu; Fujiwara, Wakaya; Yoshikawa, Daiji; Mukaide, Daisuke; Sugishita, Yoshinori; Yoshinaga, Masataka; Ito, Takehiro; Ozaki, Yukio; Izawa, Hideo

2015-01-01

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.

The incidence of kidney injury for patients treated with a high-potency versus moderate-potency statin regimen after an acute coronary syndrome.

PubMed

Sarma, Amy; Cannon, Christopher P; de Lemos, James; Rouleau, Jean L; Lewis, Eldrin F; Guo, Jianping; Mega, Jessica L; Sabatine, Marc S; O'Donoghue, Michelle L

2014-05-01

Observational studies have raised concerns that high-potency statins increase the risk of acute kidney injury. We therefore examined the incidence of kidney injury across 2 randomized trials of statin therapy. PROVE IT-TIMI 22 enrolled 4162 subjects after an acute coronary syndrome (ACS) and randomized them to atorvastatin 80 mg/day versus pravastatin 40 mg/day. A-to-Z enrolled 4497 subjects after ACS and randomized them to a high-potency (simvastatin 40 mg/day × 1 months, then simvastatin 80 mg/day) versus a delayed moderate-potency statin strategy (placebo × 4 months, then simvastatin 20 mg/day). Serum creatinine was assessed centrally at serial time points. Adverse events (AEs) relating to kidney injury were identified through database review. Across both trials, mean serum creatinine was similar between treatment arms at baseline and throughout follow-up. In A-to-Z, the incidence of a 1.5-fold or ≥ 0.3 mg/dL rise in serum creatinine was 11.4% for subjects randomized to a high-potency statin regimen versus 12.4% for those on a delayed moderate-potency regimen (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.76 to 1.10; P=0.33). In PROVE IT-TIMI 22, the incidence was 9.4% for subjects randomized to atorvastatin 80 mg/day and 10.6% for subjects randomized to pravastatin 40 mg/day (OR, 0.88; 95% CI, 0.71 to 1.09; P=0.25). Consistent results were observed for different kidney injury thresholds and in individuals with diabetes mellitus or with moderate renal dysfunction. The incidence of kidney injury-related adverse events (AEs) was not statistically different for patients on a high-potency versus moderate-potency statin regimen (OR, 1.06; 95% CI, 0.68 to 1.67; P=0.78). For patients enrolled in 2 large randomized trials of statin therapy after ACS, the use of a high-potency statin regimen did not increase the risk of kidney injury.

Mapping SLCO1B1 Genetic Variation for Global Precision Medicine in Understudied Regions in Africa: A Focus on Zulu and Cape Admixed Populations.

PubMed

Hoosain, Nisreen; Pearce, Brendon; Jacobs, Clifford; Benjeddou, Mongi

2016-09-01

The U.S. President Barack Obama has announced, in his State of the Union address on January 20, 2015, the Precision Medicine Initiative, a US$215-million program. For global precision medicine to become a reality, however, biological and environmental "variome" in previously understudied populations ought to be mapped and catalogued. Chief among the molecular targets that warrant global mapping is the organic anion-transporting polypeptide 1B1 (OATP1B1), encoded by solute carrier organic anion transporter family member 1B1 (SLCO1B1), a hepatic uptake transporter predominantly expressed in the basolateral side of hepatocytes. Human OATP1B1 plays a crucial role in the transport of a wide variety of substrates. This includes endogenous compounds such as bile salts as well as medicines, including benzylpenicillin, methotrexate, pravastatin, and rifampicin, and natural toxins microcystin and phalloidin. Genetic variations observed in the SLCO1B1 gene have been associated with altered in vitro and in vivo OATP1B1 transport activity, and consequently influencing patients' response to medicines, toxins, and susceptibility to common complex diseases. Well-characterized haplotypes, *5 (RS4149056C) and *15 (RS4149056T), have been associated with a strikingly reduced uptake of multiple OATP1B1 substrates, including estrone-3-sulfate, estradiol-17β-d-glucuronide, atorvastatin, cerivastatin, pravastatin, and rifampicin. In particular, RS4149056C is observed in 60% of the Cape admixed (CA) population and is associated with increased plasma concentrations of many statins as well as fexofenadine and repaglinide. We designed and optimized a SNaPshot minisequencing panel to characterize the variants of relevance for precision medicine in the clinic. We report here the first study on allele and genotype frequencies for 10 nonsynonymous, 4 synonymous, and 6 intronic single-nucleotide polymorphisms of SLCO1B1 in the Zulu and CA populations of South Africa. These variants are further contextualized here, in relation to their potential clinical relevance. These observations collectively contribute to current efforts to advance global precision medicine in understudied populations and resource-limited regions of the world.

Heme oxygenase is not involved in the anti-proliferative effects of statins on pancreatic cancer cells.

PubMed

Vanova, K; Boukalova, S; Gbelcova, H; Muchova, L; Neuzil, J; Gurlich, R; Ruml, T; Vitek, L

2016-05-12

Pancreatic cancer is recognized as one of the most fatal tumors due to its aggressiveness and resistance to therapy. Statins were previously shown to inhibit the proliferation of cancer cells via various signaling pathways. In healthy tissues, statins activate the heme oxygenase pathway, nevertheless the role of heme oxygenase in pancreatic cancer is still controversial. The aim of this study was to evaluate, whether anti-proliferative effects of statins in pancreatic cancer cells are mediated via the heme oxygenase pathway. In vitro effects of various statins and hemin, a heme oxygenase inducer, on cell proliferation were evaluated in PA-TU-8902, MiaPaCa-2 and BxPC-3 human pancreatic cancer cell lines. The effect of statins on heme oxygenase activity was assessed and heme oxygenase-silenced cells were used for pancreatic cancer cell proliferation studies. Cell death rate and reactive oxygen species production were measured in PA-TU-8902 cells, followed by evaluation of the effect of cerivastatin on GFP-K-Ras trafficking and expression of markers of invasiveness, osteopontin (SPP1) and SOX2. While simvastatin and cerivastatin displayed major anti-proliferative properties in all cell lines tested, pravastatin did not affect the cell growth at all. Strong anti-proliferative effect was observed also for hemin. Co-treatment of cerivastatin and hemin increased anti-proliferative potential of these agents, via increased production of reactive oxygen species and cell death compared to individual treatment. Heme oxygenase silencing did not prevent pancreatic cancer cells from the tumor-suppressive effect of cerivastatin or hemin. Cerivastatin, but not pravastatin, protected Ras protein from trafficking to the cell membrane and significantly reduced expressions of SPP1 (p < 0.05) and SOX2 (p < 0.01). Anti-proliferative effects of statins and hemin on human pancreatic cancer cell lines do not seem to be related to the heme oxygenase pathway. While hemin triggers reactive oxygen species-induced cell death, cerivastatin targets Ras protein trafficking and affects markers of invasiveness.

Surface modification of endovascular stents with rosuvastatin and heparin-loaded biodegradable nanofibers by electrospinning.

PubMed

Janjic, Milka; Pappa, Foteini; Karagkiozaki, Varvara; Gitas, Christakis; Ktenidis, Kiriakos; Logothetidis, Stergios

2017-01-01

This study describes the development of drug-loaded nanofibrous scaffolds as a nanocoating for endovascular stents for the local and sustained delivery of rosuvastatin (Ros) and heparin (Hep) to injured artery walls after endovascular procedures via the electrospinning process. The proposed hybrid covered stents can promote re-endothelialization; improve endothelial function; reduce inflammatory reaction; inhibit neointimal hyperplasia of the injured artery wall, due to well-known pleiotropic actions of Ros; and prevent adverse events such as in-stent restenosis (ISR) and stent thrombosis (ST), through the antithrombotic action of Hep. Biodegradable nanofibers were prepared by dissolving cellulose acetate (AC) and Ros in N , N -dimethylacetamide (DMAc) and acetone-based solvents. The polymeric solution was electrospun (e-spun) into drug-loaded AC nanofibers onto three different commercially available stents (Co-Cr stent, Ni-Ti stent, and stainless steel stent), resulting in nonwoven matrices of submicron-sized fibers. Accordingly, Hep solution was further used for fibrous coating onto the engineered Ros-loaded stent. The functional encapsulation of Ros and Hep drugs into polymeric scaffolds further underwent physicochemical analysis. Morphological characterization took place via scanning electron microscopy (SEM) and atomic force microscopy (AFM) analyses, while scaffolds' wettability properties were obtained by contact angle (CA) measurements. The morphology of the drug-loaded AC nanofibers was smooth, with an average diameter of 200-800 nm, and after CA measurement, we concluded to the superhydrophobic nature of the engineered scaffolds. In vitro release rates of the pharmaceutical drugs were determined using a high-performance liquid chromatography assay, which showed that after the initial burst, drug release was controlled slowly by the degradation of the polymeric materials. These results imply that AC nanofibers encapsulated with Ros and Hep drugs have great potential in the development of endovascular grafts with anti-thrombogenic properties that can accelerate the re-endothelialization, reduce the neointimal hyperplasia and inflammatory reaction, and improve the endothelial function.

High-Resolution Magnetic Resonance Imaging Enhanced With Superparamagnetic Nanoparticles Measures Macrophage Burden in Atherosclerosis

PubMed Central

Morishige, Kunio; Kacher, Daniel F.; Libby, Peter; Josephson, Lee; Ganz, Peter; Weissleder, Ralph; Aikawa, Masanori

2010-01-01

Background Macrophages contribute to the progression and acute complications of atherosclerosis. Macrophage imaging may serve as a biomarker to identify subclinical inflamed lesions, to predict future risk, and to aid in the assessment of novel therapies. Methods and Results To test the hypothesis that nanoparticle-enhanced, high-resolution magnetic resonance imaging (MRI) can measure plaque macrophage accumulation, we used 3-T MRI with a macrophage-targeted superparamagnetic nanoparticle preparation (monocrystalline iron oxide nanoparticles-47 [MION-47]) in cholesterol-fed New Zealand White rabbits 6 months after balloon injury. In vivo MRI visualized thickened abdominal aortas on both T1- and T2-weighted spin-echo images (T1 spin echo, 20 axial slices per animal; T2 spin echo, 28 slices per animal). Seventy-two hours after MION-47 injection, aortas exhibited lower T2 signal intensity compared with before contrast imaging (signal intensity ratio, aortic wall/muscle: before, 1.44±0.26 versus after, 0.95±0.22; 164 slices; P<0.01), whereas T1 spin echo images showed no significant change. MRI on ex vivo specimens provided similar results. Histological studies colocalized iron accumulation with immunoreactive macrophages in atheromata. The magnitude of signal intensity reduction on T2 spin echo in vivo images further correlated with macrophage areas in situ (150 slices; r=0.73). Treatment with rosuvastatin for 3 months yielded diminished macrophage content (P<0.05) and reversed T2 signal intensity changes (P<0.005). Signal changes in rosuvastatin-treated rabbits correlated with reduced macrophage burden (r=0.73). In vitro validation studies showed concentration-dependent MION-47 uptake by human primary macrophages. Conclusion The magnitude of T2 signal intensity reduction in high-resolution MRI after administration of superparamagnetic phagocytosable nanoparticles can assess macrophage burden in atheromata, providing a clinically translatable tool to identify inflamed plaques and to monitor therapy-mediated changes in plaque inflammation. PMID:20937980

Moving branded statins to lowest copay tier improves patient adherence.

PubMed

Chen, Shih-Yin; Shah, Sonali N; Lee, Yuan-Chi; Boulanger, Luke; Mardekian, Jack; Kuznik, Andreas

2014-01-01

Statins are efficacious in reducing the risk of major cardiovascular events for both primary and secondary prevention, yet long-term adherence is poor. Their effectiveness could be compromised in actual practice when patients are not adherent to the treatments. Higher copayments have been shown to be associated with lower adherence to statins. To assess the effect on patient adherence of moving branded atorvastatin and rosuvastatin from the second to the first tier by a Medicare Part D plan sponsor. Pharmacy claims and eligibility records between July 1, 2009, and July 31, 2011, of Medicare Part D members not receiving the low-income subsidy were analyzed. New atorvastatin and rosuvastatin users in January 2010 (2010 cohort) were compared with those in January 2011 (2011 cohort) after this formulary tier change (tier-reduction group). Adherence was defined by the proportion of days covered (PDC) over 6 months. The impact of tier reduction on adherence was evaluated via logistic regression for binary outcome (PDC≥0.8) and generalized linear regression for continuous PDC by comparing the 2011 cohort with the 2010 cohort, adjusting for demographic and clinical characteristics. Other statin users (97% on generic statins) were also analyzed, serving as a nontier-reduction comparator group. We identified 12,437 members in the tier-reduction group. Between the 2010 and 2011 cohorts, mean PDC increased from 0.77 to 0.83, and the proportion of members with high adherence increased from 62.0% to 72.9% (both P < 0.001). After regression adjustment, members in the 2011 cohort were more likely to be adherent (OR=1.68; 95% CI=1.55-1.82) and had a 5.9% increase in PDC (P < 0.05). There was no significant increase in adherence observed in the comparator nontier-reduction group. Findings from this study suggest that financial incentives may improve medication adherence. Future studies should evaluate whether such formulary strategies improve long-term adherence and patient outcomes.

Risk Assessment Integrated QbD Approach for Development of Optimized Bicontinuous Mucoadhesive Limicubes for Oral Delivery of Rosuvastatin.

PubMed

Javed, Md Noushad; Kohli, Kanchan; Amin, Saima

2018-04-01

Statins are widely prescribed for hyperlipidemia, cancer, and Alzheimer's disease but are facing some inherent challenges such as low solubility and drug loading, higher hepatic metabolism, as well as instability at gastric pH. So, relatively higher circulating dose, required for exerting the therapeutic benefits, leads to dose-mediated severe toxicity. Furthermore, due to low biocompatibility, high toxicity, and other regulatory caveats such as product conformity, reproducibility, and stability of conventional formulations as well as preferentially higher bioabsorption of lipids in their favorable cuboidal geometry, enhancement in in vivo biopharmaceutical performance of Rosuvastatin could be well manifested in Quality by Design (QbD) integrated cuboidal-shaped mucoadhesive microcrystalline delivery systems (Limicubes). Here, quality-target-product-profile (QTPPs), critical quality attributes (CQAs), Ishikawa fishbone diagram, and integration of risk management through risk assessment matrix for failure mode and effects analysis (FMEA) followed by processing of Plackett-Burman design matrix using different statistical test for the first time established an approach to substantiate the claims that controlling levels of only these three screened out independent process variables, i.e., Monoolein (B = 800-1100 μL), Poloxamer (C = 150-200 mg), and stirring speed (F = 700-1000 rpm) were statistically significant to modulate and improve the biopharmaceutical performance affecting key attributes, viz., average particle size (Y 1  = 1.40-2.70 μ), entrapment efficiency (Y 2  = 62.60-88.80%), and drug loading (Y 3  = 0.817-1.15%), in QbD-enabled process. The optimal performance of developed Limicubes exhibited an average particle size of 1.8 ± 0.2 μ, entrapment efficiency 80.32 ± 2.88%, and drug loading 0.93 ± 0.08% at the level of 1100 μL (+ 1), 200 mg (+ 1), and 700 rpm (- 1) for Monoolein, Poloxamer, and stirring speed, respectively.

Idarubicin, Cytarabine, and Pravastatin Sodium in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

ClinicalTrials.gov

2017-10-16

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Refractory Anemia With Excess Blasts; Untreated Adult Acute Myeloid Leukemia

Statins as antiarrhythmics: a systematic review part I: effects on risk of atrial fibrillation.

PubMed

Abuissa, Hussam; O'Keefe, James H; Bybee, Kevin A

2009-10-01

Recent studies have demonstrated that statins may possess antiarrhythmic properties in addition to their lipid-lowering effects. Studies which reported the association of statins with the incidence of atrial arrhythmias were identified through a systematic review of published literature. One randomized, placebo-controlled trial of 200 patients undergoing cardiac surgery showed that atorvastatin decreased the incidence of postoperative atrial fibrillation by 61%. Observational studies in patients with stable coronary disease, left ventricular dysfunction, or those undergoing cardiac or noncardiac surgery show that statin therapy is associated with an approximately 50% lower rate of atrial fibrillation. Two small randomized trials reported conflicting results: one showing that atorvastatin reduced the recurrence of AF after electrical cardioversion and the other finding that pravastatin did not. Published data suggests that statins may possess antiarrhythmic properties that reduce the propensity for atrial fibrillation. Most of this data is observational; more randomized, placebo-controlled trials are needed.

[Pentraxin 3].

PubMed

Inoue, Kenji

2011-07-01

Pentraxin 3 (PTX3) is a called as 'brand-new protein in traditional family' because it belongs with pentraxin family included C-reactive protein(CRP) or serum protein A (SAP), but the clinical papers published explosively in clinical situation in this 3 years. Unlike CRP, PTX3 express in atherosclerotic lesion which involve macrophages, neutrophils, dendritic cells, or smooth muscle cells, predominantly. Interestingly pitavastatin suppress PTX3 gene expression mostly in human endothelial cells among more than 6000 human genes. Therefore, we expect PTX3 to be a new biomarker for inflammatory vascular disease. Recently we developed an ELISA system for the detection of human PTX3 in plasma. Using this system, we demonstrated that PTX3 predicted patients with unstable angina pectoris(UAP). But it remains unclear why levels of PTX3 are increased in patients with acute coronary syndrome (ACS). We collected blood samples directly from the site of plaque rupture in 114 subjects with ACS who underwent PCI with an aspiration catheter. In addition, we performed immunohistochemical analyses on ACS patients' aspirated-thrombi to identify the cellular populations expressing PTX3. From these results, we concluded that infiltrating neutrophils in thrombi represent a diagnostically important source of PTX3 in patients with ACS.

A cross-media content analysis of motivational themes in direct-to-consumer prescription drug advertising.

