Mevacor scientific update |
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2010 Jun 21. [Epub ahead of print]
Zhao TT, Le Francois BG, Goss G, Ding K, Bradbury PA, Dimitroulakos J.
[1] Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada [2] Department of Medical Oncology, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Lovastatin inhibits EGFR dimerization and AKT activation in squamous cell carcinoma cells: potential regulation by targeting rho proteins.
We recently showed the ability of lovastatin to inhibit the function of the epidermal growth factor receptor (EGFR) and its downstream signaling of the phosphatidylinositol-3 kinase/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in various tumor-derived cell lines. In this study, lovastatin treatment was found to inhibit ligand-induced EGFR dimerization in squamous cell carcinoma cells and its activation of AKT and its downstream targets 4E-binding protein 1 and S6 kinase 1. This inhibition was associated with global protein translational inhibition shown by a decrease in RNA associated polysome fractions. The effects of lovastatin on EGFR function were reversed by the addition of geranylgeranyl pyrophosphate, which functions as a protein membrane anchor. Lovastatin treatment induced actin cytoskeletal disorganization and the expression of geranylgeranylated rho family proteins that regulate the actin cytoskeleton, including rhoA. Lovastatin-induced rhoA was inactive as EGF stimulation failed to activate rhoA and inhibition of the rho-associated kinase, a target and mediator of rhoA function, with Y-27632 also showed inhibitory effects on EGFR dimerization. The ability of lovastatin to inhibit EGFR dimerization is a novel exploitable mechanism regulating this therapeutically relevant target. To explore the potential clinical significance of this combination, we evaluated the effect of statin on the overall survival (OS) and disease-specific survival (DSS) of patients with advanced non-small-cell lung cancer enrolled in the NCIC Clinical Trials Group phase III clinical trials BR21 (EGFR tyrosine kinase inhibitor erlotinib versus placebo) and BR18 (carboplatin and paclitaxel with or without the metalloproteinase inhibitor BMS275291). In BR18, use of statin did not affect OS or DSS. In BR21, patients showed a trend for improvement in OS (HR: 0.69, P=0.098) and DSS (HR: 0.62, P=0.048), but there was no statin x treatment interaction effect (P=0.34 and P=0.51 for OS and DSS, respectively).Oncogene advance online publication, 21 June 2010; doi:10.1038/onc.2010.219.
2010 Jun 15. [Epub ahead of print]
Feidt DM, Klein K, Hofmann U, Riedmaier S, Knobeloch D, Thasler WE, Weiss TS, Schwab M, Zanger UM.
1 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology;
Profiling Induction of Cytochrome P450 Enzyme Activity by Statins Using A New LC-MS/MS Cocktail Assay in Human Hepatocytes.
Human hepatocytes in primary culture are a very useful model to directly assess induction of gene expression by xenobiotics. We developed a novel cytochrome P450 (CYP) activity cocktail assay using model substrates for the seven important CYPs 1A2 (phenacetin), 2B6 (bupropion), 2C8 (amodiaquine), 2C9 (tolbutamide), 2C19 (S-mephenytoin), 2D6 (propafenone), and 3A4 (atorvastatin). Metabolite formation was determined by LC-MS/MS in hepatocyte culture supernatants. Atorvastatin has not been previously assessed as CYP3A probe drug. We demonstrate highly selective atorvastatin ortho-hydroxylation by CYP3A4 by recombinant CYPs. In human liver microsomes ortho-OH-atorvastatin formation was highly correlated to CYP3A4 protein content (rs=0.78, p<0.0001, n=150). We profiled induction of these CYP activities in primary human hepatocytes following treatment with 30 muM of atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin for 24 to 72 hours. Except for pravastatin, all statins induced CYP activities to various degrees, approximately in the order atorvastatin > simvastatin > lovastatin > rosuvastatin. Inducibility of CYPs followed the order CYP2C8 > CYP3A4 > CYP2C9 > CYP2B6 > CYP2C19 ~ CYP2D6 > CYP1A2. The strongest induction was observed for amodiaquine N-desalkylation, which was induced approximately 20-fold. Quantitative RT-PCR confirmed corresponding changes on the mRNA level with even more dramatic induction up to almost 100-fold. These data suggest a broader inducing effect of statins on cytochrome P450s and possibly other ADME genes than previously known, thus further emphasizing their drug-drug interaction potential. Our cocktail assay should be useful for economical use of human hepatocytes in the assessment of P450 induction by drugs and drug candidates
2010 Apr;30(4):1105-12.
Björkhem-Bergman L, Acimovic J, Torndal UB, Parini P, Eriksson LC.
Division of Clinical Pharmacology C1-68, Karolinska University Hospital, Huddinge, Karolinska Institutet, Stockholm, Sweden. linda.bjorkhem-bergman@karolinska.se
Lovastatin prevents carcinogenesis in a rat model for liver cancer. Effects of ubiquinone supplementation.
AIM: This study tests the hypothesis that statins (HMGCoA reductase inhibitors) inhibit carcinogenesis and that this effect may be mediated by the statin-induced inhibition of ubiquinone synthesis. MATERIALS AND METHODS: The effects of lovastatin, with and without addition of ubiquinone, were studied in a rat model for chemically induced hepatocarcinogenesis. Intermediates in the mevalonate pathway were measured. RESULTS: Lovastatin treatment reduced the volume fraction of liver nodules by 50% and the cell proliferation within the liver nodules was reduced to one third. Ubiquinone (Q10) treatment reversed the statin-induced inhibition of cell proliferation. Lathosterol levels were reduced significantly in the statin-treated rats, indicating inhibition of the mevalonate pathway, but cholesterol levels were not affected. CONCLUSION: Lovastatin inhibits carcinogenesis in a rat model for liver cancer, despite unaffected cholesterol levels. The statin-induced inhibition of cell proliferation may, at least in part, be explained by the inhibition of ubiquinone synthesis.
2010;10(3):187-92. doi: 10.2165/11536130-000000000-00000.
Stolcpart RS, Olson KL, Delate T, Rasmussen J, Rehring TF, Merenich JA.
EPIC Systems Corporation, Madison, Wisconsin, USA.
The risk for significant creatine kinase elevation with statins.
