Downregulation of monocytic differentiation via modulation of CD147 by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

PubMed

Sasidhar, Manda V; Chevooru, Sai Krishnaveni; Eickelberg, Oliver; Hartung, Hans-Peter; Neuhaus, Oliver

2017-01-01

CD147 is an activation induced glycoprotein that promotes the secretion and activation of matrix metalloproteinases (MMPs) and is upregulated during the differentiation of macrophages. Interestingly, some of the molecular functions of CD147 rely on its glycosylation status: the highly glycosylated forms of CD147 induce MMPs whereas the lowly glycosylated forms inhibit MMP activation. Statins are hydroxy-methylglutaryl coenzyme A reductase inhibitors that block the synthesis of mevalonate, thereby inhibiting all mevalonate-dependent pathways, including isoprenylation, N-glycosylation and cholesterol synthesis. In this study, we investigated the role of statins in the inhibition of macrophage differentiation and the associated process of MMP secretion through modulation of CD147. We observed that differentiation of the human monocytic cell line THP-1 to a macrophage phenotype led to upregulation of CD147 and CD14 and that this effect was inhibited by statins. At the molecular level, statins altered CD147 expression, structure and function by inhibiting isoprenylation and N-glycosylation. In addition, statins induced a shift of CD147 from its highly glycosylated form to its lowly glycosylated form. This shift in N-glycosylation status was accompanied by a decrease in the production and functional activity of MMP-2 and MMP-9. In conclusion, these findings describe a novel molecular mechanism of immune regulation by statins, making them interesting candidates for autoimmune disease therapy.

Musculoskeletal safety outcomes of patients receiving daptomycin with HMG-CoA reductase inhibitors.

PubMed

Bland, Christopher M; Bookstaver, P Brandon; Lu, Z Kevin; Dunn, Brianne L; Rumley, Kathey Fulton

2014-10-01

Daptomycin, a cyclic lipopeptide antibiotic, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly administered in the inpatient setting and are associated with creatine phosphokinase (CPK) elevations, myalgias, and muscle weakness. Safety data for coadministration of daptomycin with statins are limited. To determine the safety of coadministration of daptomycin with statin therapy, a multicenter, retrospective, observational study was performed at 13 institutions in the Southeastern United States. Forty-nine adult patients receiving statins concurrently with daptomycin were compared with 171 patients receiving daptomycin without statin therapy. Detailed information, including treatment indication and duration, infecting pathogen, baseline and subsequent CPK levels, and presence of myalgias or muscle complaints, was collected. Myalgias were noted in 3/49 (6.1%) patients receiving combination therapy compared with 5/171 (2.9%) of patients receiving daptomycin alone (P = 0.38). CPK elevations of >1,000 U/liter occurred in 5/49 (10.2%) patients receiving combination therapy compared to 9/171 (5.3%) patients receiving daptomycin alone (P = 0.32). Two of five patients experiencing CPK elevations of >1,000 U/liter in the combination group had symptoms of myopathy. Three patients (6.1%) discontinued therapy due to CPK elevations with concurrent myalgias in the combination group versus 6 patients (3.5%) in the daptomycin-alone group (P = 0.42). CPK levels and myalgias reversed upon discontinuation of daptomycin therapy. Overall musculoskeletal toxicity was numerically higher in the combination group but this result was not statistically significant. Further prospective study is warranted in a larger population. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Statins inhibit blastocyst formation by preventing geranylgeranylation

PubMed Central

Alarcon, Vernadeth B.; Marikawa, Yusuke

2016-01-01

STUDY HYPOTHESIS Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the mevalonate pathway and prescription drugs that treat hypercholesterolemia, compromise preimplantation mouse development via modulation of HIPPO signaling. STUDY FINDING HMG-CoA reductase activity is required for trophectoderm specification, namely blastocyst cavity formation and Yes-associated protein (YAP) nuclear localization, through the production of isoprenoid geranylgeranyl pyrophosphate (GGPP) and the action of geranylgeranyl transferase. WHAT IS KNOWN ALREADY Previous studies have shown that treatment of mouse embryos with mevastatin prevents blastocyst formation, but how HMG-CoA reductase is involved in preimplantation development is unknown. HIPPO signaling regulates specification of the trophectoderm lineage of the mouse blastocyst by controlling the nuclear localization of YAP. In human cell lines, the mevalonate pathway regulates YAP to mediate self-renewal and survival through geranylgeranylation of RHO proteins. These studies suggest that in preimplantation development, statins may act through HIPPO pathway to interfere with trophectoderm specification and thereby inhibit blastocyst formation. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Eight-cell stage (E2.5) mouse embryos were treated in hanging drop culture with chemical agents, namely statins (lovastatin, atorvastatin, cerivastatin and pravastatin), mevalonic acid (MVA), cholesterol, squalene, farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), geranylgeranyltransferase inhibitor GGTI-298, RHO inhibitor I, and squalene synthase inhibitor YM-53601, up to the late blastocyst stage (E4.5). Efficiency of blastocyst formation was assessed based on gross morphology and the measurement of the cavity size using an image analysis software. Effects on cell lineages and HIPPO signaling were analyzed using immunohistochemistry with confocal microscopy based on the expression patterns of the