PubMed

Sumpradit, Nithima; Ascione, Frank J; Bagozzi, Richard P

2004-01-01

Direct-to-consumer (DTC) advertising of prescription drugs is a widely discussed issue in health care. However, little is known about the characteristics of the motivational themes used in this type of advertising. The aim of this study was to investigate the concurrent presentation of motivational themes in DTC print and television advertisements. The content analyses focused on advertisements of 2 targeted drug classes (cyclooxygenase-2 enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) in magazines and on television. Targeted print advertisements (for celecoxib, rofecoxib, atorvastatin, pravastatin, and simvastatin) from September to December 2001 and targeted television advertisements (for celecoxib, rofecoxib, and simvastatin) from November 2001 were investigated. The motivational themes were assessed using a theoretical framework based on self-regulatory focus theory and cultural orientation. Self-regulatory focus was examined in terms of goal orientation (promotion vs prevention) and emotional aspects, (e.g., cheerfulness, dejection, quiescence, agitation). The cultural orientation was examined in terms of individualism versus collectivism. The visual-verbal match was categorized as direct if the audio and visual information was semantically redundant, as partial if it was partially related, and as no match at all if it was different or conflicting. Twelve print advertisements in 10 magazines and 4 television advertisements on 4 television networks were examined; the interrater reliability scores from 3 independent, trained judges ranged from 0.93 to 0.99. The score was low (0.57) in the visual-verbal match measurement for television advertisements. Products in the same category appeared to be promoted using different self-regulatory foci. For example, celecoxib and atorvastatin advertisements tended to be promotion oriented, whereas pravastatin advertisements tended to be prevention oriented. Motivational themes were found throughout the print advertisements (e.g., pictures, headlines, main text). Only a few advertisements illustrated factual information about a product in a pictorial format. The cultural orientation of the advertisements was similar across brands, with individualistic appeals being common. On television, visual-verbal matches (either direct or partial matches) were generally found, except in the section where risk information was presented. In this content analysis, prescription drugs in the same class appeared to be promoted using different self-regulatory foci, but individualistic appeals were found more often than collectivistic appeals across brands.

Uptake and Disposition of Select Pharmaceuticals by Bluegill Exposed at Constant Concentrations in a Flow-Through Aquatic Exposure System.

PubMed

Zhao, Jian-Liang; Furlong, Edward T; Schoenfuss, Heiko L; Kolpin, Dana W; Bird, Kyle L; Feifarek, David J; Schwab, Eric A; Ying, Guang-Guo

2017-04-18

The increasing use of pharmaceuticals has led to their subsequent input into and release from wastewater treatment plants, with corresponding discharge into surface waters that may subsequently exert adverse effects upon aquatic organisms. Although the distribution of pharmaceuticals in surface water has been extensively studied, the details of uptake, internal distribution, and kinetic processing of pharmaceuticals in exposed fish have received less attention. For this research, we investigated the uptake, disposition, and toxicokinetics of five pharmaceuticals (diclofenac, methocarbamol, rosuvastatin, sulfamethoxazole, and temazepam) in bluegill sunfish (Lepomis macrochirus) exposed to environmentally relevant concentrations (1000-4000 ng L -1 ) in a flow-through exposure system. Temazepam and methocarbamol were consistently detected in bluegill biological samples with the highest concentrations in bile of 4, 940, and 180 ng g -1 , respectively, while sulfamethoxazole, diclofenac, and rosuvastatin were only infrequently detected. Over 30-day exposures, the relative magnitude of mean concentrations of temazepam and methocarbamol in biological samples generally followed the order: bile ≫ gut > liver and brain > muscle, plasma, and gill. Ranges of bioconcentration factors (BCFs) in different biological samples were 0.71-3960 and 0.13-48.6 for temazepam and methocarbamol, respectively. Log BCFs were statistically positively correlated to pH adjusted log K ow (that is, log D ow ), with the strongest relations for liver and brain (r 2 = 0.92 and 0.99, respectively), implying that bioconcentration patterns of ionizable pharmaceuticals depend on molecular status, that is, whether a pharmaceutical is un-ionized or ionized at ambient tissue pH. Methocarbamol and temazepam underwent rapid uptake and elimination in bluegill biological compartments with uptake rate constants (K u ) and elimination rate constants (K e ) at 0.0066-0.0330 h -1 and 0.0075-0.0384 h -1 , respectively, and half-lives at 18.1-92.4 h. Exposure to mixtures of diclofenac, methocarbamol, sulfamethoxazole, and temazepam had little or no influence on the uptake and elimination rates, suggesting independent multiple uptake and disposition behaviors of pharmaceuticals by fish would occur when exposed to effluent-influenced surface waters.

Combined Effects of Rosuvastatin and Exercise on Gene Expression of Key Molecules Involved in Cholesterol Metabolism in Ovariectomized Rats

PubMed Central

Ngo Sock, Emilienne Tudor; Mayer, Gaétan; Lavoie, Jean-Marc

2016-01-01

The purpose of this study was to investigate the effects of three weeks of rosuvastatin (Ros) treatment alone and in combination with voluntary training (Tr) on expression of genes involved in cholesterol metabolism (LDLR, PCSK9, LRP-1, SREBP-2, IDOL, ACAT-2 and HMGCR) in the liver of eight week-old ovariectomized (Ovx) rats. Sprague Dawley rats were Ovx or sham-operated (Sham) and kept sedentary for 8 weeks under a standard diet. Thereafter, rats were transferred for three weeks in running wheel cages for Tr or kept sedentary (Sed) with or without Ros treatment (5mg/kg/day). Six groups were formed: Sham-Sed treated with saline (Sal) or Ros (Sham-Sed-Sal; Sham-Sed-Ros), Ovx-Sed treated with Sal or Ros (Ovx-Sed-Sal; Ovx-Sed-Ros), Ovx trained treated with Sal or Ros (Ovx-Tr-Sal; Ovx-Tr-Ros). Ovx-Sed-Sal rats depicted higher (P < 0.05) body weight, plasma total cholesterol (TC) and LDL-C, and liver TC content compared to Sham-Sed-Sal rats. In contrast, mRNA levels of liver PCSK9, LDLR, LRP-1 as well as plasma PCSK9 concentrations and protein levels of LRP-1 were reduced (P < 0.01) in Ovx-Sed-Sal compared to Sham-Sed-Sal rats. However, protein levels of LDLR increased (P < 0.05) in Ovx-Sed-Sal compared to Sham-Sed-Sal rats. Treatment of Ovx rats with Ros increased (P < 0.05) mRNA and protein levels of LRP-1 and PCSK9 but not mRNA levels of LDLR, while its protein abundance was reduced at the level of Sham rats. As a result, plasma LDL-C was not reduced. Exercise alone did not affect the expression of any of these markers in Ovx rats. Overall, Ros treatment corrected Ovx-induced decrease in gene expression of markers of cholesterol metabolism in liver of Ovx rats, but without reducing plasma LDL-C concentrations. Increased plasma PCSK9 levels could be responsible for the reduction of liver LDLR protein abundance and the absence of reduction of plasma LDL-C after Ros treatment. PMID:27442011

Achievement of lipid targets with the combination of rosuvastatin and fenofibric Acid in patients with type 2 diabetes mellitus.

PubMed

Rosenson, Robert S; Carlson, Dawn M; Kelly, Maureen T; Setze, Carolyn M; Hirshberg, Boaz; Stolzenbach, James C; Williams, Laura A

2011-02-01

The objective of this study was to assess the proportion of patients with type 2 diabetes mellitus (T2DM) attaining individual and combined targets of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), non-HDL-C, and apolipoprotein B (ApoB) after treatment with rosuvastatin (R) + fenofibric acid (FA) compared with corresponding-dose R monotherapy. This post hoc analysis evaluated data from the T2DM subset of patients with mixed dyslipidemia (LDL-C ≥130 mg/dL, HDL-C <40/50 mg/dL in men/women, and TG ≥150 mg/dL) from 2 randomized studies. Patients included in the analysis (N = 456) were treated with R (5, 10, or 20 mg), FA 135 mg, or R (5, 10, or 20 mg) + FA 135 mg for 12 weeks. Attainment of LDL-C <100 mg/dL, HDL-C >40/50 mg/dL in men/women, TG <150 mg/dL, non-HDL-C <130 mg/dL, ApoB <90 mg/dL, and the combined targets of these parameters was assessed. Treatment with R + FA resulted in a significantly higher proportion of patients achieving optimal levels of HDL-C (46.8% vs. 20.8%, P = 0.009 for R 10 mg + FA), TG (60.0% vs. 34.0%, P = 0.02 for R 10 mg + FA; 54.0% vs. 26.4%, P = 0.005 for R 20 mg + FA), non-HDL-C (55.1% vs. 36.4%, P = 0.04 for R 5 mg + FA), ApoB (58.0% vs. 36.4%, P = 0.02 for R 5 mg + FA); and the combined targets of LDL-C, HDL-C, and TG (28.3% vs. 8.3%, P = 0.02 for R 10 mg + FA) and all 5 parameters (26.1% vs. 8.3%, P = 0.03 for R 10 mg + FA) than corresponding-dose R monotherapies. A significantly greater proportion of T2DM patients achieved individual and combined lipid targets when treated with the combination of R + FA than corresponding-dose R monotherapies.

Investigation of the Bioequivalence of Rosuvastatin 20 mg Tablets after a Single Oral Administration in Mediterranean Arabs Using a Validated LC-MS/MS Method

PubMed Central

Zaid, Abdel Naser; Al Ramahi, Rowa; Cortesi, Rita; Mousa, Ayman; Jaradat, Nidal; Ghazal, Nadia; Bustami, Rana

2016-01-01

There is a wide inter-individual response to statin therapy including rosuvastatin calcium (RC), and it has been hypothesized that genetic differences may contribute to these variations. In fact, several studies have shown that pharmacokinetic (PK) parameters for RC are affected by race. The aim of this study is to demonstrate the interchangeability between two generic RC 20 mg film-coated tablets under fasting conditions among Mediterranean Arabs and to compare the pharmacokinetic results with Asian and Caucasian subjects from other studies. A single oral RC 20 mg dose, randomized, open-label, two-way crossover design study was conducted in 30 healthy Mediterranean Arab volunteers. Blood samples were collected prior to dosing and over a 72-h period. Concentrations in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method. Twenty-six volunteers completed the study. Statistical comparison of the main PK parameters showed no significant difference between the generic and branded products. The point estimates (ratios of geometric mean %) were 107.73 (96.57–120.17), 103.61 (94.03–114.16), and 104.23 (94.84–114.54) for peak plasma concentration (Cmax), Area Under the Curve (AUC)0→last, and AUC0→∞, respectively. The 90% confidence intervals were within the pre-defined limits of 80%–125% as specified by the Food and Drug Administration and European Medicines Agency for bioequivalence studies. Both formulations were well-tolerated and no serious adverse events were reported. The PK results (AUC0→last and Cmax) were close to those of the Caucasian subjects. This study showed that the test and reference products met the regulatory criteria for bioequivalence following a 20 mg oral dose of RC under fasting conditions. Both formulations also showed comparable safety results. The PK results of the test and reference in the study subjects fall within the acceptable interval of 80%–125% and they were very close to the results among Caucasians. These PK results may be useful in order to determine the suitable RC dose among Arab Mediterranean patients. PMID:28117319

Uptake and disposition of select pharmaceuticals by bluegill exposed at constant concentrations in a flow-through aquatic exposure system

USGS Publications Warehouse

Zhao, Jian-Liang; Furlong, Edward T.; Schoenfuss, Heiko L.; Kolpin, Dana W.; Bird, Kyle L.; Feifarek, David J.; Schwab, Eric A.; Ying, Guang-Guo

2017-01-01

The increasing use of pharmaceuticals has led to their subsequent input into and release from wastewater treatment plants, with corresponding discharge into surface waters that may subsequently exert adverse effects upon aquatic organisms. Although the distribution of pharmaceuticals in surface water has been extensively studied, the details of uptake, internal distribution, and kinetic processing of pharmaceuticals in exposed fish have received less attention. For this research, we investigated the uptake, disposition, and toxicokinetics of five pharmaceuticals (diclofenac, methocarbamol, rosuvastatin, sulfamethoxazole, and temazepam) in bluegill sunfish (Lepomis macrochirus) exposed to environmentally relevant concentrations (1000–4000 ng L–1) in a flow-through exposure system. Temazepam and methocarbamol were consistently detected in bluegill biological samples with the highest concentrations in bile of 4, 940, and 180 ng g–1, respectively, while sulfamethoxazole, diclofenac, and rosuvastatin were only infrequently detected. Over 30-day exposures, the relative magnitude of mean concentrations of temazepam and methocarbamol in biological samples generally followed the order: bile ≫ gut > liver and brain > muscle, plasma, and gill. Ranges of bioconcentration factors (BCFs) in different biological samples were 0.71–3960 and 0.13–48.6 for temazepam and methocarbamol, respectively. Log BCFs were statistically positively correlated to pH adjusted log Kow (that is, log Dow), with the strongest relations for liver and brain (r2 = 0.92 and 0.99, respectively), implying that bioconcentration patterns of ionizable pharmaceuticals depend on molecular status, that is, whether a pharmaceutical is un-ionized or ionized at ambient tissue pH. Methocarbamol and temazepam underwent rapid uptake and elimination in bluegill biological compartments with uptake rate constants (Ku) and elimination rate constants (Ke) at 0.0066–0.0330 h–1 and 0.0075–0.0384 h–1, respectively, and half-lives at 18.1–92.4 h. Exposure to mixtures of diclofenac, methocarbamol, sulfamethoxazole, and temazepam had little or no influence on the uptake and elimination rates, suggesting independent multiple uptake and disposition behaviors of pharmaceuticals by fish would occur when exposed to effluent-influenced surface waters.

Comparative Proteomic Analysis of Human Liver Tissue and Isolated Hepatocytes with a Focus on Proteins Determining Drug Exposure.

PubMed

Vildhede, Anna; Wiśniewski, Jacek R; Norén, Agneta; Karlgren, Maria; Artursson, Per

2015-08-07

Freshly isolated human hepatocytes are considered the gold standard for in vitro studies of liver functions, including drug transport, metabolism, and toxicity. For accurate predictions of the in vivo outcome, the isolated hepatocytes should reflect the phenotype of their in vivo counterpart, i.e., hepatocytes in human liver tissue. Here, we quantified and compared the membrane proteomes of freshly isolated hepatocytes and human liver tissue using a label-free shotgun proteomics approach. A total of 5144 unique proteins were identified, spanning over 6 orders of magnitude in abundance. There was a good global correlation in protein abundance. However, the expression of many plasma membrane proteins was lower in the isolated hepatocytes than in the liver tissue. This included transport proteins that determine hepatocyte exposure to many drugs and endogenous compounds. Pathway analysis of the differentially expressed proteins confirmed that hepatocytes are exposed to oxidative stress during isolation and suggested that plasma membrane proteins were degraded via the protein ubiquitination pathway. Finally, using pitavastatin as an example, we show how protein quantifications can improve in vitro predictions of in vivo liver clearance. We tentatively conclude that our data set will be a useful resource for improved hepatocyte predictions of the in vivo outcome.

Statins: cost analysis in Indian scenario from eight major clinical trials.

PubMed

Sanmukhani, J; Shah, V

2010-01-01

Coronary heart disease (CHD) is the leading cause of death in India resulting in loss of young Indians. Statins have proved to reduce the CHD mortality in various clinical trials. The aim of the study is to find the cost-effectiveness ratio (CER) for each major coronary event averted and a coronary death avoided by use of statins in different clinical settings based on the data from the major clinical trials on statins. Using electronic database and as per our inclusion and exclusion criteria we selected the West of Scotland Coronary Prevention Study (WOSCOPS), the Air Force Coronary Atherosclerosis Prevention Study (AFCAPS) and the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA) study for primary prevention; the Cholesterol and Recurrent Events Trial (CARE), the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study and the Scandinavian Simvastatin Survival Study (4S) for secondary prevention and two studies, the Heart Protection Study (HPS) and the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) study for high-risk patients. The results of these studies were used for cost-effectiveness analysis of statins in different patient groups. Absolute risk reduction, Number Needed to Benefit (NNTB), NNTB/year for total sample and in subgroups of males, females and age >65 was derived. CER for branded and generic versions was calculated by using the prices of statins listed in Indian Drug Review Triple i. Cost-effectiveness ratio (CER) in primary prevention studies i.e., the WOSCOPS, the AFCAPS and the ASCOT-LLA was Rs. 25.8 lacs, Rs. 23.8 lacs and Rs. 7.9 lacs per major coronary event averted respectively. CER in secondary prevention studies i.e., the CARE and the LIPID was approximately Rs. 20 lacs per major coronary event averted while it was Rs. 52.4 lacs and Rs. 37 lacs per coronary heart disease (CHD) death avoided. CER from the 4S was Rs. 6.9 lacs per major coronary event and Rs. 16.9 lacs per CHD death averted. CER in the HPS and the PROSPER study was Rs. 17.9 lacs and Rs. 27.1 lacs per major coronary event avoided in high-risk patients. Cost associated with the use of statins is higher in primary prevention as compared to secondary prevention. More studies are needed to confirm the cost-effectiveness of statins to make any decision for health policy.

Plasma Selenium Concentrations Are Sufficient and Associated with Protease Inhibitor Use in Treated HIV-Infected Adults123

PubMed Central

Hileman, Corrilynn O; Dirajlal-Fargo, Sahera; Lam, Suet Kam; Kumar, Jessica; Lacher, Craig; Combs, Gerald F; McComsey, Grace A

2015-01-01

Background: Selenium is an essential constituent of selenoproteins, which play a substantial role in antioxidant defense and inflammatory cascades. Selenium deficiency is associated with disease states characterized by inflammation, including cardiovascular disease (CVD). Although HIV infection has been associated with low selenium, the role of selenium status in HIV-related CVD is unclear. Objectives: We sought to assess associations between plasma selenium and markers of inflammation, immune activation, and subclinical vascular disease in HIV-infected adults on contemporary antiretroviral therapy (ART) and to determine if statin therapy modifies selenium status. Methods: In the Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN trial, HIV-infected adults on stable ART were randomly assigned 1:1 to rosuvastatin or placebo. Plasma selenium concentrations were determined at entry, week 24, and week 48. Spearman correlation and linear regression analyses were used to assess relations between baseline selenium, HIV-related factors and markers of inflammation, immune activation, and subclinical vascular disease. Changes in selenium over 24 and 48 wk were compared between groups. Results: One hundred forty-seven HIV-infected adults were included. All participants were on ART. Median current CD4+ count was 613, and 76% had HIV-1 RNA ≤48 copies/mL (range: <20–600). Median plasma selenium concentration was 122 μg/L (range: 62–200). At baseline, higher selenium was associated with protease inhibitor (PI) use, lower body mass index, and a higher proportion of activated CD8+ T cells (CD8+CD38+human leukocyte antigen-DR+), but not markers of inflammation or subclinical vascular disease. Over 48 wk, selenium concentrations increased in the statin group (P < 0.01 within group), but the change did not differ between groups (+13.1 vs. +5.3 μg/L; P = 0.14 between groups). Conclusions: Plasma selenium concentrations were within the normal range for the background population and were not associated with subclinical vascular disease in HIV-infected adults on contemporary ART. The association between current PI use and higher selenium may have implications for ART allocation, especially in resource-limited countries. Also, it appears that statin therapy may increase selenium concentrations; however, larger studies are necessary to confirm this finding. This trial was registered at clinicaltrials.gov as NCT01218802. PMID:26269240

Lipoprotein(a) and coronary atheroma progression rates during long-term high-intensity statin therapy: Insights from SATURN.