The HMG-CoA reductase inhibitors (statins) are effective for reducing long-term cardiovascular morbidity and mortality in both primary and secondary prevention. The most serious adverse reaction is significant elevation of creatine kinase (CK) leading to rhabdomyolysis. The incidence of CK elevation is low in randomized, controlled trials. The rate may be higher in 'real-world', less controlled settings. Data on the risks of statin-associated rhabdomyolysis in 'real-world' practice settings are limited. The aim of this study was to examine the risk for CK elevation among statin users in a clinical practice setting. Potential risk factors were identified and evaluated to quantify the risk for CK elevation with statins. This case-control study was conducted at Kaiser Permanente Colorado. Patients with prescriptions for lovastatin or simvastatin between 1 January 1999 and 30 June 2006 were identified. Cases (n = 183), i.e. patients with a CK >/=10x the upper limit of normal (ULN) while receiving a statin during this time period, were each matched on the date of statin purchase to ten control patients (n = 1830) without CK >/=10x ULN while receiving a statin. Multivariate, conditional logistic regression was used to assess the associations between the statin, statin dose, demographic, co-morbidity, laboratory, and medication factors potentially associated with CK >/=10x ULN. The mean (SD) age of patients was 64.9 (11.5) years and 56.9% were male. Overall, simvastatin use was associated with a higher likelihood for CK >/=10x ULN than lovastatin (adjusted odds ratio [OR] 4.6; 95% CI 1.1, 12.4). Using simvastatin 40 mg daily as the referent, and in the absence of interacting medications, only simvastatin 80 mg was associated with a higher likelihood for CK >/=10x ULN (OR 2.7; 95% CI 1.1, 6.9). In the presence of interacting medications, all doses of simvastatin and only lovastatin 80 mg were associated with a higher likelihood for CK >/=10x ULN. In this study, simvastatin was associated with a higher likelihood for CK >/=10x ULN than lovastatin. High-dose simvastatin, in particular, appears to confer a greater risk than lower doses of either simvastatin or lovastatin.
2010 May 28. [Epub ahead of print]
Kostapanos MS, Liamis GL, Milionis HJ, Elisaf MS.
Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece. egepi@cc.uoi.gr.
Do Statins Beneficially or Adversely Affect Glucose Homeostasis?
The effect of statin treatment on glucose metabolism and the risk of diabetes remains an issue of controversy. Since statins are drugs commonly prescribed for the prevention of cardiovascular disease even in patients with prediabetes or diabetes, it is of great importance to identify the role of statin treatment on glucose homeostasis. In this review, we have scrutinized available data with regard to the effect of every drug of the class on glycemic outcomes. Experimental data describing mechanisms through which these drugs potentially modify the metabolism of carbohydrates have been described. In order to identify statins which may be preferentially used to improve parameters of glycemic control, studies comparing different agents of this class as to their effect on glucose homeostasis have been discussed. According to experimental studies statin lipophilicity as well as the potential to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase should be regarded as prognostic factors of an adverse impact of statin treatment on carbohydrate metabolism. On the other hand, the hypotriglyceridemic capacity, the endothelial-dependent increase in pancreatic islet blood flow, the anti-inflammatory properties along with the capacity of statins to alter circulating levels of several adipokines known to affect glucose homeostasis, including adiponectin, leptin, visfatin and resistin, may beneficially alter glycemic status. In clinical trials, a beneficial, neutral or adverse impact on glycemic control of different populations has been ascribed to various statins. From all drugs of the class pravastatin seems to beneficially affect glucose metabolism and decrease the risk of diabetes. Controversial findings have come to the fore with regard to other statins commonly prescribed in the clinical setting, including rosuvastatin, atorvastatin and simvastatin. More data are needed to clarify the exact role of lovastatin, fluvastatin and the newest statin pitavastatin on carbohydrate metabolism. Comparison trials suggest a potential preferable effect of the hydrophilic statins pravastatin, rosuvastatin and pitavastatin as compared to lipophilic components of the class, including atorvastatin and simvastatin.
2009 Nov-Dec;56(96):1704-9.
Mihăilă R, Nedelcu L, Frăţilă O, Rezi EC, Domnariu C, Ciucă R, Zaharie AV, Olteanu A, Bera L, Deac M, Mihăilă R.
"Lucian Blaga" University of Sibiu, Romania. romeomihaila@yahoo.com
Lovastatin and fluvastatin reduce viremia and the pro-inflammatory cytokines in the patients with chronic hepatitis C.
BACKGROUNDS/AIMS: Certain statins interfere with the mechanism of the hepatitis C virus replication. We aimed at studying the effect of statins on the level of viremia and of the pro-and anti-inflammatory cytokines in the patients with chronic hepatitis C. METHODOLOGY: We took in our study all the patients with chronic hepatitis C placed in the evidence of the clinics of internal medicine of the Emergency County Clinical Hospitals of Braşov, Oradea and Sibiu, who had been identified with viremias. The patients were treated with fluvastatin 40 mg/day or lovastatin 20 mg/day for 28 days. The level of viremia, hemoleukogram, hepatic biochemical tests and the pro and anti-inflammatory hepatic cytokines were analysed before and after the treatment. The final results were compared with the initial ones, as well as between the 2 groups. RESULTS: Regarding those 99 analysed patients, the initial average viremia was of 2376074 +/- 3427596 UI/ml, while the final one was of 1321136 +/- 1343570 UI/ml (p = 0.000987). Both, in the group treated with lovastatin, as well as in that treated with fluvastatin, the decrease of viremia was significant from the statistics point of view (p = 0.032, respectively p = 0.00092). Lovastatin administration resulted in the significant decrease of the pro-inflammatory cytokines IL-6 and TNF-alfa, while that of fluvastatin brought about the significant decrease of the serum levels of IL-6, IL-8 and TNF-alfa. There were no significant differences, statistically speaking, between the 2 determinations, regarding the levels of IL-10 (anti-inflammatory cytokine) and those of erythropoietin. Transaminases average level did not vary significantly after those 4 weeks of statins treatment. CONCLUSIONS: Lovastatin and fluvastatin, significantly decrease the level of viremia, of IL-6 and TNF-alpha in the patients with chronic hepatitis C.
. 2009 Nov;35(5):1037-43.
Guruswamy S, Rao CV.
Department of Medicine, Hem-Onc Section, University of Oklahoma Cancer Institute, OUHSC, Oklahoma City, OK 73104, USA.