PubMed

Puri, Rishi; Ballantyne, Christie M; Hoogeveen, Ron C; Shao, Mingyuan; Barter, Philip; Libby, Peter; Chapman, M John; Erbel, Raimund; Arsenault, Benoit J; Raichlen, Joel S; Nissen, Steven E; Nicholls, Stephen J

2017-08-01

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle that associates with major adverse cardiovascular events (MACE). We examined relationships between Lp(a) measurements and changes in coronary atheroma volume following long-term maximally-intensive statin therapy in coronary artery disease patients. Study of coronary atheroma by intravascular ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. Baseline and follow-up Lp(a) levels were measured in 915 of the 1039 SATURN participants, and were correlated with changes in percent atheroma volume (ΔPAV). Mean age was 57.7 ± 8.6 years, 74% were men, 96% were Caucasian, with statin use prior to study enrolment occurring in 59.3% of participants. Baseline [median (IQR)] LDL-cholesterol (LDL-C) and measured Lp(a) levels (mg/dL) were 114 (99, 137) and 17.4 (7.6, 52.9) respectively; follow-up measures were 60 (47, 77), and 16.5 (6.7, 57.7) (change from baseline: p < 0.001, p = 0.31 respectively). At baseline, there were 676 patients with Lp(a) levels <50 mg/dL [median Lp(a) of 10.9 mg/dL], and 239 patients with Lp(a) levels ≥ 50 mg/dL [median Lp(a) of 83.2 mg/dL]. Quartiles of baseline and follow-up Lp(a) did not associate with ΔPAV. Irrespective of the achieved LDL-C ( 50 mg/dL. In coronary artery disease patients prescribed long-term maximally intensive statin therapy with low on-treatment LDL-C levels, measured Lp(a) levels (predominantly below the 50 mg/dL threshold) do not associate with coronary atheroma progression. Alternative biomarkers may thus associate with residual cardiovascular risk in such patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2003-05-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 2F5, 2G12, abetimus sodium, ABI-007, adalimumab, adefovir dipivoxil, AE-941, alefacept, altropane, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminopterin, anakinra, aprinocarsen sodium, atazanavir, atlizumab, atomoxetine hydrochloride; B7-1 vaccine, bevacizumab, biricodar dicitrate, BMS-188667, brasofensine sulfate, bryostatin 1; cantuzumab mertansine, CHS-828, cinacalcet hydrochloride, cipamfylline, creatine, CVT-3146; darbepoetin alfa, DITPA, drotrecogin alfa (activated), duloxetine hydrochloride; edatrexate, efalizumab, ENMD-0997, epoetin, erlosamide, esomeprazole magnesium, etiprednol dicloacetate, etoricoxib, everolimus, ezetimibe; fampridine, fenretinide, FTY-720; IGF-I/IGFBP-3, IL-1 cytokine trap, ilodecakin, interferon beta, ISIS-104838, ISIS-2503, ISIS-5132, ivabradine hydrochloride; lafutidine, lanthanum carbonate, l-Arginine hydrochloride, LEA29Y, lerdelimumab, levetiracetam, levobupivacaine hydrochloride, levosimendan, lopinavir; melagatran, mibefradil hydrochloride, miglustat, morphine-6-glucuronide; nesiritide; omalizumab, omapatrilat; p24-VLP, parecoxib sodium, peginterferon alfa-2a, peginterferon alfa-2b, pegsunercept, pitavastatin calcium, plevitrexed, prasterone, pregabalin, PRO-2000, prucalopride; rapacuronium bromide, rebimastat, RGA-0853, rubitecan, ruboxistaurin mesilate hydrate, RWJ-67657; S-16020-2, sarizotan, SLV-306, stiripentol; TA-CIN, tenecteplase, teriparatide, tezacitabine, tipifarnib, trabectedin, troglitazone; valdecoxib, vardenafil; Z-338, ziconotide.

A systematic strategy for the identification and determination of pharmaceuticals in environment using advanced LC-MS tools: application to ground water samples.

PubMed

Jindal, Kriti; Narayanam, Mallikarjun; Singh, Saranjit

2015-04-10

In the present study, a novel analytical strategy was employed to study the occurrence of 40 drug residues belonging to different medicinal classes, e.g., antibiotics, β blockers, NSAIDs, antidiabetics, proton pump inhibitors, H2 receptor antagonists, antihypertensives, antihyperlipidemics, etc. in ground water samples collected from villages adjoining to S.A.S. Nagar, Punjab, India. The drug residues were extracted from the samples using solid-phase extraction, and LC-ESI-HRMS and LC-ESI-MS/MS were used for identification and quantitation of the analytes. Initially, qualifier and quantifier MRM transitions were classified for 40 targeted drugs, followed by development of LC-MS methods for the separation of all the drugs, which were divided into three categories to curtail overlapping of peaks. Overall identification was done through matching of retention times and MRM transitions; matching of intensity ratio of qualifier to quantifier transitions; comparison of base peak MS/MS profiles; and evaluation of isotopic abundances (wherever applicable). Final confirmation was carried out through comparison of accurate masses obtained from HRMS studies for both standard and targeted analytes in the samples. The application of the strategy allowed removal of false positives and helped in identification and quantitation of diclofenac in the ground water samples of four villages, and pitavastatin in a sample of one village. Copyright © 2015 Elsevier B.V. All rights reserved.

Discontinuation of statin therapy due to muscular side effects: a survey in real life.

PubMed

Rosenbaum, D; Dallongeville, J; Sabouret, P; Bruckert, E

2013-09-01

To assess the burden of statin related muscular symptom in real life. We conducted a wide survey on 10,409 French subjects. Among these, 2850 (27%) had hypercholesterolemia and 1074 were treated with statins. Muscular symptoms were reported by 104 (10%) statin treated patients and led to discontinuation in 30% of the symptomatic patients. The main prescribed statins were low doses rosuvastatin, atorvastatin and simvastatin. Pains were the most commonly described symptoms (87%) but many patients also reported stiffness (62%), cramps (67%), weakness or a loss of strength during exertion (55%). Pain was localized in 70% but mostly described as affecting several muscular groups. Approximately 38% of patients reported that their symptoms prevented even moderate exertion during everyday activities, while 42% of patients suffered major disruption to their everyday life. Muscular symptoms associated with average dosage statin therapy are more frequent than in clinical trials and have a greater impact on patients' life than usually thought. Copyright © 2012 Elsevier B.V. All rights reserved.

Quality and efficiency of statin prescribing across countries with a special focus on South Africa: findings and future implications.

PubMed

Godman, Brian; Bishop, Iain; Campbell, Stephen M; Malmström, Rickard E; Truter, Ilse

2015-04-01

Statins are recommended first-line treatment for hyperlipidemia, with published studies suggesting limited differences between them. However, there are reports of under-dosing. South Africa has introduced measures to enhance generic utilization. Part one documents prescribed doses of statins in 2011. Part two determines the extent of generics versus originator and single-sourced statins in 2011 and their costs. Underdosing of simvastatin in 2011 with average prescribed dose of 23.7 mg; however, not for atorvastatin (20.91 mg) or rosuvastatin (15.02 mg). High utilization of generics versus originators at 93-99% for atorvastatin and simvastatin, with limited utilization of single-sourced statins (22% of total statins - defined daily dose basis), mirroring Netherlands, Sweden and UK. Generics priced 33-51% below originator prices. Opportunity to increase simvastatin dosing through education, prescribing targets and incentives. Opportunity to lower generic prices with generic simvastatin 96-98% below single-sourced prices in some European countries.

The Risk of Hepatotoxicity, New Onset Diabetes and Rhabdomyolysis in the Era of High-Intensity Statin Therapy: Does Statin Type Matter?

PubMed

Benes, Lane B; Bassi, Nikhil S; Davidson, Michael H

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management have placed greater emphasis on high-intensity statin dosing for those with known cardiovascular disease or diabetes mellitus. Differences in risk of hepatotoxicity, new onset diabetes and rhabdomyolysis specifically between the high-intensity statins and the most common moderate-intensity statin, simvastatin, were not found to a significant degree in this review. Rather, baseline characteristics and drug-drug interactions (DDIs) appear to be more important regarding the risk of these adverse effects. Pharmacogenetic differences in statin metabolism may explain individual susceptibility, however genetic testing is not felt to be cost effective at this time. More importantly, statin choice should consider concomitant use of the many prevalent CYP3A4 inhibitors or inducers, and when present, rosuvastatin selection is recommended to reduce DDIs and risk of statin-induced adverse effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Experimental Design for Determination of Effects of Superdisintegrant Combinations on Liquisolid System Properties.

PubMed

Vraníková, Barbora; Pavloková, Sylvie; Gajdziok, Jan

2017-03-01

The preparation of liquisolid systems presents a promising and innovative possibility for enhancing dissolution profiles and improving the bioavailability of poorly soluble drugs. This study aims to evaluate the differences in the properties of liquisolid systems containing combinations of 3 commercially used superdisintegrants (sodium starch glycolate, crospovidone, and croscarmellose sodium). Multiple regression models and contour plots were used to study how the amount and the type of superdisintegrant used affected the quality parameters of liquisolid tablets. The results revealed that an increased amount of crospovidone in the mixture improves disintegration and wetting time and enhances drug release from the prepared liquisolid tablets. Moreover, it was observed that a binary blend of crospovidone and sodium starch glycolate improved tablet disintegration. Considering the obtained results, it could be stated that crospovidone showed the best properties to be used as superdisintegrant for the preparation of liquisolid systems containing rosuvastatin. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Statins: antimicrobial resistance breakers or makers?

PubMed Central

Lareu, Ricky R.; Dix, Brett R.; Hughes, Jeffery D.

2017-01-01

Introduction The repurposing of non-antibiotic drugs as adjuvant antibiotics may help break antimicrobial resistance (AMR). Statins are commonly prescribed worldwide to lower cholesterol. They also possess qualities of AMR “breakers”, namely direct antibacterial activity, synergism with antibiotics, and ability to stimulate the host immune system. However, statins’ role as AMR breakers may be limited. Their current extensive use for cardiovascular protection might result in selective pressures for resistance, ironically causing statins to be AMR “makers” instead. This review examines statins’ potential as AMR breakers, probable AMR makers, and identifies knowledge gaps in a statin-bacteria-human-environment continuum. The most suitable statin for repurposing is identified, and a mechanism of antibacterial action is postulated based on structure-activity relationship analysis. Methods A literature search using keywords “statin” or “statins” combined with “minimum inhibitory concentration” (MIC) was performed in six databases on 7th April 2017. After screening 793 abstracts, 16 relevant studies were identified. Unrelated studies on drug interactions; antifungal or antiviral properties of statins; and antibacterial properties of mevastatin, cerivastatin, antibiotics, or natural products were excluded. Studies involving only statins currently registered for human use were included. Results Against Gram-positive bacteria, simvastatin generally exerted the greatest antibacterial activity (lowest MIC) compared to atorvastatin, rosuvastatin, and fluvastatin. Against Gram-negative bacteria, atorvastatin generally exhibited similar or slightly better activity compared to simvastatin, but both were more potent than rosuvastatin and fluvastatin. Discussion Statins may serve as AMR breakers by working synergistically with existing topical antibiotics, attenuating virulence factors, boosting human immunity, or aiding in wound healing. It is probable that statins’ mechanism of antibacterial activity involves interference of bacterial cell regulatory functions via binding and disrupting cell surface structures such as wall teichoic acids, lipoteichoic acids, lipopolysaccharides, and/or surface proteins. The widespread use of statins for cardiovascular protection may favor selective pressures or co-selection for resistance, including dysbiosis of the human gut microbiota, sublethal plasma concentrations in bacteremic patients, and statin persistence in the environment, all possibly culminating in AMR. Conclusion Simvastatin appears to be the most suitable statin for repurposing as a novel adjuvant antibiotic. Current evidence better supports statins as potential AMR breakers, but their role as plausible AMR makers cannot be excluded. Elucidating the mechanism of statins’ antibacterial activity is perhaps the most important knowledge gap to address as this will likely clarify statins’ role as AMR breakers or makers. PMID:29085751

Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia

PubMed Central

Tan, Ricardo; Giral, Philippe; Robillard, Paul; Kontush, Anatol; Chapman, M. John

2016-01-01

Atherogenic mixed dyslipidemia associates with oxidative stress and defective HDL antioxidative function in metabolic syndrome (MetS). The impact of statin treatment on the capacity of HDL to inactivate LDL-derived, redox-active phospholipid hydroperoxides (PCOOHs) in MetS is indeterminate. Insulin-resistant, hypertriglyceridemic, hypertensive, obese males were treated with pitavastatin (4 mg/day) for 180 days, resulting in marked reduction in plasma TGs (−41%) and LDL-cholesterol (−38%), with minor effects on HDL-cholesterol and apoAI. Native plasma LDL (baseline vs. 180 days) was oxidized by aqueous free radicals under mild conditions in vitro either alone or in the presence of the corresponding pre- or poststatin HDL2 or HDL3 at authentic plasma mass ratios. Lipidomic analyses revealed that statin treatment i) reduced the content of oxidizable polyunsaturated phosphatidylcholine (PUPC) species containing DHA and linoleic acid in LDL; ii) preferentially increased the content of PUPC species containing arachidonic acid (AA) in small, dense HDL3; iii) induced significant elevation in the content of phosphatidylcholine and phosphatidylethanolamine (PE) plasmalogens containing AA and DHA in HDL3; and iv) induced formation of HDL3 particles with increased capacity to inactivate PCOOH with formation of redox-inactive phospholipid hydroxide. Statin action attenuated LDL oxidability Concomitantly, the capacity of HDL3 to inactivate redox-active PCOOH was enhanced relative to HDL2, consistent with preferential enrichment of PE plasmalogens and PUPC in HDL3. PMID:27581680

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-03-01

ABT-869, Acadesine, Acetylsalicylic acid/omeprazole, Adefovir, Adefovir dipivoxil, AEG-35156, Agatolimod sodium, Albiglutide, Alemtuzumab, Alipogene tiparvovec, Alogliptin benzoate, AMG-386, Amrubicin hydrochloride, Apremilast, Aripiprazole, Asoprisnil, Atorvastatin/fenofibrate, AVN-944, Axitinib; Belinostat, Bevacizumab, BHT-3021, BI-2536, Biapenem, Bilastine, Biphasic insulin aspart, Blinatumomab, Bortezomib, Bosentan; Catumaxomab, CD-NP, Cediranib, Certolizumab pegol, Cetuximab, Choline fenofibrate, Ciclesonide, CK-1827452,Clevudine, Clofarabine, CSL-360, CYT-997; Dapagliflozin, Darinaparsin, Denosumab, Densiron 68, Desloratadine, Dulanermin; Edoxaban tosilate, Emtricitabine, Entecavir, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Fidaxomicintiacumiv, Fulvestrant; G-207, GCR-8015, Gefitinib, Ghrelin (human), Glufosfamide; HPV16L1E7CVLP; Ibutamoren mesilate, Imatinib mesylate, Insulin detemir, Insulin glargine, Iodine (I131) tositumomab, Istaroxime, ITMN-191, Ixabepilone; JZP-4, Lenalidomide; Levetiracetam, Linaclotide acetate, Liposomal cytarabine/daunorubicin, Liposomal doxorubicin, Liraglutide, LY-518674; Milatuzumab, MMR-V, Motesanib diphosphate, Mycophenolic acid sodium salt; Niacin/simvastatin; Obatoclax mesylate, Odanacatib; Paclitaxel nanoparticles, Paclitaxel-eluting stent, Pazufloxacin, PBT-2, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pemetrexed disodium, Perampanel, PfCP2.9, Pitavastatin calcium, Poly I:CLC, Pomalidomide, Pralatrexate, Pramlintide acetate, Prucalopride; rhGAD65, Roflumilast; RTS,S/AS02D; SCH-530348, Semagacestat, Sirolimus-eluting coronary stent, Sirolimus-Eluting Stent, SIR-Spheres, Sivelestat sodium hydrate, Sorafenib, Sunitinib malate; Tadalafil, Tafluprost, Tanespimycin, Teduglutide, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tiotropium bromide, TMC-435350, Tositumomab/iodine (I131) tositumomab, Travoprost/timolol, Triciribine phosphate; Vandetanib, VIA-2291, Vinflunine, Vorinostat; XL-019; Yttrium 90 (90Y) ibritumomab tiuxetan. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Cost-effectiveness analysis of applying the Cholesterol and Recurrent Events (CARE) study protocol in Hong Kong.

PubMed

Chau, J; Cheung, B M; McGhee, S M; Lauder, I J; Lau, C P; Kumana, C R

2001-12-01

To determine the cost-effectiveness of secondary prevention with pravastatin in Hong Kong patients with coronary heart disease and average cholesterol levels. Cost-effectiveness analysis based on published results of the CARE study. Men and women post-myocardial infarction with average cholesterol levels. Cost-effectiveness analysis: cost per life saved, cost per fatal or non-fatal coronary event prevented, cost per procedure prevented, and cost per fatal or non-fatal stroke prevented. Cost-utility analysis: gross cost and net cost per quality-adjusted life year gained calculated using two alternative models. Cost per life saved or death prevented was HK$4,442,350 (non-discounted); cost per fatal or non-fatal cardiac event prevented HK$1,146,413; cost per procedure prevented HK$732,759; and cost per fatal or non-fatal stroke prevented HK$2,961,566. Net cost per quality adjusted life year gained was HK$73,218 and HK$65,280 non-discounted, respectively using the two alternative models. The results of this study can assist in prioritising the use of health care resources in Hong Kong but should be considered alongside the benefits and costs of alternative interventions for coronary heart disease.

The Complex Interplay Between Cholesterol and Prostate Malignancy

PubMed Central

Solomon, Keith R.; Freeman, Michael R.

2011-01-01

Research into the topic of the role of cholesterol and prostate disease has been ongoing for many years, however our mechanistic and translational understanding is still poor. Recent evidence indicates that cholesterol lowering drugs reduce the risk of aggressive prostate cancer, however the studies in this area, performed over many years, reflect much controversy and uncertainty. Here we explore the entire literature on the relationship between circulating cholesterol and prostate cancer, with consideration and criticism of the older as well as the newer studies. We consider why low cholesterol is associated with both increased and decreased risk of advanced prostate cancer, and explain why both observations are probably correct. We discuss the conflicting results of randomized placebo-controlled trials of statin drugs vs. observational studies and demonstrate that a predominance of pravastatin in the randomized trials paints a distorted view of statin effects. Lastly, we discuss new data suggesting that a critical aspect of the role of cholesterol in prostate cancer progression is through its role in intratumoral steroidogenesis. With these points addressed, the data strongly point to hypercholesterolemia as a risk factor for prostate cancer progression and suggest clinical opportunities for the use of cholesterol lowering therapies to alter disease course. PMID:21798387

Pravastatin chitosan nanogels-loaded erythrocytes as a new delivery strategy for targeting liver cancer

PubMed Central

Harisa, Gamaleldin I.; Badran, Mohamed M.; AlQahtani, Saeed A.; Alanazi, Fars K.; Attia, Sabry M.

2015-01-01

Chitosan nanogels (CNG) are developed as one of the most promising carriers for cancer targeting. However, these carriers are rapidly eliminated from circulation by reticuloendothelial system (RES), which limits their application. Therefore, erythrocytes (ER) loaded CNG as multifunctional carrier may overcome the massive elimination of nanocarriers by RES. In this study, erythrocytes loaded pravastatin–chitosan nanogels (PR–CNG–ER) were utilized as a novel drug carrier to target liver cancer. Thus, PR–CNG formula was developed in nanosize, with good entrapment efficiency, drug loading and sustained release over 48 h. Then, PR–CNG loaded into ER were prepared by hypotonic preswelling technique. The resulting PR–CNG–ER showed 36.85% of entrapment efficiency, 66.82% of cell recovery and release consistent to that of hemoglobin over 48 h. Moreover, PR–CNG–ER exhibited negative zeta potential, increasing of hemolysis percent, marked phosphatidylserine exposure and stomatocytes shape compared to control unloaded erythrocytes. PR–CNG–ER reduced cells viability of HepG2 cells line by 28% compared to unloaded erythrocytes (UER). These results concluded that PR–CNG–ER are promising drug carriers to target liver cancer. PMID:26903771

Infratentorial Microbleeds: Another Sign of Microangiopathy in Migraine.

PubMed

Arkink, Enrico B; Terwindt, Gisela M; de Craen, Anton J M; Konishi, Junya; van der Grond, Jeroen; van Buchem, Mark A; Ferrari, Michel D; Kruit, Mark C

2015-07-01

Migraine is a risk factor for clinical stroke and for subclinical white matter hyperintensities and infratentorial infarcts. These subclinical lesions are linked to small-vessel pathology. Cerebral microbleeds (CMBs) are another biomarker of small-vessel disease but have not yet been studied in migraine. Identification of CMBs in 63 migraineurs (25 with aura/35 without aura/3 unknown aura status) and 359 controls (aged, 73-85 years) from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) magnetic resonance imaging study. We assessed the modifying role of migraine in the co-occurrence of CMBs, infarcts, and white matter hyperintensity-load. Infratentorial microbleeds were more prevalent in migraine without aura patients than controls (14% versus 4%). Prevalence of other CMBs, infarcts, and white matter hyperintensities did not differ between groups. Migraineurs with CMBs had more often infarcts than controls with CMBs (65% versus 43%). In comparison with controls with infarcts, migraineurs with infarcts had more commonly CMBs (55% versus 30%). Migraine, notably without aura, is associated with infratentorial CMBs at older age. CMBs and infarcts co-occur more often in migraine than in controls. This supports the hypothesis of small-vessel involvement in migraine pathophysiology. © 2015 American Heart Association, Inc.

Effect of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) on Conduction System Disease.

PubMed

Dewland, Thomas A; Soliman, Elsayed Z; Davis, Barry R; Magnani, Jared W; Yamal, Jose-Miguel; Piller, Linda B; Haywood, L Julian; Alonso, Alvaro; Albert, Christine M; Marcus, Gregory M

2016-08-01

Cardiac conduction abnormalities are associated with an increased risk for morbidity and mortality, and understanding factors that accelerate or delay conduction system disease could help to identify preventive and therapeutic strategies. Antifibrotic and anti-inflammatory properties of angiotensin-converting enzyme inhibitors and treatment for hyperlipidemia may reduce the risk for incident conduction system disease. To identify the effect of pharmacologic therapy randomization and clinical risk factors on the incidence of conduction system disease. This secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) investigation acquired data from 623 North American centers. A total of 21 004 ambulatory individuals 55 years or older with hypertension and at least 1 other cardiac risk factor were included in the analysis. Participants were randomly assigned to receive amlodipine besylate, lisinopril, or chlorthalidone. Individuals with elevated fasting low-density lipoprotein cholesterol levels were also randomized to pravastatin sodium vs usual care. An electrocardiogram (ECG) was obtained at study enrollment and every 2 years of follow-up. The development of incident first-degree atrioventricular block, left anterior fascicular block, incomplete left bundle branch block (LBBB), LBBB, incomplete right bundle branch block (RBBB), RBBB, or intraventricular conduction delay was assessed by serial ECGs. The 21 004 participants (11 758 men [56.0%]; 9246 women [44.0%]; mean [SD] age, 66.5 [7.3] years) underwent a mean (SD) follow-up of 5.0 (1.2) years. Among the 1114 participants who developed any conduction defect, 389 developed LBBB, 570 developed RBBB, and 155 developed intraventricular conduction delay. Compared with chlorthalidone, randomization to lisinopril was associated with a significant 19% reduction in conduction abnormalities (hazard ratio [HR], 0.81; 95% CI, 0.69-0.95; P = .01). Treatment with amlodipine, however, was not associated with a significant difference in conduction outcome events (HR, 0.94; 95% CI, 0.81-1.09; P = .42). Similarly, pravastatin treatment was not associated with a reduced adjusted risk for incident disease compared with usual hyperlipidemia treatment (HR, 1.13; 95% CI, 0.95-1.35; P = .18). Increased age (HR, 1.47; 95% CI, 1.34-1.63; P < .001), male sex (HR, 0.59; 95% CI, 0.50-0.73; P < .001), white race (HR, 0.59; 95% CI, 0.50-0.70; P < .001), diabetes (HR, 1.23; 95% CI, 1.07-1.42; P = .003), and left ventricular hypertrophy (HR, 3.20; 95% CI, 2.61-3.94; P < .001) were also independently associated with increased risk for conduction system disease. Incident conduction system disease is significantly reduced by lisinopril therapy and is independently associated with multiple clinical factors. Further studies are warranted to determine whether pharmacologic treatment affects conduction abnormality outcomes, including pacemaker implantation. clinicaltrials.gov Identifier: NCT00000542.

Serum levels of C-reactive protein in patients with stable coronary artery disease: JUPITER in perspective.

PubMed

Saely, Christoph H; Rein, Philipp; Vonbank, Alexander; Drexel, Heinz

2010-10-29

The JUPITER trial has recently demonstrated an outstanding reduction of cardiovascular events by 20 mg rosuvastatin/day in subjects with high CRP who were apparently healthy at baseline. However, absence of atherosclerosis in JUPITER was based on the subjects' history and not proven objectively. To put the results of JUPITER in perspective, we evaluated serum CRP in a consecutive series of 703 statin-naïve Caucasian patients with angiographically proven stable CAD. From these stable CAD patients, only 69.2% met the ≥2.0 mg/l serum CRP inclusion criterion of the JUPITER trial. Median CRP [interquartile range] in our CAD patients was 3.3 [1.6-6.6] mg/l, which was significantly (p<0.001) lower than the median CRP in JUPITER (4.2 mg/l). Our results point to considerable subclinical atherosclerosis in the patients studied in JUPITER. The impressive results of that trial may not be generalizable to healthy populations all over the world. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis.

PubMed

Kunutsor, Setor K; Seidu, Samuel; Khunti, Kamlesh

2017-02-01

Statins have been suggested to have a protective effect on venous thromboembolism (which includes deep vein thrombosis and pulmonary embolism), but the evidence is uncertain. We sought to evaluate the extent to which statins are associated with first venous thromboembolism events. We did a systematic review and meta-analysis of observational cohort studies and randomised controlled trials (RCTs). Relevant studies that reported associations between statins and first venous thromboembolism outcomes were identified from MEDLINE, Embase, Web of Science, Cochrane Library, and a manual search of bibliographies for studies published up until July 18, 2016, and from email correspondence with investigators. Observational cohorts that assessed the association of statin use with venous thromboembolism, deep vein thrombosis, or pulmonary embolism in adults were included, as were intervention studies that assessed the effects of statin therapy compared with a placebo or no treatment and collected data on venous thromboembolism, deep vein thrombosis, or pulmonary embolism outcomes. Studies that compared statins with another statin or lipid-lowering agent were excluded. Study specific relative risks (RRs) were aggregated using random-effects models and were grouped by study-level characteristics. The review has been registered with PROSPERO, number CRD42016035622. 36 eligible studies (13 cohort studies comprising 3 148 259 participants and 23 RCTs of statins vs placebo or no treatment comprising 118 464 participants) were included. In observational studies, the pooled RR for venous thromboembolism was 0·75 (95% CI 0·65-0·87; p<0·0001) when statin use was compared with no statin use. This association remained consistent when grouped by various study-level characteristics. In RCTs, the RR for venous thromboembolism was 0·85 (0·73-0·99; p=0·038) when statin therapy was compared with placebo or no treatment. Subgroup analyses suggested significant differences in the effect of statins by type of statin, with rosuvastatin having the lowest risk on venous thromboembolism compared with other statins 0·57 (0·42-0·75; p=0·015). There was no evidence of an effect of statin use on pulmonary embolism. Statin use was associated with a significant reduction in risk of the specific endpoint of deep vein thrombosis compared with no statin use (RR 0·77, 95% CI 0·69-0·86; p<0·0001). Available evidence from observational and intervention studies suggest a beneficial effect of statin use on venous thromboembolism. In intervention studies, therapy with rosuvastatin significantly reduced venous thromboembolism compared with other statins. Further evidence is however needed to validate these findings. None. Copyright © 2017 Elsevier Ltd. All rights reserved.

Statin Therapy: Review of Safety and Potential Side Effects.

PubMed

Ramkumar, Satish; Raghunath, Ajay; Raghunath, Sudhakshini

2016-11-01

Hydroxymethyl glutaryl coenzyme A reductase inhibitors, commonly called statins, are some of the most commonly prescribed medications worldwide. Evidence suggests that statin therapy has significant mortality and morbidity benefit for both primary and secondary prevention from cardiovascular disease. Nonetheless, concern has been expressed regarding the adverse effects of long term statin use. The purpose of this article was to review the current medical literature regarding the safety of statins. Major trials and review articles on the safety of statins were identified in a search of the MEDLINE database from 1980 to 2016, which was limited to English articles. Myalgia is the most common side effect of statin use, with documented rates from 1-10%. Rhabdomyolysis is the most serious adverse effect from statin use, though it occurs quite rarely (less than 0.1%). The most common risk factors for statin-related myopathy include hypothyroidism, polypharmacy and alcohol abuse. Derangement in liver function tests is common, affecting up to 1% of patients; however, the clinical significance of this is unknown. Some statin drugs are potentially diabetogenic and the risk appears to increase in those patients on higher doses. Pitavastatin has not been associated with increased risk of diabetes. Statins have not been proven to increase the risk of malignancy, dementia, mood disorders or acute interstitial nephritis. However, statins do have multiple drug interactions, primarily those which interact with the cytochrome p450 enzyme group. Overall, statin drugs appear to be safe for use in the vast majority of patients. However, patients with multiple medical co-morbidities are at increased risk of adverse effects from long-term statin use.

A novel use of oxidative coupling reactions for determination of some statins (cholesterol-lowering drugs) in pharmaceutical formulations

NASA Astrophysics Data System (ADS)

Ashour, Safwan; Bahbouh, Mahmoud; Khateeb, Mouhammed

2011-03-01

New, accurate and reliable spectrophotometric methods for the assay of three statin drugs, atorvastatin calcium (AVS), fluvastatin sodium (FVS) and pravastatin sodium (PVS) in pure form and pharmaceutical formulations have been described. All methods involve the oxidative coupling reaction of AVS, FVS and PVS with 3-methyl-2-benzothiazolinone hydrazone hydrochloride monohydrate (MBTH) in the presence of Ce(IV) in an acidic medium to form colored products with λmax at 566, 615 and 664 nm, respectively. Beer's law was obeyed in the ranges of 2.0-20.0, 4.9-35.4 and 7.0-30.0 μg mL -1 for AVS-MBTH, FVS-MBTH and PVS-MBTH, respectively. Molar absorptivities for the above three methods were found to be 3.24 × 10 4, 1.05 × 10 4 and 0.68 × 10 4 L mol -1 cm -1, respectively. Statistical treatment of the experimental results indicates that the methods are precise and accurate. The proposed methods have been applied to the determination of the components in commercial forms with no interference from the excipients. A comparative study between the suggested procedures and the official methods for these compounds in the commercial forms showed no significant difference between the two methods.

Oral carcinogenesis is not achieved in different carcinogen-treated PAI-1 transgenic and wild-type mouse models.

PubMed

Avgoustidis, Dimitris; Nisyrios, Themistoklis; Nkenke, Emeka; Lijnen, Roger; Ragos, Vassilis; Perrea, Despina; Donta, Ismini; Vaena, Apostolia; Yapijakis, Christos; Vairaktaris, Eleftherios

2012-01-01

In an effort to assess the role of plasminogen activator inhibitor-1 (PAI-1) in oral squamous cancer development and progression, two different carcinogen treatment protocols were conducted. Protocol I included mice from a PAI-1 transgenic (Tg) breed (n=56) and their wild-type (WT) counterparts (n=56), divided into one control group and two main experimental groups, treated with 7,12-dimethylbenz[a]anthracene (DMBA) for 8 and 16 weeks, respectively. Protocol II included the same number and types of animals and groups, which were similarly treated with 4-Nitroquinoline 1-oxide (4-NQO) in drinking water. Two drugs that affect plasma PAI-1 levels, enalapril and pravastatin, were administered to certain subgroups of animals in both protocols. None of the animals developed macroscopically-visible oral cancer lesions. Eleven animals under Protocol I and 52 animals under Protocol II died. Skin lesions were noted only in DMBA-treated animals (n=9). Almost all animals administered with 4-NQO developed alopecia and lost weight, while two of them developed stomach tumours, and one female mouse developed a large ovarian cyst. Transgenic mice may respond differently when used in well-established carcinogen models and oral carcinogenesis is hard to achieve in these rodents.

Ocimum gratissmum aqueous extract reduces plasma lipid in hypercholesterol-fed hamsters

PubMed Central

Chao, Pei-Yu; Lin, James A.; Ting, Wei-Jen; Lee, Hsueh-Hui; Hsieh, Kuanghui; Chiu, Yung-Wei; Lai, Te-Jen; Hwang, Jin-Ming; Liu, Je-rYuh; Huang, Chih-Yang

2016-01-01

Objectives: Hyperlipidemia is a significant risk factor in the development of atherosclerosis and related diseases which are major health problem in many developed and developing countries that can lead to fatality due to the changes in lifestyle and dietary habits in this modern age. Methods: In the present study, the Ocimum gratissimum aqueous extract (OGE) was tested for the lowering effect on the serum lipid level of male hamsters on a high-fat (12%) and high-cholesterol (0.2%) diet (HFCD). Results: The results showed that the levels of serum high-density-lipoprotein-cholesterol (HDL-C) low-density-lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and triglycerols (TG) were increased in the HFCD group (113±11, 259±87, 629±175 and 625±262, respectively), as compared to the control normal diet group (51±8, 19±5, 77±16 and 101±44, respectively). When co-treated with various doses (10 and 20 mg/kg) of the OGE or rosuvastatin, the rats exhibited the restoration of normal serum LDL-C, TC, and TG levels. Conclusion: Therefore, we suggest that the Ocimum gratissimum aqueous extract may have the potential function of lowering serum lipid in rats. PMID:27877073

New drugs of 2003.

PubMed

Hussar, Daniel A

2004-01-01

To provide information regarding the most important properties of the new therapeutic agents marketed in 2003. Product labeling supplemented selectively with published studies and drug information reference sources. By the author. By the author. The 28 new therapeutic agents marketed in the United States during 2003 are reviewed in this article: adalimumab, agalsidase beta, alefacept, alfuzosin hydrochloride, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, bortezomib, daptomycin, efalizumab, eletriptan hydrobromide, emtricitabine, enfuvirtide, eplerenone, gefitinib, icodextrin, laronidase, memantine hydrochloride, mequinol/tretinoin, miglustat, nitazoxanide, omalizumab, palonosetron hydrochloride, pegvisomant, rosuvastatin calcium, tadalafil, tositumomab and iodine I 131 tositumomab, and vardenafil hydrochloride. Indications and information on dosage and administration for these agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. When possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. A number of the new therapeutic agents marketed in 2003 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.