Synergistic effects of lovastatin and celecoxib on caveolin-1 and its down-stream signaling molecules: Implications for colon cancer prevention.
Progression of colon cancer is associated with the up-regulation of cyclooxygenase-2 (COX-2) and hydroxymethyl glutaryl CoA reductase (HMG-R). Clinical and preclinical evidence shows that a combination of COX-2 and HMG-R inhibitors provide additive/synergistic chemopreventive effects against colorectal cancer. However, the mechanism by which statins and NSAIDs inhibit cancer growth is not yet fully understood. We aimed to identify critical molecules and signal pathways modulated by a combination of lovastatin and celecoxib in the human HCT-116 colon cancer cell line. HCT-116 cells were exposed to 50 microM celecoxib, 25 microM lovastatin or a combination of both to assess their effect in modulating caveolin-1 expression and its down-stream signaling pathways. Our results suggest that a combination of lovastatin and/or celecoxib suppressed caveolin-1 expression and membrane localization profoundly when compared to either agent alone. Lovastatin and/or celecoxib also inhibited caveolin-1-dependent cell survival signals mediated through Akt activation as well as its down-stream effectors such as phosphorylated ERK and STAT3 in HCT-116 cells. Treatment with lovastatin or celecoxib decreased the levels of cyclin D1, CDK2, pRb and E2F1, while the combination treatment showed more pronounced suppression. In addition, lovastatin and celecoxib also decreased the amount of cholesterol rich cytoplasmic lipid bodies (storehouses of esteridied arachidonates) by 80%, while the combination showed a complete inhibition. Overall, our data suggest that a combination of COX-2 and HMG-R inhibitors synergistically inhibits caveolin-1 and its associated signaling pathways.
2009 Nov;25(11):2765-75.
Balu S, Simko RJ, Quimbo RM, Cziraky MJ.
Pharmaceutical Products Group, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, IL 60064, USA.
Impact of fixed-dose and multi-pill combination dyslipidemia therapies on medication adherence and the economic burden of sub-optimal adherence.
OBJECTIVE: To compare medication adherence between patients initiating fixed-dose combination versus multi-pill combination dyslipidemia therapies and assess the association between optimal adherence (MPR > or = 80%) and cardiovascular disease (CVD)-associated total healthcare resource utilization (THR) and costs (THC). RESEARCH DESIGN AND METHODS: The HealthCore Integrated Research Database was used to identify patients > or =18 years newly initiating fixed-dose combination [niacin extended-release (NER) and lovastatin (NERL)] or multi-pill combination therapies [NER and simvastatin (NER/S) or lovastatin (NER/L)] between 1/1/2000 and 6/30/2006 (index date), with minimum 18 months of follow-up. Adherence was measured using medication possession ratio (MPR). Three multivariate models were developed controlling for demographic and clinical characteristics. A logistic model evaluated the association between study cohorts and optimal adherence, while negative binomial and gamma models estimated the association between optimal adherence and CVD-associated THR and THC, respectively. RESULTS: In all, 6638 NERL, 1687 NER/S, and 663 NER/L patients were identified. Fixed-dose combination patients were younger [mean (SD) ages of 51.9 (10.5) vs. 56.0 (9.4) [NER/S] and 56.1 (10.6) [NER/L]; p < 0.01], had lower comorbidity (Deyo-Charlson Index 0.50 +/- 0.9 vs. 0.7 +/- 1.1 and 0.6 +/- 1.1, p < 0.01 and p < 0.05) and comprised fewer males (73.1 vs. 83.0% and 77.7%; p < 0.01 and p = 0.1). Fixed-dose combination patients had higher average 1-year MPR versus NER/S and NER/L patients (0.54 +/- 0.35 vs. 0.50 +/- 0.35 and 0.47 +/- 0.34, p < 0.01). NER/S and NER/L patients were 31.3% (95% CI: 22.9-39.5%) and 39.1% (95% CI: 26.7-49.4%) less likely to be optimally adherent than fixed-dose combination patients (p < 0.01). Additionally, optimally adherent patients had 8% and 40% decreases in annual CVD-attributable THR [0.920 (95% CI: 0.857-0.989); p = 0.023] and THC [0.601 (95% CI: 0.427-0.845); p = 0.003] versus sub-optimally adherent patients. Key limitations of the study include the limited ability of MPR to analyze the continuity of medication usage, inability to capture data on other key variables including race, income, and clinical characteristics such as smoking history, absence of laboratory values on all study patients, inability to capture over-the-counter fills of niacin, and inability to show causality of results obtained. CONCLUSIONS: Adherence was significantly higher among patients initiating fixed-dose combination versus multi-pill combination dyslipidemia therapies in this managed-care population. Additionally, patients with optimal adherence had a significantly lower CVD-associated THR and THC versus patients with sub-optimal adherence.
2009 Jul;40(4):730-3.
Liao DX, Qin YP, Gong XL, Liang MZ, Yu Q, Nan F, Xiang J.
Department of Clinical Pharmacology, West China Hospital, Sichuan University, Chengdu 610041, China.
[Determination of lovastatin and its active metabolites in human plasma with high performance liquid chromatography-tandem mass spectrometry] [Article in Chinese]
OBJECTIVE: To develop a sensitive LC-MS/MS method for analyzing lovastatin and its active metabolites lovastatin acid in human plasma. METHODS: Lovastatin and lovastatin acid were extracted from plasma by ethyl ether -dichloromethane (V/V, 1:1), with simvastatin serving as an internal standard. The analytes went through the column of Phenomenex Gemini C18 (50 x 3 mm, 3 microm) with mobile phase acetonitrile-water (85:15), and was analyzed by API3000 after protonated with ESI mode. The ion pairs being detected were 427.4-->325.4, 445.4-->343.4 and 436.4-->325.4, respectively. RESULTS: The established method was able to determine lovastatin in human plasma over the range of 0.03125-64 microg/L, with recovery rates ranging from 96% to 102%. The intra and inter day variances were below 9.3%. CONCLUSION: The LC-MS/MS method for analyzing lovastatin is validated and is suitable for clinical pharmacokinetic studies.
2009 Jul;40(5):380-6. Epub 2009 Jul 25.
Shidfar F, Homayounfar R, Fereshtehnejad SM, Kalani A.
Gastrointestinal & Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran.