Simultaneous determination of multiple angiotensin type 1 receptor antagonists and its application to high-throughput pharmacokinetic study

NASA Astrophysics Data System (ADS)

Zhu, Xiaoyan; Sun, Jianguo; Hao, Haiping; Wang, Guangji; Hu, Xiaoling; Lv, Hua; Gu, Shenghua; Wu, Xiaoming; Xu, Jinyi

2008-05-01

A rapid and sensitive high performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-ESI-MS/MS) detection was developed for the simultaneous determination of multiple angiotensin type 1 receptor antagonists (AT1RAs) WX472, WX581, 1b and telmisartan in rat plasma for the purpose of high-throughout pharmacokinetic screening. The method was operated under selected reaction monitoring (SRM) mode in the positive ion mode. The analytes and the internal standard (pitavastatin) were extracted from 100 [mu]L rat plasma under acidic conditions by liquid-liquid extraction with ethyl acetate. The analytes and internal standard were baseline separated on a Gemini analytical column (3 [mu]m, 150 mm × 2.0 mm) with the adoption of a gradient elution using acetonitrile and 0.05% aqueous formic acid. The standard curves were linear in the concentration ranges of 4.5-900 ng/mL for WX472, 5-1000 ng/mL for WX581 and 0.5-100 ng/mL for 1b and telmisartan. Intra- and inter-batch precisions (R.S.D.%) were all within 15% and the method assessed a quite good accuracy (R.E.%). Recoveries were found to be >65% for all the compounds and no obvious matrix effects were found. This method has been successfully applied to the high-throughput pharmacokinetic screening study for both cassette dosing and cassette analysis of four compounds to rats. Significant drug-drug interactions were observed after cassette dosing. The study suggested that cassette analysis of pooled samples would be a better choice for the high-throughput pharmacokinetic screening of angiotensin type 1 receptor antagonists.

[Dyslipidemia management in patients with high cardiovascular risk in Spain. ALMA study].

PubMed

Pintó, Xavier; Trias Vilagut, Ferran; Rius Taruella, Joan; Mairal Sallán, Esther

2018-01-01

To assess the attitude of primary care (PCPs) and specialized care (SCPs) physicians towards the general set of patients with dyslipidemia, particularly those with cardiovascular risk factors. Observational, descriptive, multi-center study based on a survey. Different healthcare regions in Spain. 1,402 PCPs, and 596 SCPs. Physician's profile, routine practices in the management of patients with dyslipidemia. 84.3% took the global cardiovascular risk into account when prescribing the treatment. Target LDL-C concentration in patients without cardiovascular risk factors was <130mg/dL and <160mg/dL for 51.9% and 29.0% of physicians, respectively. In smokers and patients with hypertension or diabetes, the LDL target was <100mg/dL for 49-55% of physicians, whereas in patients with cardiovascular complication, ischemic cardiopathy or stroke, target LDL-C was <70mg/dL in 71-88% of them. First-line treatment for patients without cardiovascular risk factors was atorvastatin (66%), whereas in patients with diabetes, kidney disease or metabolic syndrome, most physicians (80-89%) used pitavastatin. SCPs showed a greater trend than PCPs to establish a LDL-C target of <70mg/dL in patients with previous stroke (77.5% vs 66.8%) or coronary disease (92.1% vs 80.6%) (P<.0001), as well as to prescribe a combined treatment in patients not achieving the target LDL-C concentrations (58.1% vs 50.2%, P=.0013). Although CVR assessment is generally accepted, there is broad disagreement in defining the objectives of LDL-C. Most often than PCPs, the SCPs consider more ambitious targets for LDL-C and the association of lipid-lowering drugs. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

LC-MS-MS simultaneous determination of atorvastatin and ezetimibe in human plasma.

PubMed

El-Bagary, Ramzia I; Elkady, Ehab F; El-Sherif, Zeinab Abdelaziz; Kadry, Ahmed M

2014-09-01

Atorvastatin and ezetimibe are lipid-lowering drugs prescribed for the treatment of hypercholesterolemia. An LC-MS-MS method has been developed and validated for the simultaneous estimation of atorvastatin and ezetimibe in human plasma using pitavastatin as an internal standard. Liquid-liquid extraction was used for the purification and preconcentration of analytes from human plasma matrix. The chromatographic separation was achieved within 3.0 min by an isocratic mobile phase consisting of 0.2% formic acid in water-acetonitrile (30:70, v/v), flowing through Agilent Eclipse-plus C18, 100 × 4.6 mm, 3.5 µm analytical column, at a flow rate of 0.6 mL min(-1). Multiple reaction monitoring transitions were measured in the positive ion mode for atorvastatin and internal standard, while ezetimibe was measured in negative ion mode. A detailed validation of the method was performed as per US-FDA guidelines and the standard curves were found to be linear in the range of 0.2-30.0 ng mL(-1) with a mean correlation coefficient >0.999 for both drugs. In human plasma, atorvastatin and ezetimibe were stable for at least 36 days at -70 ± 5 °C and 6 h at ambient temperature. After extraction from plasma, the reconstituted samples of atorvastatin and ezetimibe were stable in an autosampler at ambient temperature for 6 h. Also, the cited drugs were stable in plasma samples upon subjecting to three freeze thaw cycles. The method is simple, specific, sensitive, precise, accurate and suitable for bioequivalence and pharmacokinetic studies of this combination. © The Author [2013]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.

PubMed

Robinson, Jennifer G; Nedergaard, Bettina S; Rogers, William J; Fialkow, Jonathan; Neutel, Joel M; Ramstad, David; Somaratne, Ransi; Legg, Jason C; Nelson, Patric; Scott, Rob; Wasserman, Scott M; Weiss, Robert

2014-05-14

In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin. Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%). In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering. clinicaltrials.gov Identifier: NCT01763866.

Physicians' Experiences as Patients with Statin Side Effects: A Case Series.

PubMed

Koslik, Hayley J; Meskimen, Athena Hathaway; Golomb, Beatrice Alexandra

2017-12-01

Physicians are among those prescribed statins and therefore, subject to potential statin adverse effects (AEs). There is little information on the impact of statin AEs on physicians affected by them. We sought to assess the character and impact of statin AEs occurring in physicians and retired physicians, and to ascertain whether/how personal experience of AEs moderated physicians' attitude toward statin use. Seven active or retired physicians from the United States communicated with the Statin Effects Study group regarding their personal experience of statin AEs. AE characteristics, experience with (their own) physicians, and impact of AE was ascertained. We inquired whether or how their experience altered their own attitude toward statins or statin AEs. Patient A: Atorvastatin 40 then 80 mg was followed by cognitive problems, neuropathy, and glucose intolerance in a Radiologist in his 50s (Naranjo criteria: probable causality). Patient B: Atorvastatin 10 mg was followed in 2 months by muscle weakness and myalgia in an Internist in his 40s (probable causality). Patient C: Atorvastatin, ezetimibe/simvastatin, rosuvastatin at varying doses was followed shortly after by irritability, myalgia, and fatigue in a Cardiac Surgeon in his 40s (probable causality). Patient D: Simvastatin 20 then 40 mg was followed in 4 years by mitochondriopathy, myopathy, neuropathy, and exercise intolerance in an Emergency Medicine physician in his 50s (definite causality). Patient E: Simvastatin 20 mg and niacin 1000 mg was followed in one month by muscle weakness and myalgia in a Physical Medicine and Rehabilitation physician in his 50s (probable causality). Patient F: Lovastatin 20 mg then simvastatin 20 mg, atorvastatin 20 mg, rosuvastatin 5 mg, niacin 20 mg and ezetimbe 10 mg was followed by muscle weakness and myalgia in an Obstetrician/Gynecologist in his 70s (definite causality). Patient G: Ezetimibe/simvastatin and atorvastatin (dose unavailable) was followed shortly after by cognitive problems in a Radiologist in her 80s (probable causality). Thus AEs affected multiple quality-of-life relevant domains, often in combination, encompassing muscle (N = 5), fatigue (N = 2), peripheral neuropathy (N = 2), cognitive (N = 2), dysglycemia (N = 1) and behavioral manifestations (N = 1). In five, the AEs affected the physician professionally. Five physicians experienced dismissive attitudes in some of their own healthcare encounters. One noted that his experience helped not only his own attention to statin AEs, but that of other physicians in his community. Several stated that their experience altered their understanding of and/or attitude toward statin AEs, and/or their view of settings in which statin use is warranted. Statin AEs can have profound impact in high functioning professionals with implications to the individual, their professional life, and those whom they serve professionally.

Fluorescence spectroscopic detection of virus-induced atherosclerosis

NASA Astrophysics Data System (ADS)

Yan, Wei-dong; Perk, Masis; Nation, Patric N.; Power, Robert F.; Liu, Liying; Jiang, Xiuyan; Lucas, Alexandra

1994-07-01

Laser-induced fluorescence (LF) has been developed as a diagnostic tool for the detection of atherosclerosis. We have examined the use of LF for the identification of accelerated atherosclerotic plaque growth induced by Marek's Disease Virus (MDV) infection in White Leghorn rooster chicks (R) as well as plaque regression after treatment. Twenty-eight newborn R were infected with 12,000 cfu of MDV. Twelve parallel control R had saline injection. LF spectra were recorded from the arteries in vitro with a CeramOptec laser angioplasty catheter during 308 nm XeCl excimer laser excitation. Significant differences were detected at 440 to 475, 525, 550, 600, and 650 nm in MDV-R (p<0.05). In a subsequent study, 60 R were infected with 5,000 cfu of MDV, and were then treated with either Pravastatin (PRV) or placebo at 3 months post infection. These PRV-R were followed for 6 months to detect changes in atherosclerotic plaque development. PRV reduced intimal proliferation produced by MDV infection on histological examination (PRV-R 128.0+/- 44.0 micrometers , placebo-R 412.2+/- 91.5 micrometers , pequals0.007). MDV infected, PRV treated R were examined for LF changes that correlated with decreased atherosclerosis. There was an associated significant increase in LF intensity in PRV-R at 405 to 425 nm (p<0.001). In conclusion, LF can detect intimal proliferation in virus- induced atherosclerosis and atherosclerotic plaque regression after PRV therapy.

Rapid and label-free microfluidic neutrophil purification and phenotyping in diabetes mellitus

NASA Astrophysics Data System (ADS)

Hou, Han Wei; Petchakup, Chayakorn; Tay, Hui Min; Tam, Zhi Yang; Dalan, Rinkoo; Chew, Daniel Ek Kwang; Li, King Ho Holden; Boehm, Bernhard O.

2016-07-01

Advanced management of dysmetabolic syndromes such as diabetes will benefit from a timely mechanistic insight enabling personalized medicine approaches. Herein, we present a rapid microfluidic neutrophil sorting and functional phenotyping strategy for type 2 diabetes mellitus (T2DM) patients using small blood volumes (fingerprick ~100 μL). The developed inertial microfluidics technology enables single-step neutrophil isolation (>90% purity) without immuno-labeling and sorted neutrophils are used to characterize their rolling behavior on E-selectin, a critical step in leukocyte recruitment during inflammation. The integrated microfluidics testing methodology facilitates high throughput single-cell quantification of neutrophil rolling to detect subtle differences in speed distribution. Higher rolling speed was observed in T2DM patients (P < 0.01) which strongly correlated with neutrophil activation, rolling ligand P-selectin glycoprotein ligand 1 (PSGL-1) expression, as well as established cardiovascular risk factors (cholesterol, high-sensitive C-reactive protein (CRP) and HbA1c). Rolling phenotype can be modulated by common disease risk modifiers (metformin and pravastatin). Receiver operating characteristics (ROC) and principal component analysis (PCA) revealed neutrophil rolling as an important functional phenotype in T2DM diagnostics. These results suggest a new point-of-care testing methodology, and neutrophil rolling speed as a functional biomarker for rapid profiling of dysmetabolic subjects in clinical and patient-oriented settings.

Statins Reduce the Risks of Relapse to Addiction in Rats

PubMed Central

Chauvet, Claudia; Nicolas, Celine; Lafay-Chebassier, Claire; Jaber, Mohamed; Thiriet, Nathalie; Solinas, Marcello

2016-01-01

Statins are drugs that have been used for decades in humans for the treatment of hypercholesterolemia. More recently, several lines of evidence demonstrate that statins, in addition to their peripheral effects, produce a wide variety of effects in the brain and may be beneficial in neurological and psychiatric conditions. In this study, we allowed rats to self-administer cocaine for several weeks and, at the end of self-administration training, we treated them with low doses of statins daily for a 21-day period of abstinence. Chronic administration of brain-penetrating statins, simvastatin (1 mg/kg) and atorvastatin (1 mg/kg), reduced cocaine seeking compared with vehicle, whereas administration of pravastatin (2 mg/kg), a statin with low brain penetrability, did not. Importantly, the effects of brain-penetrating statins persisted even after discontinuation of the treatment and were specific for drug seeking because drug taking was not altered by simvastatin treatment. Finally, the effects of simvastatin were found to generalize to another drug of abuse such as nicotine, but not to food reward, and to reinstatement of cocaine seeking induced by stress. These results demonstrate that brain-penetrating statins can reduce risks of relapse to addiction. Given their well-known safety profile in humans, statins could be a novel effective treatment for relapse to cocaine and nicotine addiction and their use could be implemented in clinical settings without major health risks. PMID:26466819

Uremic toxins enhance statin-induced cytotoxicity in differentiated human rhabdomyosarcoma cells.

PubMed

Uchiyama, Hitoshi; Tsujimoto, Masayuki; Shinmoto, Tadakazu; Ogino, Hitomi; Oda, Tomoko; Yoshida, Takuya; Furukubo, Taku; Izumi, Satoshi; Yamakawa, Tomoyuki; Tachiki, Hidehisa; Minegaki, Tetsuya; Nishiguchi, Kohshi

2014-09-03

The risk of myopathy and rhabdomyolysis is considerably increased in statin users with end-stage renal failure (ESRF). Uremic toxins, which accumulate in patients with ESRF, exert cytotoxic effects that are mediated by various mechanisms. Therefore, accumulation of uremic toxins might increase statin-induced cytotoxicity. The purpose of this study was to determine the effect of four uremic toxins-hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate, indole-3-acetic acid, and 3-indoxyl sulfate-on statin-induced myopathy. Differentiated rhabdomyosarcoma cells were pre-treated with the uremic toxins for seven days, and then the cells were treated with pravastatin or simvastatin. Cell viability and apoptosis were assessed by viability assays and flow cytometry. Pre-treatment with uremic toxins increased statin- but not cisplatin-induced cytotoxicity (p < 0.05 vs. untreated). In addition, the pre-treatment increased statin-induced apoptosis, which is one of the cytotoxic factors (p < 0.05 vs. untreated). However, mevalonate, farnesol, and geranylgeraniol reversed the effects of uremic toxins and lowered statin-induced cytotoxicity (p < 0.05 vs. untreated). These results demonstrate that uremic toxins enhance statin-induced apoptosis and cytotoxicity. The mechanism underlying this effect might be associated with small G-protein geranylgeranylation. In conclusion, the increased severity of statin-induced rhabdomyolysis in patients with ESRF is likely due to the accumulation of uremic toxins.

Molecular rationale delineating the role of lycopene as a potent HMG-CoA reductase inhibitor: in vitro and in silico study.

PubMed

Alvi, Sahir Sultan; Iqbal, Danish; Ahmad, Saheem; Khan, M Salman

2016-09-01

This study initially aimed to depict the molecular rationale evolving the role of lycopene in inhibiting the enzymatic activity of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase via in vitro and in silico analysis. Our results illustrated that lycopene exhibited strong HMG-CoA reductase inhibitory activity (IC50 value of 36 ng/ml) quite better than pravastatin (IC50 = 42 ng/ml) and strong DPPH free radical scavenging activity (IC50 value = 4.57 ± 0.23 μg/ml) as compared to ascorbic acid (IC50 value = 9.82 ± 0.42 μg/ml). Moreover, the Ki value of lycopene (36 ng/ml) depicted via Dixon plot was well concurred with an IC50 value of 36 ± 1.8 ng/ml. Moreover, molecular informatics study showed that lycopene exhibited binding energy of -5.62 kcal/mol indicating high affinity for HMG-CoA reductase than HMG-CoA (ΔG: -5.34 kcal/mol). Thus, in silico data clearly demonstrate and support the in vitro results that lycopene competitively inhibit HMG-CoA reductase activity by binding at the hydrophobic portion of HMG-CoA reductase.

Left Ventricular Hypertrophy and Cognitive Decline in Old Age.

PubMed

Mahinrad, Simin; Vriend, Annelotte E; Jukema, J Wouter; van Heemst, Diana; Sattar, Naveed; Blauw, Gerard Jan; Macfarlane, Peter W; Clark, Elaine N; de Craen, Anton J M; Sabayan, Behnam

2017-01-01

Patients with advanced heart failure run a greater risk of dementia. Whether early cardiac structural changes also associate with cognitive decline is yet to be determined. We tested whether left ventricular hypertrophy (LVH) derived from electrocardiogram associates with cognitive decline in older subjects at risk of cardiovascular disease. We included 4,233 participants (mean age 75.2 years, 47.8% male) from PROSPER (PROspective Study of Pravastatin in the Elderly at Risk). LVH was assessed from baseline electrocardiograms by measuring the Sokolow-Lyon index. Higher levels of Sokolow-Lyon index indicate higher degrees of LVH. Cognitive domains involving selective attention, processing speed, and immediate and delayed memory were measured at baseline and repeated during a mean follow-up of 3.2 years. At baseline, LVH was not associated with worse cognitive function. During follow-up, participants with higher levels of LVH had a steeper decline in cognitive function including in selective attention (p = 0.009), processing speed (p = 0.010), immediate memory (p < 0.001), and delayed memory (p = 0.002). These associations were independent of cardiovascular risk factors, co-morbidities, and medications. LVH assessed by electrocardiogram associates with steeper decline in cognitive function of older subjects independent of cardiovascular risk factors and co-morbidities. This study provides further evidence on the link between subclinical cardiac structural changes and cognitive decline in older subjects.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE.