Effect of folate supplementation on serum homocysteine and plasma total antioxidant capacity in hypercholesterolemic adults under lovastatin treatment: a double-blind randomized controlled clinical trial.
BACKGROUND AND AIMS: Hypercholesterolemia is one of the predisposing factors of cardiovascular diseases. A positive correlation of homocysteine (Hcy) concentration with total cholesterol is described. Lovastatin, one of the most administered agents in hypercholesterolemia, is not effective in lowering the level of serum Hcy and increasing serum total antioxidant capacity (TAC). This study was performed to evaluate the effects of folate supplementation on lowering Hcy level and changes of TAC in asymptomatic hypercholesterolemic adults under lovastatin treatment. METHODS: This was a double-blind randomized controlled clinical trial. Forty asymptomatic newly diagnosed hypercholesterolemic individuals were recruited. Patients were randomized into two groups: group A--20 patients supplemented for 8 weeks with folate (5mg daily) and group B--20 patients receiving placebo. Lovastatin was administered to both groups. Laboratory lipid profiles, serum Hcy and folate concentration, and TAC were measured at the beginning and after the 8(th) week of the study period. RESULTS: After folate supplementation in group A subjects, serum Hcy was significantly decreased (13.35+/-5.01 micromol/L to 8.43+/-2.52 micromol/L, p=0.001), whereas no significant changes occurred in group B (p>0.05). A significant increase in TAC was only observed in group A (1.54+/-0.24 micromol/L to 1.96+/-0.42 micromol/L, p<0.001). CONCLUSIONS: Folate supplementation decreases the serum level of Hcy and increases TAC. It seems that a pharmacological dose of folate supplementation could potentially decrease the risk of cardiovascular diseases by reducing serum level of Hcy in adults with hypercholesterolemia.
2008 Dec;30(12):2280-97.
Strony J, Hoffman R, Hanson M, Veltri E.
Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0530, USA. john.strony@sprcorp.com
Tolerability and effects on lipids of ezetimibe coadministered with pravastatin or simvastatin for twelve months: results from two open-label extension studies in hypercholesterolemic patients.
OBJECTIVE: The aim of these studies was to assess the long-term tolerability and effects on lipids of ezetimibe coadministered with pravastatin or simvastatin during treatment of hypercholesterolemic patients. METHODS: Two separate 12-month, open-label extension studies enrolled patients who had successfully completed one of three 12-week, double-blind, placebo-controlled trials of ezetimibe coadministered with pravastatin, lovastatin, or simvastatin. In the extensions, the initial dose of each drug administered was 10 mg/d, with the option to up-titrate the statins if low-density lipoprotein cholesterol (LDL-C) goals were not met. Tolerability was assessed using monitoring of clinical and laboratory adverse events (AEs). Changes from baseline in LDL-C, total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were calculated. RESULTS: Overall, 436 patients received ezetimibe + pravastatin 10 to 40 mg/d, including patients from the parent studies who received coadministration treatment but did not continue in the extension studies; 359 patients received ezetimibe + simvastatin 10 to 80 mg/d in the extension study. The majority of patients in both studies were white (ezetimibe + pravastatin, 374 [86%]; ezetimibe + simvastatin, 314 [87%]) and female (ezetimibe + pravastatin, 246 [56%]; ezetimibe + simvastatin, 210 [58%]). The mean ages were 55.7 and 57.7 years and the mean body mass indexes were 29.4 and 28.8 kg/m2 in the ezetimibe + pravastatin and ezetimibe + simvastatin studies, respectively. The most commonly reported AEs with ezetimibe + pravastatin were upper respiratory tract infection (78 [18%]), headache (47 [11%]), musculoskeletal pain (45 [10%]), arthralgia (43 [10%]), and sinusitis (42 [10%]); with ezetimibe + simvastatin, they were upper respiratory tract infection (67 [19%]), arthralgia (39 [11%]), and musculoskeletal pain (37 [10%]). AEs considered treatment related were reported in 98 (22%) and 80 (22%) patients in the ezetimibe + pravastatin and ezetimibe + simvastatin studies, respectively. Serious AEs were reported in 29 patients (7%) who received ezetimibe + pravastatin and 36 patients (10%) who received ezetimibe + simvastatin; <1% were considered treatment related in either study. Forty-one (9%) and 29 patients (8%), respectively, were withdrawn due to AEs. One death occurred due to cardiopulmonary arrest in the ezetimibe + simvastatin study and was not considered treatment related. Percentage changes from baseline in LDL-C were -36.5% and -40.4% in patients who received ezetimibe + pravastatin and ezetimibe + simvastatin. CONCLUSION: In these 12-month, open-label extension studies in these patients with hypercholesterolemia, ezetimibe + pravastatin or simvastatin was generally well tolerated. Both treatments were associated with maintaining improvements in lipid parameters throughout the studies in these patients.
2008 Mar 13;46(4):808-13. Epub 2007 Dec 8.
Yuan H, Wang F, Tu J, Peng W, Li H.
Clinical Pharmacy & Pharmacology Institute, Second Xiangya Hospital, Central South University, Changsha 410011, PR China.
Determination of lovastatin in human plasma by ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry and its application in a pharmacokinetic study.
A selective, rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the quantitative determination of lovastatin in human plasma and its application in a pharmacokinetic study. With mycophenolate mofetil as internal standard, sample pretreatment involved a one-step extraction with tert-butyl methyl ether of 0.2 ml plasma. The analysis was carried out on an ACQUITY UPLCTM BEH C18 column (50 mm x 2.1 mm, i.d., 1.7 microm) with flow rate of 0.35 ml/min. The mobile phase was 20% water and 80% acetonitrile (v/v). The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI). Linear calibration curves were obtained in the concentration range of 0.08-24.50 ng/ml, with a lower limit of quantification of 0.08 ng/ml. The intra- and inter-day precision (RSD) values were below 15% and accuracy (RE) was -7.6 to 9.3% at all QC levels. The method was applicable to clinical pharmacokinetic study of lovastatin in healthy volunteers following oral administration.
2008 Feb;155(2):316-23. Epub 2007 Oct 25.
Rinfret S, Behlouli H, Eisenberg MJ, Humphries K, Tu JV, Pilote L.
Division of Cardiology, Department of Medicine, Centre Hospitalier de l'Université de Montréal, University of Montreal, Montreal, Quebec, Canada.
Class effects of statins in elderly patients with congestive heart failure: a population-based analysis.
BACKGROUND: Long-term treatment with statins reduces mortality in patients with congestive heart failure (CHF). Whether statin agents exert a class effect is unknown. METHODS: We analyzed long-term mortality in Canadian patients aged > or = 65 years who were discharged from hospital with a diagnosis of CHF from January 1998 to December 2002. Administrative data from Quebec, Ontario, and British Columbia were merged. We compared patients prescribed with atorvastatin, simvastatin, pravastatin, and lovastatin. RESULTS: A total of 15,368 patients hospitalized with a diagnosis of CHF fulfilled the inclusion criteria for this study. In this final dataset, 6670 (43.4%) filled a prescription for atorvastatin, 4261 (27.7%) for simvastatin, 3209 (20.9%) for pravastatin, and 1228 (8.0%) for lovastatin. Clinical characteristics and proportion of days covered with a statin prescription were similar across groups. Drug dosages were relatively low, with 82% of patients who received the agent at a dose of < or = 20 mg. Although controlling for time-dependent covariates representing current use and dosage, as well as for age, sex, coronary artery disease, and several other comorbidities, treatment with pravastatin (adjusted hazards ratio [HR] 0.94, 95% CI 0.83-1.07), lovastatin (adjusted HR 1.02, 95% CI 0.88-1.17), or simvastatin (adjusted HR 0.92, 95% CI 0.83-1.01) had a similar effectiveness to prevent mortality compared to atorvastatin (reference in this analysis) in this population with CHF. Time-dependent exposure to a statin was highly protective against mortality. CONCLUSIONS: Statins exert a class effect in patients with CHF, when used at a relatively low dose. The favorable effects appear largely independent of drug dosage.
2008 Jan;32(1):249-55.
Mrówka P, Glodkowska E, Nowis D, Legat M, Issat T, Makowski M, Szokalska A, Janowska S, Stoklosa T, Jakóbisiak M, Golab J.
Department of Immunology, Center of Biostructure Research, The Medical University of Warsaw, 02-097 Warsaw, Poland.
Ciglitazone, an agonist of peroxisome proliferator-activated receptor gamma, exerts potentiated cytostatic/cytotoxic effects against tumor cells when combined with lovastatin.
Thiazolidinediones are ligands of PPAR-gamma, a member of the nuclear receptor family. These drugs have shown promising pre-clinical activity in tumor models but clinical studies failed to confirm their beneficial effect. We have studied the in vitro antitumor effects of a combination of ciglitazone, a thiazolidinedione drug, and lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. We observed a marked synergism in several different tumor cell lines resulting from both inhibition of cell proliferation and induction of apoptosis. These results strongly suggest that combining PPAR-gamma agonists with statins can produce significant antitumor effects.
2008 Oct;25(10):1229-30.
Kao DP, Kohrt HE, Kugler J.
Stanford University School of Medicine, Department of Medicine, Stanford, CA, USA. dkao42@yahoo.com
Renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use.
BACKGROUND: Sitagliptin is a new oral glucose-lowering medication that acts via the incretin hormone system. The most common side-effects are headache and pharyngitis, and few serious adverse events were observed during clinical trials. Dose adjustment is recommended in renal insufficiency, but long-term safety experience is limited. CASE REPORT: We present a patient with chronic renal insufficiency who developed leg pain, weakness and tenderness after starting treatment with high-dose sitagliptin while on simvastatin. The patient had acute renal failure and rhabdomyolysis that resolved with cessation of sitagliptin, simvastatin, ezetimibe, diuretics and olmesartan. All drugs except sitagliptin, ezetimibe and simvastatin were resumed, and the patient was subsequently started on lovastatin without recurrence of rhabdomyolysis. CONCLUSIONS: High doses of sitagliptin may have worsened this patient's renal failure and precipitated rhabdomyolysis by increasing circulating levels of simvastatin. Given the high likelihood that sitagliptin will be co-administered with statins and renally active medications, further study of long-term safety of sitagliptin in renal sufficiency may be warranted.
2007;108(9):388-92.
Gajdos M, Krivosikova Z, Uhliar R.
Slovak Medical University, Bratislava, Slovakia. martin.gajdos@szu.sk
A critical gap between recommended and achieved LDL-cholesterol levels. Results of statin therapy in Slovakia.
BACKGROUND: The achievement of low density lipoprotein cholesterol (LDL-C) target levels, as recommended by the evidence-based international guidelines, represents the crucial prerequisite for maximal cardiovascular risk reduction in patients with dyslipidemia. OBJECTIVES: The efficacy of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) monotherapy administered in ambulatory practice was evaluated in cooperation with 387 ambulatory specialists in Slovakia. PATIENTS AND METHODS: Data of 5640 adult patients (21-88 years, 42.8% males) with low (7.4%), high (16.8%), and very high cardiovascular risks (75.7%), treated at least for 12 weeks with a stable statin dose were evaluated regarding the achievement of target LDL-C levels (< 4.2 mmol/L in low risk patients, < 3.4 mmol/L in high risk patients and < 2.6 mmol/L in very high risk patients). RESULTS: The target levels were achieved in 74% of low risk patients (mean level of LDL-C 3.55 mmol/L), in 37.9% of high risk patients (3.7 mmol/L), and in 12.4% of very high risk patients (3.64 mmol/L). The proportion of received statins and their average daily doses were as follows: 64.3% simvastatin (22.5 mg); 21.3% atorvastatin (15.6 mg); 12.2% fluvastatin (69.7 mg); 1.5% pravastatin (19.4 mg), and 0.7% lovastatin (25.4 mg). CONCLUSION: Statin therapy does not correspond with the current guidelines in common clinical practice. In patients with treated hypercholesterolemia the use of low doses of statins without titration seems to be the main reason of poor achieving of LDL-C target levels representing the critical values for reducing the atherosclerosis and its life-threatening complications (Tab. 3, Fig. 1, Ref 19). Full Text (Free, PDF) www.bmj.sk.
2007 Dec;13 Suppl 10:S276-81.
Harley CR, Gandhi SK, Anoka N, Bullano MF, McKenney JM.
Health Economics and Outcomes, i3 Innovus, 12125 Technology Drive, Minnesota, MN 55244, USA.
Understanding practice patterns and low-density lipoprotein cholesterol goal attainment implications of switching patients from simvastatin in a health plan setting.