PubMed

Jellinger, Paul S; Handelsman, Yehuda; Rosenblit, Paul D; Bloomgarden, Zachary T; Fonseca, Vivian A; Garber, Alan J; Grunberger, George; Guerin, Chris K; Bell, David S H; Mechanick, Jeffrey I; Pessah-Pollack, Rachel; Wyne, Kathleen; Smith, Donald; Brinton, Eliot A; Fazio, Sergio; Davidson, Michael

2017-04-01

The development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. The Executive Summary of this document contains 87 recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 (10.3%) are Grade D. These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world medical care. The evidence base presented in the subsequent Appendix provides relevant supporting information for Executive Summary Recommendations. This update contains 695 citations of which 203 (29.2 %) are EL 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 236 (34.0%) are EL 4 (no clinical evidence). This CPG is a practical tool that endocrinologists, other health care professionals, health-related organizations, and regulatory bodies can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of individuals with various lipid disorders. The recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously endorsed and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to individuals with diabetes, familial hypercholesterolemia, women, and youth with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions. 4S = Scandinavian Simvastatin Survival Study A1C = glycated hemoglobin AACE = American Association of Clinical Endocrinologists AAP = American Academy of Pediatrics ACC = American College of Cardiology ACE = American College of Endocrinology ACS = acute coronary syndrome ADMIT = Arterial Disease Multiple Intervention Trial ADVENT = Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study AHA = American Heart Association AHRQ = Agency for Healthcare Research and Quality AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides trial ASCVD = atherosclerotic cardiovascular disease ATP = Adult Treatment Panel apo = apolipoprotein BEL = best evidence level BIP = Bezafibrate Infarction Prevention trial BMI = body mass index CABG = coronary artery bypass graft CAC = coronary artery calcification CARDS = Collaborative Atorvastatin Diabetes Study CDP = Coronary Drug Project trial CI = confidence interval CIMT = carotid intimal media thickness CKD = chronic kidney disease CPG(s) = clinical practice guideline(s) CRP = C-reactive protein CTT = Cholesterol Treatment Trialists CV = cerebrovascular CVA = cerebrovascular accident EL = evidence level FH = familial hypercholesterolemia FIELD = Secondary Endpoints from the Fenofibrate Intervention and Event Lowering in Diabetes trial FOURIER = Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial HATS = HDL-Atherosclerosis Treatment Study HDL-C = high-density lipoprotein cholesterol HeFH = heterozygous familial hypercholesterolemia HHS = Helsinki Heart Study HIV = human immunodeficiency virus HoFH = homozygous familial hypercholesterolemia HPS = Heart Protection Study HPS2-THRIVE = Treatment of HDL to Reduce the Incidence of Vascular Events trial HR = hazard ratio HRT = hormone replacement therapy hsCRP = high-sensitivity CRP IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial IRAS = Insulin Resistance Atherosclerosis Study JUPITER = Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin LDL-C = low-density lipoprotein cholesterol Lp-PLA2 = lipoprotein-associated phospholipase A2 MACE = major cardiovascular events MESA = Multi-Ethnic Study of Atherosclerosis MetS = metabolic syndrome MI = myocardial infarction MRFIT = Multiple Risk Factor Intervention Trial NCEP = National Cholesterol Education Program NHLBI = National Heart, Lung, and Blood Institute PCOS = polycystic ovary syndrome PCSK9 = proprotein convertase subtilisin/kexin type 9 Post CABG = Post Coronary Artery Bypass Graft trial PROSPER = Prospective Study of Pravastatin in the Elderly at Risk trial QALY = quality-adjusted life-year ROC = receiver-operator characteristic SOC = standard of care SHARP = Study of Heart and Renal Protection T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus TG = triglycerides TNT = Treating to New Targets trial VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial VLDL-C = very low-density lipoprotein cholesterol WHI = Women's Health Initiative.

Development, Verification, and Prediction of Osimertinib Drug-Drug Interactions Using PBPK Modeling Approach to Inform Drug Label.

PubMed

Pilla Reddy, Venkatesh; Walker, Michael; Sharma, Pradeep; Ballard, Peter; Vishwanathan, Karthick

2018-02-22

Osimertinib is a potent, highly selective, irreversible inhibitor of epidermal growth factor receptor (EGFR) and T790M resistance mutation. In vitro metabolism data suggested osimertinib is a substrate of cytochrome P450 (CYP)3A4/5, a weak inducer of CYP3A, and an inhibitor of breast cancer resistance protein (BCRP). A combination of in vitro data, clinical pharmacokinetic data, and drug-drug interaction (DDI) data of osimertinib in oncology patients were used to develop the physiologically based pharmacokinetic (PBPK) model and verify the DDI data of osimertinib. The model predicted the observed monotherapy concentration profile of osimertinib within 1.1-fold, and showed good predictability (within 1.7-fold) to the observed peak plasma concentration (C max ) and area under the curve (AUC) DDI ratio changes, when co-administered with rifampicin, itraconazole, and simvastatin, but not with rosuvastatin. Based on observed clinical data and PBPK simulations, the recommended dose of osimertinib when dosed with strong CYP3A inducers is 160 mg once daily. PBPK modeling suggested no dose adjustment with moderate and weak CYP3A inducers. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for CPT: Pharmacometrics & Systems Pharmacology.

Clinical Drug-Drug Interaction Potential of BFE1224, Prodrug of Antifungal Ravuconazole, Using Two Types of Cocktails in Healthy Subjects.

PubMed

Ishii, Yasuyuki; Ito, Yuko; Matsuki, Shunji; Sanpei, Kasumi; Ogawa, Osamu; Takeda, Kenji; Schuck, Edgar L; Uemura, Naoto

2018-05-16

BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug-drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2. In addition, repaglinide was separately administered to the same subjects in study 2. There were no major effects on the pharmacokinetics of CYP and transporter substrates, except for an approximate threefold increase in midazolam exposure after oral administration of BFE1224. The clinical DDIs of BFE1224 were mild for CYP3A and minor for other major CYPs (CYP1A2/2C8/2C9/2C19/2D6) as well as those of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Comparative effectiveness of lipid-lowering treatments to reduce cardiovascular disease.

PubMed

Suh, Dong-Churl; Griggs, Scott K; Henderson, Emmett R; Lee, Seung-Mi; Park, Taehwan

2018-02-01

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is a new treatment option for patients with hypercholesterolemia. The objective of this study was to systematically review the cost-effectiveness of lipid-lowering agents. Areas covered: Based on Pubmed, Embase, and Cochrane Database of Systematic Reviews, we identified 29 relevant articles. Studies found statins were cost-effective compared with placebo or no treatment in general. Atorvastatin was reported to be cost-effective against simvastatin. In most cases, rosuvastatin was more cost-effective than atorvastatin or simvastatin. Additionally, ezetimibe was considered to be cost-effective compared with no treatment for statin intolerant patients. For patients not meeting treatment goals with their statins, switching to ezetimibe plus simvastatin was consistently reported cost-effective. The cost-effectiveness of ezetimibe plus a hybrid of a statin varied by the source of clinical data and cost of ezetimibe. Finally, the cost-effectiveness of PCSK9 inhibitor plus a statin against statin monotherapy was uncertain. The PCSK9 inhibitor plus a stain was cost-ineffective compared with ezetimibe plus a statin. Expert commentary: Drug costs and treatment efficacy were the key drivers of the cost-effectiveness results in prior analyses. Future evaluations are warranted to reflect the decreasing drug prices and the long-term treatment effects of PCSK9 inhibitors.

Directed Evolution of Carbonyl Reductase from Rhodosporidium toruloides and Its Application in Stereoselective Synthesis of tert-Butyl (3R,5S)-6-Chloro-3,5-dihydroxyhexanoate.

PubMed

Liu, Zhi-Qiang; Wu, Lin; Zhang, Xiao-Jian; Xue, Ya-Ping; Zheng, Yu-Guo

2017-05-10

tert-Butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate ((3R,5S)-CDHH) is a key intermediate of atorvastatin and rosuvastatin synthesis. Carbonyl reductase RtSCR9 from Rhodosporidium toruloides exhibited excellent activity toward tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH). For the activity of RtSCR9 to be improved, random mutagenesis and site-saturation mutagenesis were performed. Three positive mutants were obtained (mut-Gln95Asp, mut-Ile144Lys, and mut-Phe156Gln). These mutants exhibited 1.94-, 3.03-, and 1.61-fold and 1.93-, 3.15-, and 1.97-fold improvement in the specific activity and k cat /K m , respectively. Asymmetric reduction of (S)-CHOH by mut-Ile144Lys coupled with glucose dehydrogenase was conducted. The yield and enantiomeric excess of (3R,5S)-CDHH reached 98 and 99%, respectively, after 8 h bioconversion in a single batch reaction with 1 M (S)-CHOH, and the space-time yield reached 542.83 mmol L -1 h -1 g -1 wet cell weight. This study presents a new carbonyl reductase for efficient synthesis of (3R,5S)-CDHH.

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice.

PubMed

Schonewille, Marleen; de Boer, Jan Freark; Mele, Laura; Wolters, Henk; Bloks, Vincent W; Wolters, Justina C; Kuivenhoven, Jan A; Tietge, Uwe J F; Brufau, Gemma; Groen, Albert K

2016-08-01

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we investigated the effects on cholesterol metabolism in mice in detail. Surprisingly, direct measurement of whole body cholesterol synthesis revealed that cholesterol synthesis was robustly increased in statin-treated mice. Measurement of organ-specific cholesterol synthesis demonstrated that the liver is predominantly responsible for the increase in cholesterol synthesis. Excess synthesized cholesterol did not accumulate in the plasma, as plasma cholesterol decreased. However, statin treatment led to an increase in cholesterol removal via the feces. Interestingly, enhanced cholesterol excretion in response to rosuvastatin and lovastatin treatment was mainly mediated via biliary cholesterol secretion, whereas atorvastatin mainly stimulated cholesterol removal via the transintestinal cholesterol excretion pathway. Moreover, we show that plasma cholesterol precursor levels do not reflect cholesterol synthesis rates during statin treatment in mice. In conclusion, cholesterol synthesis is paradoxically increased upon statin treatment in mice. However, statins potently stimulate the excretion of cholesterol from the body, which sheds new light on possible mechanisms underlying the cholesterol-lowering effects of statins. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

PubMed Central

Schonewille, Marleen; Freark de Boer, Jan; Mele, Laura; Wolters, Henk; Bloks, Vincent W.; Wolters, Justina C.; Kuivenhoven, Jan A.; Tietge, Uwe J. F.; Brufau, Gemma; Groen, Albert K.

2016-01-01

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we investigated the effects on cholesterol metabolism in mice in detail. Surprisingly, direct measurement of whole body cholesterol synthesis revealed that cholesterol synthesis was robustly increased in statin-treated mice. Measurement of organ-specific cholesterol synthesis demonstrated that the liver is predominantly responsible for the increase in cholesterol synthesis. Excess synthesized cholesterol did not accumulate in the plasma, as plasma cholesterol decreased. However, statin treatment led to an increase in cholesterol removal via the feces. Interestingly, enhanced cholesterol excretion in response to rosuvastatin and lovastatin treatment was mainly mediated via biliary cholesterol secretion, whereas atorvastatin mainly stimulated cholesterol removal via the transintestinal cholesterol excretion pathway. Moreover, we show that plasma cholesterol precursor levels do not reflect cholesterol synthesis rates during statin treatment in mice. In conclusion, cholesterol synthesis is paradoxically increased upon statin treatment in mice. However, statins potently stimulate the excretion of cholesterol from the body, which sheds new light on possible mechanisms underlying the cholesterol-lowering effects of statins. PMID:27313057

Evaluation of pharmaceuticals in surface water: reliability of PECs compared to MECs.

PubMed

Celle-Jeanton, Hélène; Schemberg, Dimitri; Mohammed, Nabaz; Huneau, Frédéric; Bertrand, Guillaume; Lavastre, Véronique; Le Coustumer, Philippe

2014-12-01

Due to the current analytical processes that are not able to measure all the pharmaceutical molecules and to the high costs and the consumption of time to sample and analyze PhACs, models to calculate Predicted Environmental Concentrations (PECs) have been developed. However a comparison between MECs and PECs, taking into account the methods of calculations and peculiarly the parameters included in the calculation (consumption data, pharmacokinetic parameters, elimination rate in STPs and in the environment), is necessary to assess the validity of PECs. MEC variations of sixteen target PhACs [acetaminophen (ACE), amlodipine (AML), atenolol (ATE), caffeine (CAF), carbamazepine (CAR), doxycycline (DOX), epoxycarbamazepine (EPO), fluvoxamine (FLU), furosemide (FUR), hydrochlorothiazide (HYD), ifosfamide (IFO), losartan (LOS), pravastatin (PRA), progesterone (PROG), ramipril (RAM), trimetazidine (TRI)] have been evaluated during one hydrological cycle, from October 2011 to October 2012 and compared to PECs calculated by using an adaptation of the models proposed by Heberer and Feldmann (2005) and EMEA (2006). Comparison of PECs and MECS has been achieved for six molecules: ATE, CAR, DOX, FUR, HYD and PRA. DOX, FUR and HYD present differences between PECs and MECs on an annual basis but their temporal evolutions follow the same trends. PEC evaluation for these PhACs could then be possible but need some adjustments of consumption patterns, pharmacokinetic parameters and/or mechanisms of (bio)degradation. ATE, CAR and PRA are well modeled; PECs can then be used as reliable estimation of concentrations without any reserve. Copyright © 2014 Elsevier Ltd. All rights reserved.

Analysis of pharmaceuticals in wastewater and removal using a membrane bioreactor

PubMed Central

Radjenovic, Jelena; Barceló, Damiá

2006-01-01

Much attention has recently been devoted to the life and behaviour of pharmaceuticals in the water cycle. In this study the behaviour of several pharmaceutical products in different therapeutic categories (analgesics and anti-inflammatory drugs, lipid regulators, antibiotics, etc.) was monitored during treatment of wastewater in a laboratory-scale membrane bioreactor (MBR). The results were compared with removal in a conventional activated-sludge (CAS) process in a wastewater-treatment facility. The performance of an MBR was monitored for approximately two months to investigate the long-term operational stability of the system and possible effects of solids retention time on the efficiency of removal of target compounds. Pharmaceuticals were, in general, removed to a greater extent by the MBR integrated system than during the CAS process. For most of the compounds investigated the performance of MBR treatment was better (removal rates >80%) and effluent concentrations of, e.g., diclofenac, ketoprofen, ranitidine, gemfibrozil, bezafibrate, pravastatin, and ofloxacin were steadier than for the conventional system. Occasionally removal efficiency was very similar, and high, for both treatments (e.g. for ibuprofen, naproxen, acetaminophen, paroxetine, and hydrochlorothiazide). The antiepileptic drug carbamazepine was the most persistent pharmaceutical and it passed through both the MBR and CAS systems untransformed. Because there was no washout of biomass from the reactor, high-quality effluent in terms of chemical oxygen demand (COD), ammonium content (N-NH4), total suspended solids (TSS), and total organic carbon (TOC) was obtained. PMID:17115140

[Indications for the combination of pravastatin and fenofibrate according to the cardiovascular risk level. Common clinical situations].

PubMed

Pintó, Xavier

2014-07-01

In diabetes, metabolic syndrome, some types of familial dyslipidemia, ischemic pathology of atheromatous origin and renal failure, the presence of mixed dyslipidemia is common. In other words, there is an excess of cholesterol and triglycerides, associated or not with HDL-c deficiency. These clinical conditions are associated with high to very high cardiovascular risk. It is appropriate when treating these conditions to achieve an overall control of lipid metabolism abnormalities, in terms of excess cholesterol carried by atherogenic lipoproteins (LDL-c and non-HDL-c) and triglyceride excess and deficit of HDL-c. To achieve this overall control is necessary to correct the potential causes of secondary dyslipidemia, improve lifestyle habits and use a drug from the statin family, and it is often necessary to combine a drug from the fibrate family. This combination has been shown to be effective and safe in the overall control of dyslipidemia and the cardiovascular risk prevention in patients at high risk. This combination has been shown to have a favorable eff ect in the population with diabetes and microangiopathy, both in the retina and in the glomerulus. For patients with moderate renal failure, the use of fibrates is controversial, and there are marked disagreements between the recommendations issued by various organizations and expert consensus groups. Copyright © 2014 Sociedad Española de Arteriosclerosis y Elsevier España, S.L. All rights reserved.

Statins: novel additions to the dermatologic arsenal?

PubMed

Namazi, M R

2004-06-01

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), atorvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin and simvastatin, reduce atherogenesis and cardiovascular morbidity. Besides, there is growing evidence that statins have immunomodulatory activities. Statins downregulate the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MAC-1) and lymphocyte function-associated antigen-1 (LFA-1), on leucocytes and endothelial cells and, through binding to LFA-1, interfere with ICAM-1-LFA-1 interaction, which is crucial for activation of lymphocytes by antigen-presenting cells, ingress of leucocytes into the inflammation sites and immunologic cytotoxicity. Statins inhibit the inducible expression of major histocompatibility complex class II in several cell types including macrophages and downregulate the expression of T-helper-1 (Th1) chemokine receptors on T cells, leading further to inhibition of activation of lymphocytes and their infiltration into the inflammation sites. Statins block the induction of inducible nitric oxide synthase and the expression of several proinflammatory cytokines such as tumour necrosis factor-alpha and interferon-gamma in macrophages and possess antioxidant effects. These agents inhibit the proliferation of immunocytes and the activation of natural killer cells. Regarding the above facts and in view of their safety and inexpensiveness, statins may prove invaluable in the treatment of a multiplicity of dermatologic disorders, especially those characterized by ingress of activated leucocytes into the skin, such as alopecia areata, vitiligo, lichen planus, subacute cutaneous lupus erythematosus, erythema multiforme, psoriasis, bullous pemphigoid, systemic sclerosis, mycosis fungoides, toxic epidermal necrolysis and Behcet's disease.

Study of HMG-CoA Reductase Inhibition Activity of the Hydrolyzed Product of Snakehead Fish (Channa striata) Skin Collagen with 50 kDa Collagenase from Bacillus licheniformis F11.4.