OBJECTIVE: To understand the practice patterns and National Cholesterol Education Panel (NCEP) Adult Treatment Panel (ATP) III low-density lipoprotein cholesterol (LDL-C) goal attainment rates after switching patients from simvastatin (SMV) to other statins or the combination of SMV and ezetimibe (EZE). METHODS: This retrospective study linked claims and laboratory data from a national health plan. Patients were included if they were taking SMV and were switched to other statins or a fixed-dose combination of SMV and EZE between July 1, 2005, and June 30, 2006. Patients taking dual SMV/EZE before switch were excluded from the study. The NCEP ATP III risk status of patients at switch was assessed based on medical claims, pharmacy claims, and laboratory values in the 12-month preswitch period. Lipid data (available on a patient subset) were used to estimate patients' goal attainment status at and after switch. RESULTS: Of 134 168 patients taking SMV, 11 929 (8.9%) switched to other statins or SMV/EZE. The mean age of switching patients was 54 years (standard deviation, 9 years), 61% were men, 50% were high risk, and 30% were moderate risk. The mean time to switch among new starters of SMV (n = 3379) was 77 days. Forty percent (n = 4772) of the total switches occurred among those taking the lower doses (5, 10, and 20 mg) of SMV. Most patients switched from SMV to SMV/EZE (60.5%), followed by atorvastatin (17.3%), rosuvastatin (10.1%), lovastatin (8.6%), pravastatin (2.9%), and fluvastatin (0.7%). Similarly, most patients switching from higher doses of SMV switched to SMV/EZE (52.5%), followed by atorrestatin (21.1%) and rosuvastatin (10.1%). Overall, 55.6% (758 of 1362) of patients were at ATP III goal at the time of switch from SMV (across all doses; n = 758), and 56.1% (292 of 521) of those taking lower doses were at goal at time of switch. A majority (69.9%) of patients who were at goal and switched from SMV (across all doses) were switched to SMV/EZE, and 61.6% of those at lower doses of SMV switched to the combination drug. Of patients who were not at goal at switch (n = 604), 73.3% attained ATP III LDL-C goal after switch. The mean percent LDL-C reduction that was needed to attain LDL-C goal at switch from SMV (n = 604) was 18.1%. CONCLUSIONS: There is an opportunity to further increase LDL-C goal attainment rates among patients switched from SMV. The clinical, prescription benefit design, and economic implications of the finding that a majority of patients are at goal when switched from SMV and a majority of patients are being switched from SMV to SMV/EZE need to be further examined.
2007 Nov;29(11):2385-94.
Fox KM, Gandhi SK, Ohsfeldt RL, Blasetto JW, Davidson MH.
Department of Epidemiology & Preventive Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA.
Titration patterns with rosuvastatin as compared with other statins in clinical practice: a retrospective observational cohort study using an electronic medical record database.
BACKGROUND: Lipid management in clinical practice has been suboptimal with a significant proportion of patients not achieving recommended cholesterol levels. A reason for low goal attainment may be the limited use of upward dose titration. OBJECTIVE: The aim of this study was to determine if, in routine clinical practice, a lower rate of titration is observed among rosuvastatin patients who achieved the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) target low-density lipoprotein cholesterol (LDL-C) goals as compared with patients achieving the target LDL-C goals on other statins. METHODS: This retrospective database study included the patients, aged > or =18 years, of approximately 3000 physicians across the United States, who were newly prescribed statin treatment from August 2003 to May 2005. Patients were excluded if they started on a maximum dose of statin, were at LDL-C goal at baseline (no clinical reason for titrating), or on fluvastatin (<70 patients). Titration rate with rosuvastatin was compared with other statins. Multivariate logistic regression models adjusted for baseline LDL-C, coronary heart disease risk, treatment duration, and target LDL-C goal attainment. RESULTS: This study assessed 12,041 patients for upward titration. Of the 5955 eligible patients (mean age, 63 years; male, 47%), 7.2% were prescribed rosuvastatin, 63.5% atorvastatin, 15.3% simvastatin, 7.2% pravastatin, and 6.9% lovastatin. Overall, 4337 patients (72.8%) attained the NCEP ATP III target LDL-C goal. Mean duration of statin treatment was 188 days for rosuvastatin compared with 238 to 260 days for the other statins (all, P < 0.05). Among patients attaining the target LDL-C goal, significantly fewer rosuvastatin patients (8.3%) had titration compared with atorvastatin (17.0%), simvastatin (20.0%), pravastatin (20.7%), and lovastatin (23.5%) (all, P < 0.05). After adjusting for baseline characteristics, patients attaining the target LDL-C goal on other statins were significantly more likely to be titrated as compared with rosuvastatin (odds ratios, 2.0-3.3; P < 0.05). Lower titration rates for rosuvastatin patients were also observed in the total population (P < 0.05). CONCLUSION: Our study found that rosuvastatin patients who attained the NCEP ATP III target LDL-C goal had significantly lower titration rates than patients receiving other statins.
2007 Oct;50(4):458-61.
Turner NA, Midgley L, O'Regan DJ, Porter KE.
Academic Unit of Cardiovascular Medicine, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
Comparison of the efficacies of five different statins on inhibition of human saphenous vein smooth muscle cell proliferation and invasion.
Statins (HMG-CoA reductase inhibitors) exhibit beneficial effects on the vasculature independently of their cholesterol-lowering properties. These pleiotropic effects underlie the ability of statins to reduce intimal hyperplasia in saphenous vein (SV) bypass grafts by attenuating smooth muscle cell (SMC) invasion and proliferation. Although all statins can effectively lower cholesterol, the pleiotropic effects of individual statins may well differ. We therefore compared the concentration-dependent effects of 4 lipophilic statins (simvastatin, atorvastatin, fluvastatin, and lovastatin) and 1 hydrophilic statin (pravastatin) on the proliferation and invasion of SMC cultured from SV of 9 different patients undergoing coronary artery bypass grafting (CABG). The lipophilic statins inhibited SV-SMC proliferation over a 4-day period with an order of potency of fluvastatin > atorvastatin > simvastatin > lovastatin (IC50 range = 0.07 to 1.77 microM). Similarly, these statins also inhibited SV-SMC invasion through an artificial basement membrane barrier (fluvastatin > atorvastatin > simvastatin >> lovastatin; IC50 range = 0.92 to 26.9 microM). In contrast, the hydrophilic pravastatin had no significant effect on SV-SMC proliferation at concentrations up to 10 microM, nor did it attenuate SV-SMC invasion (up to 30 microM). Our data provide strong evidence that individual statins possess differential pleiotropic effects on SV-SMC function. This may be of clinical relevance in the selection of individual statins for the treatment of CABG patients.