PubMed

Virginia, Agnes; Rachmawati, Heni; Riani, Catur; Retnoningrum, Debbie S

2016-01-01

Bioactive peptides produced from enzymatic hydrolysis fibrous protein have been proven to have several biological activities. Previous study showed that the hydrolysis product of snakehead fish skin collagen with 26 kDa collagenase from Bacillus licheniformis F11.4 showed HMG-CoA (HMGR) inhibition activity. The aim of this research was to determine the ability of the hydrolysis product produced from snakehead fish skin collagen hydrolysed by 50 kDa collagenase from B. licheniformis F11.4 in inhibiting HMGR activity. Snakehead fish skin collagen was extracted using an acid method and collagenase was produced from B. licheniformis F11.4 using half-strength Luria Bertani (LB) medium containing 5% collagen. Crude collagenase was concentrated and fractionated using the DEAE Sephadex A-25 column eluted with increasing gradient concentrations of NaCl. Collagen, collagenase, and fractions were analyzed using SDS-PAGE and collagenolytic activity was analyzed by the zymography method. Collagenase with 50 kDa molecular weight presented in fraction one was used to hydrolyze the collagen. The reaction was done in 18 hours at 50°C. The hydrolysis product using 3.51 μg collagen and 9 ng collagenase showed 25.8% inhibition activity against pravastatin. This work shows for the first time that the hydrolysis product of snakehead fish skin collagen and 50 kDa collagenase from B. licheniformis F11.4 has potential as an anticholesterol agent.

Simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species.

PubMed

Brilhante, Raimunda Sâmia Nogueira; Caetano, Erica Pacheco de; Oliveira, Jonathas Sales; Castelo-Branco, Débora de Souza Collares Maia; Souza, Elizabeth Ribeiro Yokobatake; Alencar, Lucas Pereira de; Cordeiro, Rossana de Aguiar; Bandeira, Tereza de Jesus Pinheiro Gomes; Sidrim, José Júlio Costa; Rocha, Marcos Fábio Gadelha

2015-01-01

The antifungal activity of some statins against different fungal species has been reported. Thus, at the first moment, the in vitro antifungal activity of simvastatin, atorvastatin and pravastatin was tested against Candida spp. and Cryptococcus spp. Then, in a second approach, considering that the best results were obtained for simvastatin, this drug was evaluated in combination with antifungal drugs against planktonic growth and tested against biofilms of Candida spp. and Cryptococcus spp. Drug susceptibility testing was performed using the microdilution broth method, as described by the Clinical and Laboratory Standards Institute. The interaction between simvastatin and antifungals against planktonic cells was analyzed by calculating the fractional inhibitory concentration index. Regarding biofilm susceptibility, simvastatin was tested against growing biofilm and mature biofilm of one strain of each tested yeast species. Simvastatin showed inhibitory effect against Candida spp. and Cryptococcus spp. with minimum inhibitory concentration values ranging from 15.6 to 1000 mg L(-1) and from 62.5 to 1000 mg L(-1), respectively. The combination of simvastatin with itraconazole and fluconazole showed synergism against Candida spp. and Cryptococcus spp., while the combination of simvastatin with amphotericin B was synergistic only against Cryptococcus spp. Concerning the biofilm assays, simvastatin was able to inhibit both growing biofilm and mature biofilm of Candida spp. and Cryptococcus spp. The present study showed that simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Circulating interleukin-10 and risk of cardiovascular events: a prospective study in the elderly at risk.

PubMed

Welsh, Paul; Murray, Heather M; Ford, Ian; Trompet, Stella; de Craen, Anton J M; Jukema, J Wouter; Stott, David J; McInnes, Iain B; Packard, Chris J; Westendorp, Rudi G J; Sattar, Naveed

2011-10-01

The goal of this study was to examine the association of the antiinflammatory interleukin-10 (IL-10) with risk of cardiovascular disease (CVD). In the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) cohort, we related baseline concentrations of circulating IL-10 to risk of CVD events in a nested case (n=819)-control (n=1618) study of 3.2 years of follow-up. Circulating IL-10 showed few strong associations with classical risk factors but was positively correlated with IL-6 and C-reactive protein. IL-10 was positively associated with risk of CVD events (odds ratio [OR] 1.17, 95% CI 1.05 to 1.31 per unit increase in log IL-10) after adjusting for classical risk factors and C-reactive protein. Furthermore, IL-10 was associated more strongly with CVD risk among those with no previous history of CVD (OR 1.42, 95% CI 1.18 to 1.70), compared with those with previous CVD (OR 1.04, 95% CI 0.90 to 1.19; P=0.018). Overall, IL-10 showed a modest ability to add discrimination to classical risk factors (C-statistic +0.005, P=0.002). Baseline circulating levels of the antiinflammatory IL-10 are positively associated with risk of CVD among the elderly without prior CVD events, although the association is less evident in those with a history of CVD. Additional epidemiological and mechanistic studies investigating the role of IL-10 in CVD are warranted.

Treatment of statin compounds by advanced oxidation processes: Kinetic considerations and destruction mechanisms

NASA Astrophysics Data System (ADS)

Razavi, Behnaz; Song, Weihua; Santoke, Hanoz; Cooper, William J.

2011-03-01

This study examined the use of advanced oxidation/reduction processes (AO/RPs) for the destruction of cholesterol lowering statin pharmaceuticals. AO/RPs which utilize the oxidizing hydroxyl radical ( rad OH) and reducing aqueous electron (e -aq), to degrade chemical contaminants are alternatives to traditional water treatment methods, and are alternatives as water reuse becomes more generally implemented. Four major statin pharmaceuticals, fluvastatin, lovastatin, pravastatin and simvastatin, were studied, and the absolute bimolecular reaction rate constants with rad OH determined, (6.96±0.16)×10 9, (2.92±0.06)×10 9, (4.16±0.13)×10 9, and (3.13±0.15)×10 9 M -1 s -1, and for e -aq (2.31±0.06)×10 9, (0.45±0.01)×10 9, (1.26±0.01)×10 9, and (0.69±0.02)×10 9 M -1 s -1, respectively. To provide additional information on the radicals formed upon oxidation, transient spectra were measured and the overall reaction efficiency determined. Radical-based destruction mechanisms for destruction of the statins are proposed based on the LC-MS determination of the stable reaction by-products formed using 137Cs γ-irradiation of statin solutions. Knowing the reaction rates, reaction efficiencies and destruction mechanisms of these compounds is essential for the consideration of the use of advanced oxidation/reduction processes for the destruction of statins in aqueous systems.

Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-γ activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukuda, Kazuki; Matsumura, Takeshi, E-mail: takeshim@gpo.kumamoto-u.ac.jp; Senokuchi, Takafumi

Highlights: • Statins induce PPARγ activation in vascular smooth muscle cells. • Statin-induced PPARγ activation is mediated by COX-2 expression. • Statins suppress cell migration and proliferation in vascular smooth muscle cells. • Statins inhibit LPS-induced inflammatory responses by PPARγ activation. • Fluvastatin suppress the progression of atherosclerosis and induces PPARγ activation in the aorta of apoE-deficient mice. - Abstract: The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However,more » it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe{sup −/−} mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe{sup −/−} mice. In conclusion, statins mediate anti-atherogenic effects through PPARγ activation in SMCs. These effects of statins on SMCs may be beneficial for the prevention of atherosclerosis.« less

Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), in combination with statin treatment: Two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia.

PubMed

Arai, Hidenori; Yamashita, Shizuya; Yokote, Koutaro; Araki, Eiichi; Suganami, Hideki; Ishibashi, Shun

2017-06-01

Substantial residual cardiovascular risks remain despite intensive statin treatment. Residual risks with high triglyceride and low high-density lipoprotein cholesterol are not the primary targets of statins. K-877 (pemafibrate) demonstrated robust efficacy on triglycerides and high-density lipoprotein cholesterol and a good safety profile as a monotherapy. The aim of these studies was to evaluate the efficacy and safety of K-877 add-on therapy to treat residual hypertriglyceridaemia during statin treatment. The objectives were investigated in two, multicentre, randomised, double-blind, placebo-controlled, parallel group comparison clinical trials: (A) K-877 0.1, 0.2, and 0.4 mg/day in combination with pitavastatin for 12 weeks in 188 patients, (B) K-877 0.2 (fixed dose) and 0.2 (0.4) (conditional up-titration) mg/day in combination with any statin for 24 weeks in 423 patients. In both studies, we found a robust reduction in fasting triglyceride levels by approximately 50% in all combination therapy groups, which was significant compared to the statin-monotherapy (placebo) groups (p < 0.001). High-performance liquid chromatography analysis for lipoprotein subfractions revealed that atherogenic lipoprotein profiles were ameliorated by K-877 add-on therapy, i.e. small low-density lipoproteins decreased whereas larger ones increased, and larger high-density lipoproteins decreased whereas smaller ones increased. The incidence rates of adverse events and adverse drug reactions in K-877 combination therapy groups were comparable to those in statin-monotherapy groups without any noteworthy event in both studies. These results strongly support the favourable benefit-to-risk ratio of K-877 add-on therapy in combination with statin treatment. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Statin-related aminotransferase elevation according to baseline aminotransferases level in real practice in Korea.

PubMed

Kim, H-S; Lee, S H; Kim, H; Lee, S-H; Cho, J H; Lee, H; Yim, H W; Kim, S-H; Choi, I-Y; Yoon, K-H; Kim, J H

2016-06-01

Higher rate of statin-related hepatotoxicity has been reported for Koreans than for Westerners. Moreover, statin-related aminotransferase elevation for those who show borderline levels of aspartate transaminase (AST) and alanine transaminase (ALT) (≤×3 of UNL) at baseline has not been fully investigated. Post-statin changes AST/ALT levels during the first year for 21 233 Korean outpatients at two large academic teaching hospitals from January 2009 to December 2013 were analysed using electronic health record data. The date of the first statin prescription was set as baseline. We also performed a comparative analysis of statin-related AST/ALT elevations according to the type of statin, followed by an analysis of clinical risk factors. The progression rate to abnormal AST/ALT values [>×3 the upper normal limit (UNL)] was significantly higher (2·4-16% vs. 0·3-1·7%, P < 0·001) in subjects with borderline (>×1, but ≤×3 of UNL) compared with normal AST/ALT values at baseline. Those with normal baseline AST/ALT did not show significantly different progression rate between different statin medications (P = 0·801). However, patients taking pitavastatin (HR = 0·76, P = 0·657) were least likely to develop abnormal AST/ALT, whereas those taking fluvastatin (HR = 2·96, P = 0·029) were the most likely to develop abnormal AST/ALT compared with atorvastatin for patients who were with baseline borderline AST/ALT. However, given the small sample sizes and the observational nature of our study, these need further study. It is advisable to regularly monitor AST/ALT levels even in patients with AST/ALT increases >×1. Future studies should aim to determine the possible risk factors for each specific statin type by analysing various confounding variables. © 2016 The Authors. Journal of Clinical Pharmacy and Therapeutics Published by John Wiley & Sons Ltd.

Expression of miR-23a induces telomere shortening and is associated with poor clinical outcomes in patients with coronary artery disease.

PubMed

Satoh, Mamoru; Nasu, Takahito; Takahashi, Yuji; Osaki, Takuya; Hitomi, Sho; Morino, Yoshihiro; Nakamura, Motoyuki

2017-08-01

Telomeric repeat binding factor (TRF) 2 (TRF2) plays an important role in telomere maintenance. miR-23a may directly inhibit TRF2 expression, thereby, inducing telomere shortening and cellular senescence. The present study aimed to determine whether miR-23a and TRF2 are expressed in patients with coronary artery disease (CAD), and whether pitavastatin might affect these levels. The present study included 104 patients with CAD and 50 controls. Patients with CAD were randomly divided into two subgroups (a moderate lipid lowering therapy (LLT) group and an aggressive LLT group). Peripheral blood mononuclear cells (PBMCs) were taken from patients with CAD and from controls at baseline and after 12 months. Levels of miR-23a were higher in the CAD group than in the controls. Levels of TRF2 protein were lower in the CAD group than in the controls. Our randomized clinical study showed that aggressive LLT decreased miR-23a and increased TRF2 levels, whereas moderate LLT generated no change in these levels. Our transfected cell model showed that miR-23a controlled TRF2 expression. After a mean follow-up of 339 days, cardiovascular events were associated with high miR-23a , low TRF2 or low relative telomere length. Multivariate analysis showed that levels of miR-23a (RR: 4.9, 95% CI: 1.9-14.3) were a strong predictor of cardiovascular events after adjustment for baseline characteristics. In conclusion, elevated levels of miR-23a play an important role in coronary atherosclerosis via down-regulated TRF2, and may provide important prognostic information in patients with CAD. Additionally, aggressive LLT may prevent telomere erosion via down-regulated miR-23a . © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-05-01

O(6)-Benzylguanine; (-)-Gossypol; Abatacept, AC-2592, Adalimumab, AIDSVAX gp120 B/E, Alemtuzumab, Aliskiren fumarate, ALVAC E120TMG, Ambrisentan, Amlodipine, Anakinra, Aripiprazole, Armodafinil, Atomoxetine hydrochloride, Avotermin; Bevacizumab, BIBW-2992, Bortezomib, Bosentan, Botulinum toxin type B; Canakinumab, CAT-354, Ciclesonide, CMV gB vaccine, Corifollitropin alfa, Daptomycin, Darbepoetin alfa, Dasatinib, Denosumab; EndoTAG-1, Eplerenone, Esomeprazole sodium, Eszopiclone, Etoricoxib, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; F-50040, Fesoterodine fumavate, Fondaparinux sodium, Fulvestrant; Gabapentin enacarbil, Golimumab; Imatinib mesylate, Inhalable human insulin, Insulin glargine, Ivabradine hydrochloride; Lercanidipine hydrochloride/enalapril maleate, Levosimendan, Liposomal vincristine sulfate, Liraglutide; MDV-3100, Mometasone furoate/formoterol fumavate, Multiepitope CTL peptide vaccine, Mycophenolic acid sodium salt, Nabiximols, Natalizumab, Nesiritide; Obeticholic acid, Olmesartan medoxomil, Omalizumab, Omecamtiv mecarbil; Paclitaxel-eluting stent, Paliperidone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, Polymyxin B nonapeptide, PORxin-302, Prasugrel, Pregabalin, Pridopidine; Ranelic acid distrontium salt, Rasagiline mesilate, rDEN4delta30-4995, Recombinant human relaxin H2, rhFSH, Rilonacept, Rolofylline, Rosiglitazone maleate/metformin hydrochloride, Rosuvastatin calcium, Rotigotine; Salcaprozic acid sodium salt, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, Temsirolimus, Tenofovir, Tenofovir disoproxil fumarate, Teriparatide, Tiotropium bromide, Tocilizumab, Tolvaptan, Tozasertib, Treprostinil sodium; Ustekinumab; Vardenafil hydrochloride hydrate, Varenicline tartrate, Vatalanib succinate, Voriconazole, Vorinostat; Zotarolimus-eluting stent. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Impact of ellagic acid in bone formation after tooth extraction: an experimental study on diabetic rats.

PubMed

Al-Obaidi, Mazen M Jamil; Al-Bayaty, Fouad Hussain; Al Batran, Rami; Hussaini, Jamal; Khor, Goot Heah

2014-01-01

To estimate the impact of ellagic acid (EA) towards healing tooth socket in diabetic animals, after tooth extraction. Twenty-four Sprague Dawley male rats weighing 250-300 g were selected for this study. All animals were intraperitoneally injected with 45 mg/kg (b.w.) of freshly prepared streptozotocin (STZ), to induce diabetic mellitus. Then, the animals were anesthetized, and the upper left central incisor was extracted and the whole extracted sockets were filled with Rosuvastatin (RSV). The rats were separated into three groups, comprising 8 rats each. The first group was considered as normal control group and orally treated with normal saline. The second group was regarded as diabetic control group and orally treated with normal saline, whereas the third group comprised diabetic rats, administrated with EA (50 mg/kg) orally. The maxilla tissue stained by eosin and hematoxylin (H&E) was used for histological examinations and immunohistochemical technique. Fibroblast growth factor (FGF-2) and alkaline phosphatase (ALP) were used to evaluate the healing process in the extracted tooth socket by immunohistochemistry test. The reactions of immunohistochemistry for FGF-2 and ALP presented stronger expression, predominantly in EA treated diabetic rat, than the untreated diabetic rat. These findings suggest that the administration of EA combined with RSV may have accelerated the healing process of the tooth socket of diabetic rats, after tooth extraction.

Biosynthesis of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate by carbonyl reductase from Rhodosporidium toruloides in mono and biphasic media.

PubMed

Liu, Zhi-Qiang; Wu, Lin; Zheng, Ling; Wang, Wen-Zhong; Zhang, Xiao-Jian; Jin, Li-Qun; Zheng, Yu-Guo

2018-02-01

tert-Butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate ((3R,5S)-CDHH) is the key intermediate for synthesis of atorvastatin and rosuvastatin. Carbonyl reductase exhibits excellent activity toward tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH) to synthesize (3R,5S)-CDHH. In this study, a whole cell biosynthesis reaction system to produce (3R,5S)-CDHH was constructed in organic solvents. A solution of 10% (v/v) Tween-80 was introduced to the reaction system as a co-solvent, which greatly enhanced biotransformation process, giving 98.9% yield, >99% ee and 1.8-fold higher space time yield in 5 h bioconversion of 1 M (S)-CHOH, compared with 98.7% yield and >99% ee in 9 h bioconversion of a purely aqueous reaction system. Moreover, a water-octanol biphasic reaction system was built and 20% of octanol was added as reservoir of substrate resulting in 98% yield, >99% ee and 4.08 mmol L -1  h -1  g -1 (wet cell weight) space time yield. This study paved a way for the whole cell biosynthesis of (3R,5S)-CDHH in mono and biphasic media. Copyright © 2017 Elsevier Ltd. All rights reserved.

Silica-gold nanoparticles for atheroprotective management of plaques: results of the NANOM-FIM trial

NASA Astrophysics Data System (ADS)

Kharlamov, Alexander N.; Tyurnina, Anastasiya E.; Veselova, Vera S.; Kovtun, Olga P.; Shur, Vladimir Y.; Gabinsky, Jan L.

2015-04-01

Background: Atheroregression becomes an attractive target for cardiovascular treatment. Some clinical trials have demonstrated that intensive therapy with rosuvastatin or recombinant ApoA-I Milano can partially reduce the total atheroma volume (TAV) up to 6.38 mm3 or 14.1 mm3 respectively. Our previous bench studies of selected nanotechnologies documented TAV reduction up to an unprecedented 79.4 mm3. Methods: The completed observational three arms (n = 180) first-in-man trial (the NANOM FIM trial) assessed (NCT01270139) the safety and feasibility of two delivery techniques for nanoparticles (NP), and plasmonic photothermal therapy (PPTT). Patients were assigned to receive either (1) nano-intervention with delivery of silica-gold NP in a bioengineered on-artery patch (n = 60), or (2) nano-intervention with delivery of silica-gold iron-bearing NP with targeted micro-bubbles and stem cells using a magnetic navigation system (n = 60) versus (3) stent implantation (n = 60). The primary outcome was TAV at 12 months. Results: The mean TAV reduction at 12 months in the Nano group was 60.3 mm3 (SD 39.5; min 41.9 mm3, max 94.2 mm3; p < 0.05) up to mean 37.8% (95% CI: 31.1%, 51.7%; p < 0.05) plaque burden. The analysis of the event free survival of the ongoing clinical follow-up shows the significantly lower risk of cardiovascular death in the Nano group when compared with others (91.7% vs. 81.7% and 80% respectively; p < 0.05) with no cases of the target lesion-related complications. Conclusions: PPTT using silica-gold NP associated with significant regression of coronary atherosclerosis.Background: Atheroregression becomes an attractive target for cardiovascular treatment. Some clinical trials have demonstrated that intensive therapy with rosuvastatin or recombinant ApoA-I Milano can partially reduce the total atheroma volume (TAV) up to 6.38 mm3 or 14.1 mm3 respectively. Our previous bench studies of selected nanotechnologies documented TAV reduction up to an unprecedented 79.4 mm3. Methods: The completed observational three arms (n = 180) first-in-man trial (the NANOM FIM trial) assessed (NCT01270139) the safety and feasibility of two delivery techniques for nanoparticles (NP), and plasmonic photothermal therapy (PPTT). Patients were assigned to receive either (1) nano-intervention with delivery of silica-gold NP in a bioengineered on-artery patch (n = 60), or (2) nano-intervention with delivery of silica-gold iron-bearing NP with targeted micro-bubbles and stem cells using a magnetic navigation system (n = 60) versus (3) stent implantation (n = 60). The primary outcome was TAV at 12 months. Results: The mean TAV reduction at 12 months in the Nano group was 60.3 mm3 (SD 39.5; min 41.9 mm3, max 94.2 mm3; p < 0.05) up to mean 37.8% (95% CI: 31.1%, 51.7%; p < 0.05) plaque burden. The analysis of the event free survival of the ongoing clinical follow-up shows the significantly lower risk of cardiovascular death in the Nano group when compared with others (91.7% vs. 81.7% and 80% respectively; p < 0.05) with no cases of the target lesion-related complications. Conclusions: PPTT using silica-gold NP associated with significant regression of coronary atherosclerosis. On behalf of the team of the NANOM FIM study.

High pre-transplant serum nitrate levels predict risk of acute steroid-refractory graft-versus-host disease in the absence of statin therapy

PubMed Central

Dietrich, Sascha; Okun, Jürgen G.; Schmidt, Kathrin; Falk, Christine S.; Wagner, Andreas H.; Karamustafa, Suzan; Radujkovic, Aleksandar; Hegenbart, Ute; Ho, Anthony D.; Dreger, Peter; Luft, Thomas

2014-01-01

Steroid-refractory graft-versus-host disease is a life-threatening complication after allogeneic stem cell transplantation. Evidence is accumulating that steroid-refractory graft-versus-host disease is associated with endothelial distress. Endothelial cell homeostasis is regulated by nitric oxide, and serum nitrates are derived from nitric oxide synthase activity or dietary sources. In this retrospective study based on 417 patients allografted at our institution we investigated whether quantification of serum nitrates could predict steroid-refractory graft-versus-host disease. Elevated pre-transplant levels of serum nitrates (>26.5 μM) predicted steroid-refractory graft-versus-host disease (P=0.026) and non-relapse mortality (P=0.028), particularly in combination with high pre-transplant angiopoietin-2 levels (P=0.0007 and P=0.021, respectively). Multivariate analyses confirmed serum nitrates as independent predictors of steroid-refractory graft-versus-host disease and non-relapse mortality. Differences in serum nitrate levels did not correlate with serum levels of tumor necrosis factor or C-reactive protein or expression of inducible nitric oxide synthase in blood cells. Patients with high pre-transplant nitrate levels had significantly reduced rates of refractory graft-versus-host disease (P=0.031) when pravastatin was taken. In summary, patients at high risk of developing steroid-refractory graft-versus-host disease could be identified prior to transplantation by serum markers linked to endothelial cell function. Retrospectively, statin medication was associated with a reduced incidence of refractory graft-versus-host disease in this endothelial high-risk cohort. PMID:24142995

Regression discontinuity was a valid design for dichotomous outcomes in three randomized trials.

PubMed

van Leeuwen, Nikki; Lingsma, Hester F; Mooijaart, Simon P; Nieboer, Daan; Trompet, Stella; Steyerberg, Ewout W

2018-06-01

Regression discontinuity (RD) is a quasi-experimental design that may provide valid estimates of treatment effects in case of continuous outcomes. We aimed to evaluate validity and precision in the RD design for dichotomous outcomes. We performed validation studies in three large randomized controlled trials (RCTs) (Corticosteroid Randomization After Significant Head injury [CRASH], the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO], and PROspective Study of Pravastatin in elderly individuals at risk of vascular disease [PROSPER]). To mimic the RD design, we selected patients above and below a cutoff (e.g., age 75 years) randomized to treatment and control, respectively. Adjusted logistic regression models using restricted cubic splines (RCS) and polynomials and local logistic regression models estimated the odds ratio (OR) for treatment, with 95% confidence intervals (CIs) to indicate precision. In CRASH, treatment increased mortality with OR 1.22 [95% CI 1.06-1.40] in the RCT. The RD estimates were 1.42 (0.94-2.16) and 1.13 (0.90-1.40) with RCS adjustment and local regression, respectively. In GUSTO, treatment reduced mortality (OR 0.83 [0.72-0.95]), with more extreme estimates in the RD analysis (OR 0.57 [0.35; 0.92] and 0.67 [0.51; 0.86]). In PROSPER, similar RCT and RD estimates were found, again with less precision in RD designs. We conclude that the RD design provides similar but substantially less precise treatment effect estimates compared with an RCT, with local regression being the preferred method of analysis. Copyright © 2018 Elsevier Inc. All rights reserved.

Comparative cost-effectiveness of HMG-CoA reductase inhibitors in secondary prevention of acute myocardial infarction.

PubMed

Elliott, W J; Weir, D R

1999-09-01

The cost-effectiveness of each of the six hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors currently available was studied. For a cohort of patients between the ages of 60 and 85 years with coronary heart disease (CHD) who were taking atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, or simvastatin, the number of survivors, the annual direct cost per survivor, and the annual indirect cost saving per survivor associated with the predicted reduction in the rate of nonfatal myocardial infarction recurrences were projected. Percent reductions in excess mortality due to CHD were derived from the relative risks of cardiac mortality in treatment versus control groups in the Scandinavian Simvastatin Survival Study (4S). Doses necessary to provide a long-term 35.57% reduction in low-density- lipoprotein (LDL) cholesterol, as seen in 4S, were estimated. One-way sensitivity analyses were performed to assess the importance of the baseline assumptions. The cost per year of life saved ranged from $5,421 with atorvastatin to $15,073 with lovastatin. The patient's age at time of diagnosis of CHD had a major impact on the cost-effectiveness of the drugs; cost-effectiveness per year of life saved was higher for older patients than younger patients. The six currently marketed HMG-CoA reductase inhibitors varied widely in cost and effectiveness in producing reductions in the LDL-cholesterol concentrations that have been shown to prevent recurrent MI; there was an approximately threefold difference in the cost per year of life saved between the most cost-effective and least cost-effective agents.

Anti-inflammatory effects of Boletus edulis polysaccharide on asthma pathology.

PubMed

Wu, Songquan; Wang, Guangli; Yang, Ruhui; Cui, Yubao

2016-01-01

Asthma is a chronic airway disease common around the world. The burden of this disease could be reduced with new and effective treatments. Here, the efficacy of a polysaccharide extract from the Boletus edulis (BEP) mushroom, which has demonstrated anti-inflammatory properties, was tested in a mouse model of asthma. Five groups of BaLB/C mice were developed; one group served as a control and did not have asthma induction. The other four groups of mice were sensitized by ovalbumin challenge. FinePointe™ RC animal airway resistance and pulmonary compliance was used to assess airway function in asthma models. Three of the 4 model groups received treatments: one received pravastatin, one received dexamethasone, and one received BEP. Histopathology of lung tissues was performed using H&E and AB-PAS staining. Levels of cytokines IL-4 and IFN-g were detected using ELISA, qRT-PCR, and Western blotting. Cyclophilin A was measured by Western blot, and flow cytometry was used to determine the proportion of CD4 + CD25 + FOXP3 + Treg cells. BEP treatment resulted in improvements in lung pathology, IL-4 level (P<0.05), and IFN-γ level (P<0.05) similar to traditional dexamethasone treatment. Further, the proportion of anti-inflammatory CD4 + CD25 + FOXP3 + Treg cells significantly increased (P<0.05) compared to untreated asthma models, and expression of cyclophilin A significantly decreased (P<0.05). Thus, Boletus edulis polysaccharide reduces pro-inflammatory responses and increases anti-inflammatory responses in mouse models of asthma, suggesting this may be a novel treatment method.

Anti-inflammatory effects of Boletus edulis polysaccharide on asthma pathology

PubMed Central

Wu, Songquan; Wang, Guangli; Yang, Ruhui; Cui, Yubao

2016-01-01

Asthma is a chronic airway disease common around the world. The burden of this disease could be reduced with new and effective treatments. Here, the efficacy of a polysaccharide extract from the Boletus edulis (BEP) mushroom, which has demonstrated anti-inflammatory properties, was tested in a mouse model of asthma. Five groups of BaLB/C mice were developed; one group served as a control and did not have asthma induction. The other four groups of mice were sensitized by ovalbumin challenge. FinePointe™ RC animal airway resistance and pulmonary compliance was used to assess airway function in asthma models. Three of the 4 model groups received treatments: one received pravastatin, one received dexamethasone, and one received BEP. Histopathology of lung tissues was performed using H&E and AB-PAS staining. Levels of cytokines IL-4 and IFN-g were detected using ELISA, qRT-PCR, and Western blotting. Cyclophilin A was measured by Western blot, and flow cytometry was used to determine the proportion of CD4+CD25+FOXP3+ Treg cells. BEP treatment resulted in improvements in lung pathology, IL-4 level (P<0.05), and IFN-γ level (P<0.05) similar to traditional dexamethasone treatment. Further, the proportion of anti-inflammatory CD4+CD25+FOXP3+ Treg cells significantly increased (P<0.05) compared to untreated asthma models, and expression of cyclophilin A significantly decreased (P<0.05). Thus, Boletus edulis polysaccharide reduces pro-inflammatory responses and increases anti-inflammatory responses in mouse models of asthma, suggesting this may be a novel treatment method. PMID:27830033

Induced pluripotent stem cells reveal functional differences between drugs currently investigated in patients with hutchinson-gilford progeria syndrome.

PubMed

Blondel, Sophie; Jaskowiak, Anne-Laure; Egesipe, Anne-Laure; Le Corf, Amelie; Navarro, Claire; Cordette, Véronique; Martinat, Cécile; Laabi, Yacine; Djabali, Karima; de Sandre-Giovannoli, Annachiara; Levy, Nicolas; Peschanski, Marc; Nissan, Xavier

2014-04-01

Hutchinson-Gilford progeria syndrome is a rare congenital disease characterized by premature aging in children. Identification of the mutation and related molecular mechanisms has rapidly led to independent clinical trials testing different marketed drugs with a preclinically documented impact on those mechanisms. However, the extensive functional effects of those drugs remain essentially unexplored. We have undertaken a systematic comparative study of the three main treatments currently administered or proposed to progeria-affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin (zoledronate and pravastatin), and the macrolide antibiotic rapamycin. This work was based on the assumption that mesodermal stem cells, which are derived from Hutchinson-Gilford progeria syndrome-induced pluripotent stem cells expressing major defects associated with the disease, may be instrumental to revealing such effects. Whereas all three treatments significantly improved misshapen cell nuclei typically associated with progeria, differences were observed in terms of functional improvement in prelamin A farnesylation, progerin expression, defective cell proliferation, premature osteogenic differentiation, and ATP production. Finally, we have evaluated the effect of the different drug combinations on this cellular model. This study revealed no additional benefit compared with single-drug treatments, whereas a cytostatic effect equivalent to that of a farnesyltransferase inhibitor alone was systematically observed. Altogether, these results reveal the complexity of the modes of action of different drugs, even when they have been selected on the basis of a similar mechanistic hypothesis, and underscore the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies.

Induced Pluripotent Stem Cells Reveal Functional Differences Between Drugs Currently Investigated in Patients With Hutchinson-Gilford Progeria Syndrome

PubMed Central

Blondel, Sophie; Jaskowiak, Anne-Laure; Egesipe, Anne-Laure; Le Corf, Amelie; Navarro, Claire; Cordette, Véronique; Martinat, Cécile; Laabi, Yacine; Djabali, Karima; de Sandre-Giovannoli, Annachiara; Levy, Nicolas; Peschanski, Marc

2014-01-01

Hutchinson-Gilford progeria syndrome is a rare congenital disease characterized by premature aging in children. Identification of the mutation and related molecular mechanisms has rapidly led to independent clinical trials testing different marketed drugs with a preclinically documented impact on those mechanisms. However, the extensive functional effects of those drugs remain essentially unexplored. We have undertaken a systematic comparative study of the three main treatments currently administered or proposed to progeria-affected children, namely, a farnesyltransferase inhibitor, the combination of an aminobisphosphonate and a statin (zoledronate and pravastatin), and the macrolide antibiotic rapamycin. This work was based on the assumption that mesodermal stem cells, which are derived from Hutchinson-Gilford progeria syndrome-induced pluripotent stem cells expressing major defects associated with the disease, may be instrumental to revealing such effects. Whereas all three treatments significantly improved misshapen cell nuclei typically associated with progeria, differences were observed in terms of functional improvement in prelamin A farnesylation, progerin expression, defective cell proliferation, premature osteogenic differentiation, and ATP production. Finally, we have evaluated the effect of the different drug combinations on this cellular model. This study revealed no additional benefit compared with single-drug treatments, whereas a cytostatic effect equivalent to that of a farnesyltransferase inhibitor alone was systematically observed. Altogether, these results reveal the complexity of the modes of action of different drugs, even when they have been selected on the basis of a similar mechanistic hypothesis, and underscore the use of induced pluripotent stem cell derivatives as a critical and powerful tool for standardized, comparative pharmacological studies. PMID:24598781

The in vitro inhibitory effects of crude extracts of traditional Chinese herbs on 3-hydroxy-3-methylglutaryl-coenzyme A reductase on Vero cells.

PubMed

Liu, Ju-Chi; Chan, Paul; Hsu, Feng-Lin; Chen, Yi-Jen; Hsieh, Ming-Hsiung; Lo, Ming-Yu; Lin, Jung-Yaw

2002-01-01

Cardiovascular disease is still the leading cause of death in Western countries. Epidemiological studies have shown that hypercholesterolemia is a major risk factor for coronary artery disease. Clinical trials of lipid lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor have been shown to decrease coronary events and mortality. Flavonoids are polyphenolic natural antioxidants occurring in natural products such as traditional Chinese herbs, fruits and beverages such as tea and wine. The aim of this study was to evaluate the effects of crude extracts from traditional Chinese herbs on HMG Co-A reductase. The methods for analysis of specific inhibitors of mevalonate biosynthesis have been well-established by using Vero cells, a cell line obtained from kidneys of African green monkeys. Crude extracts from different traditional Chinese herbs were dissolved in 1% Dulbecco's modified Eagle's medium and incubated with Vero cells with or without the addition of 1 mM mevalonate or 5 mM sodium acetate for 24 hours in order to observe cell growth. Pravastatin, a specific HMG Co-A reductase inhibitor, was used as a positive control which inhibits Vero cells growth effectively and cell growth inhibition was reversible after 1 mM mevalonate. Among 100 traditional Chinese herbs used for the study, only two herbs: Curcuma zedoaria Roscoe and Poncirus trifoliata Raf. showed significant growth inhibition of Vero cells. This study shows that some crude extracts isolated from traditional medicinal herbs were effective HMG Co-A reductase inhibitors which might be developed into new hypocholesterolemic agents.

Study of HMG-CoA Reductase Inhibition Activity of the Hydrolyzed Product of Snakehead Fish (Channa striata) Skin Collagen with 50 kDa Collagenase from Bacillus licheniformis F11.4

PubMed Central

Virginia, Agnes; Rachmawati, Heni; Riani, Catur; Retnoningrum, Debbie S.

2016-01-01

Bioactive peptides produced from enzymatic hydrolysis fibrous protein have been proven to have several biological activities. Previous study showed that the hydrolysis product of snakehead fish skin collagen with 26 kDa collagenase from Bacillus licheniformis F11.4 showed HMG-CoA (HMGR) inhibition activity. The aim of this research was to determine the ability of the hydrolysis product produced from snakehead fish skin collagen hydrolysed by 50 kDa collagenase from B. licheniformis F11.4 in inhibiting HMGR activity. Snakehead fish skin collagen was extracted using an acid method and collagenase was produced from B. licheniformis F11.4 using half-strength Luria Bertani (LB) medium containing 5% collagen. Crude collagenase was concentrated and fractionated using the DEAE Sephadex A-25 column eluted with increasing gradient concentrations of NaCl. Collagen, collagenase, and fractions were analyzed using SDS-PAGE and collagenolytic activity was analyzed by the zymography method. Collagenase with 50 kDa molecular weight presented in fraction one was used to hydrolyze the collagen. The reaction was done in 18 hours at 50°C. The hydrolysis product using 3.51 μg collagen and 9 ng collagenase showed 25.8% inhibition activity against pravastatin. This work shows for the first time that the hydrolysis product of snakehead fish skin collagen and 50 kDa collagenase from B. licheniformis F11.4 has potential as an anticholesterol agent. PMID:27110500