2007 Nov;45(7):589-93.
Qiao J, Kontoyiannis DP, Wan Z, Li R, Liu W.
Department of Dermatology, Peking University First Hospital, and Research Center for Medical Mycology, Peking University, Beijing, China.
Antifungal activity of statins against Aspergillus species.
The cholesterol-lowering agents known as statins have in vitro activities against human pathogenic fungi, such as Candida species, Cryptococcus neoformans, and Zygomycetes. Synergy between statins and azoles against these fungi has also been reported. We evaluated the in vitro activities of two statins, lovastatin and simvastatin, alone and in combination with azoles and amphotericin B, against clinical isolates of Aspergillus spp. A disk diffusion assay showed that both statins were active against Aspergillus spp. The minimal inhibitory concentration (MIC) ranges for lovastatin and simvastatin against Aspergillus spp. were 16 to >256 microg/ml and 4 to >256 microg/ml, respectively. Although both statins were fungicidal for A. fumigatus, the MICs were vastly higher than clinically achievable concentrations. The results of a combined agar dilution-Epsilometer test as well as a disk diffusion assay showed that neither statin had any effect on the in vitro activities of itraconazole, voriconazole, or amphotericin B against Aspergillus spp.
2007 Sep;5(3):185-94.
Harley CR, Gandhi S, Blasetto J, Heien H, Sasane R, Nelson SP.
Health Economics and Outcomes, i3 Innovus, Palo Alto, California 94303, USA. carolyn.harley@i3innovus.com
Low-density lipoprotein cholesterol (LDL-C) levels and LDL-C goal attainment among elderly patients treated with rosuvastatin compared with other statins in routine clinical practice.
BACKGROUND: Reducing low-density lipoprotein cholesterol (LDL-C) levels lowers the risk of consequences of cardiovascular disease. Research has confirmed these benefits in elderly patients. The 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (ie, statins) have long-standing proven efficacy in reducing levels of LDL-C and total cholesterol. OBJECTIVE: The goal of this study was to compare change in LDL-C from baseline and National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL-C goal attainment in a population of elderly patients (aged > or =65 years) treated with rosuvastatin versus other statins in routine clinical practice. METHODS: This was a retrospective cohort analysis using medical and pharmacy claims data linked to clinical laboratory results from a large managed care health plan of commercial and Medicare Advantage members in the United States. Included were members aged > or =65 years who were newly treated with statins (index date) from August 1, 2003, through February 28, 2005. All subjects were continuously enrolled for 12 months preindex and > or =30 days postindex, with variable follow-up until therapy discontinuation or end of health plan eligibility. Based on NCEP ATP III guidelines, patients were grouped into risk categories with associated LDL-C goals. The primary outcomes were change in LDL-C from baseline and attainment of NCEP ATP III LDL-C goal among patients not at goal before starting therapy. Generalized linear modeling was used to assess percent change in LDL-C from baseline, controlling for covariates (including age, sex, NCEP risk level, medication possession ratio, preindex LDL-C value, days from index date to postindex LDL-C value, and number of preindex office visits for dyslipidemia). In the subset of patients not at goal before starting therapy, logistic regression was used to estimate the odds of individual patients on other statins reaching goal as compared with rosuvastatin and to produce predicted percent attaining LDL-C goal on individual statins. RESULTS: Of the 2227 elderly new users of statin therapy, 8.0% started on rosuvastatin, 38.9% started on atorvastatin, 3.0% on fluvastatin, 31.0% on lovastatin, 5.5% on pravastatin, and 13.6% on simvastatin. Females comprised 57.7% of the population, and the mean (SD) age was 73 (5.8) years (range, 65-94 years). The mean (SD) doses of rosuvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin were 10.65 (4.59), 16.0 (12.78), 66.31 (23.56), 27.38 (14.07), 32.86 (16.46), and 28.1 (26.2) mg, respectively. After controlling for covariates, rosuvastatin-treated patients had a 35.8% decrease in LDL-C from baseline, which was significantly greater compared with patients in the atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin (29.3%, 21.9%, 22.5%, 22.0%, and 24.9%, respectively; P < 0.05) groups. Atorvastatin (odds ratio [OR], 0.25; 95% CI, 0.12-0.52), fluvastatin (OR, 0.05; 95% CI, 0.02-0.14), lovastatin (OR, 0.10; 95% CI, 0.05-0.20), pravastatin (OR, 0.08; 95% CI, 0.03-0.20), and simvastatin (OR, 0.14; 95% CI, 0.06-0.30) were less likely to attain LDL-C goal compared with rosuvastatin (all, P < 0.001). Predicted percent attaining goal was 93.6% among rosuvastatin users, significantly greater than users of atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin (81.2%, 55.8%, 66.8%, 64.1%, and 72.8%, respectively; P < 0.05). CONCLUSION: In this elderly patient population, rosuvastatin was a more effective treatment for reducing LDL-C levels and attaining NCEP ATP III LDL-C goals than the other statins.
Clin Orthop Relat Res. 2006 Sep 28;
Chang JK, Ho ML, Yeh CH, Chen CH, Wang GJ.
From the *Departments of Orthopedics and daggerPhysiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; double daggerOrthopedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; section sig
Osteogenic Gene Expression Decreases in Stromal Cells of Patients with Osteonecrosis.
Nontraumatic osteonecrosis is related to alcohol and glucocorticoid with unknown pathogenesis. Increased adipogenesis decreases bone morphogenetic protein 2 (BMP2) gene expression after glucocorticoid treatment. Lovastatin enhances BMP2 gene expression in rodents, reverses the effects of glucocorticoids on bone, and prevents glucocorticoid-induced osteonecrosis in chickens and humans. We hypothesized patients with osteonecrosis are more susceptible to glucocorticoid treatment than patients without osteonecrosis. Marrow stromal cell cultures from 14 patients with osteonecrosis, and 10 patients without osteonecrosis were treated with dexamethasone (0.1 mumol/L), lovastatin (1 mumol/L), or combined treatment. BMP2 and osteocalcin gene expression were evaluated by reverse-transcriptase polymerase chain reaction and real-time polymerase chain reaction. The suppression of BMP2 by dexamethasone was more pronounced and the enhancement by lovastatin was less pronounced in the osteonecrosis group. Dexamethasone suppressed osteocalcin in the osteonecrosis group. Among the subgroups of osteonecrosis, suppression of BMP2 and osteocalcin by dexamethasone occurred in glucocorticoid-induced osteonecrosis group. Our data suggest individuals who are more susceptible to a glucocorticoid-induced decreases in BMP2 and osteocalcin gene expression are more likely to have osteonecrosis, especially glucocorticoid-induced osteonecrosis.
Metabolism. 2004 Jun;53(6):744-8.
Lupattelli G, Scarponi AM, Vaudo G, Siepi D, Roscini AR, Gemelli F, Pirro M, Latini RA, Sinzinger H, Marchesi S, Mannarino E.
Internal Medicine, Angiology and Atherosclerosis, Department of Clinical and Experimental Medicine, University of, Perugia, Italy.
Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women.
Statins are able to reduce cardiovascular morbility and mortality mainly through their hypocholesterolemic effect. Beyond the inhibition of cholesterol synthesis, the identification of "ancillary" mechanisms has motivated studies evaluating the relationship between the use of statins and the modification of bone mineral density (BMD). To date, clinical trials have provided discordant results. The aim of our study was to evaluate whether simvastatin treatment (40 mg/d) could modify BMD in hypercholesterolemic women (n = 40) after a 2-year treatment as compared with a control group treated only with diet (n = 20) and matched by gender, age, body mass index (BMI), lipids, menopausal age, and BMD and the number of osteopenic, osteoporotic, and normal women (on the basis of T-score value). Exclusion criteria were secondary hyperlipemias and osteoporosis and current or previous therapy with statins, bisphosphonates, and estrogens. The BMD was measured at the lumbar spine and hip by dual energy x-ray absorpiometry (DEXA). In the group treated by simvastatin, BMD, both on the spine and femoral hip, showed a significant increase after 8 and 24 months, respectively (0.878 +/- 0.133 v 0.893 +/- 0.130 and 0.907 +/- 0.132; 0.840 +/- 0.101 v 0.854 +/- 0.101; and 0.863 +/- 0.10, P <.001); there was a percentage increase of 1.7% after 8 months and 3.3% after 24 months at the spine; at the femoral hip, BMD increased 1.6% after 8 months and 2.7% after 24 months. The group treated only with hypolipidic diet demonstrated after 8 and 24 months a slight decrease in BMD both on the spine and femoral hip (respectively, 0.884 +/- 0.175 v 0.872 +/- 0.174 and 0.861 +/- 0.164; 0.860 +/- 0.110 v 0.853 +/- 0.096 and 0.847 +/- 0.095; P <.05). In conclusion, as partly suggested by retrospective or observational data, this longitudinal study indicates that simvastatin treatment exerts a beneficial effect on BMD.
Am J Cardiol. 2004 Jun 15;93(12):1487-94.
Ballantyne CM, Blazing MA, King TR, Brady WE, Palmisano J.
Baylor College of Medicine, Houston, Texas, USA.
Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia.
This study compared the efficacy and safety of co-administered ezetimibe + simvastatin with atorvastatin monotherapy in adults with hypercholesterolemia. Seven hundred eighty-eight patients were randomized 1:1:1 to 3 treatment groups; each group was force-titrated over four 6-week treatment periods: (1) 10 mg of atorvastatin as the initial dose was titrated to 20, 40, and 80 mg; (2) co-administration of 10 mg of ezetimibe and 10 mg of simvastatin (10/10 mg) was titrated to 10/20, 10/40, and 10/80 mg of ezetimibe + simvastatin; and (3) co-administration of 10/20 mg of ezetimibe + simvastatin was titrated to 10/40 mg (for 2 treatment periods) and 10/80 mg of ezetimibe + simvastatin. Key efficacy measures included percent changes in low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) from baseline to the ends of (1) treatment periods 1 and 2 (for LDL cholesterol) comparing co-administration of 10/20 mg and 10/10 mg of ezetimibe + simvastatin with 10 mg of atorvastatin and (2) treatment period 4 (for LDL cholesterol and HDL cholesterol) comparing co-administration of 10/80 mg of ezetimibe + simvastatin with 80 mg of atorvastatin. Baseline LDL and HDL cholesterol levels were comparable between treatment groups. At the end of treatment period 1, the mean decrease of LDL cholesterol was significantly.
J Immunol. 2005 Feb 15;174(4):2327-35.
Gegg ME, Harry R, Hankey D, Zambarakji H, Pryce G, Baker D, Adamson P, Calder V, Greenwood J.
Division of Cellular Therapy
Suppression of autoimmune retinal disease by lovastatin does not require th2 cytokine induction.
Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In an acute mouse model of autoimmune retinal disease, we demonstrate that treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage, and leukocytic infiltration into the retina. Efficacy was reversed by coadministration of mevalonolactone, the downstream product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, but not by squalene, which is distal to isoprenoid pyrophosphate metabolites within the cholesterol biosynthetic pathway. Lovastatin treatment (20 mg/kg/day i.p.) over 7 days, which resulted in plasma lovastatin hydroxyacid concentrations of 0.098 +/- 0.03 muM, did not induce splenocyte Th2 cytokine production but did cause a small reduction in Ag-induced T cell proliferation and a decrease in the production of IFN-gamma and IL-10. Thus, it is possible to dissociate the therapeutic effect of statins in experimental autoimmune uveitic mice from their activity on the Th1/Th2 balance. Statins inhibit isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase, a key molecule in the endothelial ICAM-1-mediated pathway that facilitates lymphocyte migration. Consistent with inhibition of leukocyte infiltration in vivo, lovastatin treatment of retinal endothelial cell monolayers in vitro leads to inhibition of lymphocyte transmigration, which may, in part, account for drug efficacy. Unlike lovastatin, atorvastatin treatment showed little efficacy in retinal inflammatory disease despite showing significant clinical benefit in experimental autoimmune encephalomyelitis. These data highlight the potential differential activity of statins in different inflammatory conditions and their possible therapeutic use for the treatment of human posterior uveitis.
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