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

Statin use and risk of diabetes mellitus

PubMed Central

Chogtu, Bharti; Magazine, Rahul; Bairy, KL

2015-01-01

The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, statins, are widely used in the primary and secondary prevention of cardiovascular diseases to lower serum cholesterol levels. As type 2 diabetes mellitus is accompanied by dyslipidemia, statins have a major role in preventing the long term complications in diabetes and are recommended for diabetics with normal low density lipoprotein levels as well. In 2012, United States Food and Drug Administration released changes to statin safety label to include that statins have been found to increase glycosylated haemoglobin and fasting serum glucose levels. Many studies done on patients with cardiovascular risk factors have shown that statins have diabetogenic potential and the effect varies as per the dosage and type used. The various mechanisms for this effect have been proposed and one of them is downregulation of glucose transporters by the statins. The recommendations by the investigators are that though statins can have diabetogenic risk, they have more long term benefits which can outweigh the risk. In elderly patients and those with metabolic syndrome, as the risk of diabetes increase, the statins should be used cautiously. Other than a subset of population with risk for diabetes; statins still have long term survival benefits in most of the patients. PMID:25789118

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors improve myocardial high-energy phosphate metabolism in men.

PubMed

Schocke, Michael F; Martinek, Martin; Kremser, Christian; Wolf, Christian; Steinboeck, Peter; Lechleitner, Monika; Jaschke, Werner; Pachinger, Otmar; Metzler, Bernhard

2003-01-01

We intended to prove that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins have a beneficial impact on the human myocardial, high-energy, phosphate metabolism. The present study included 18 male patients (mean age 49.8 +/- 10.3) with statin-treated, familiar hypercholesterolemia (FH) and 13 male patients with untreated FH (mean age 44.6 +/- 9.5). Twenty-six healthy male volunteers served as controls (mean age 44.2 +/- 12.1). Phosphorus-31, two-dimensional chemical shift imaging (31P 2D CSI) of the heart was performed in all subjects using a 1.5 Tesla whole-body magnetic resonance (MR) scanner. The ratios between phosphocreatine (PCr) and beta-adenosine-triphosphate (beta-ATP) were calculated for the left ventricular myocardium. Furthermore, echocardiographic evaluation and stress tests were performed in all individuals. The untreated patients with FH exhibited a significant decrease in left ventricular PCr to beta-ATP ratios (1.78 +/- 0.34) compared with statin-treated FH patients (2.15 +/- 0.26, p < 0.001) and healthy controls (2.04 +/- 0.26, p = 0.009). The left ventricular PCr-to-beta-ATP ratios of the treated FH patients were in the range of the healthy controls. Our study shows for the first time an-improvement of the high-energy, phosphate metabolism in the left ventricular myocardium of patients with statin-treated FH compared with untreated FH patients.

Natural Inhibitors of HMG-CoA Reductase-An Insilico Approach Through Molecular Docking and Simulation Studies.

PubMed

Suganya, Subramanian; Nandagopal, Balaji; Anbarasu, Anand

2017-01-01

Plant products have always been considered for many important metabolic disorders due to its abundant medicinal properties. Alarming adverse effects of overuse of statins has been reported for patients with dyslipidemia. This study was aimed to identify compounds with potent anti-dyslipidemic property from selected plants and analyze them for their efficiency in binding with HMG-CoA reductase, a key enzyme in lipid metabolism. The docking studies indicate rutin as the best compound that can inhibit HMG-CoA reductase as it had strong binding affinity to the enzyme. The molecular dynamics simulation studies confirmed the stability of the HMG-CoA reductase-rutin complex. RMSD, RMSF, Rg, H-bond results indicated that the HMG-CoA reductase-rutin complex is highly stable. Presently, statins are not preferred for individuals with pre-existing liver disease. Our study identified rutin as a promising lead compound which could be further developed into an anti-dyslipidemic molecule. Our results will be a good starting point for future experimental and clinical studies and if the results from such studies match international standards plant derived rutin might emerge as a good alternative to statins. J. Cell. Biochem. 118: 52-57, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors and antioxidant vitamins on free radical lipid oxidation in rat liver.

PubMed

Lankin, V Z; Ivanova, M V; Konovalova, G G; Tikhaze, A K; Kaminnyi, A I; Kukharchuk, V V

2007-04-01

We studied the effects of two inhibitors of beta-hydroxy-beta-methylglutaryl coenzyme A reductase, simvastatin and lovastatin, on the lag phase of ascorbate-dependent lipid oxidation in rat liver. Oxidizability of liver biological membranes significantly increased in intact animals and rats with induced hypercholesterolemia after peroral administration of these statins. The lag phase of ascorbate-dependent lipid oxidation in liver biomembranes decreased by 2.1 times in hypercholesterolemic rats. In animals of the lovastatin group this parameter decreased by 4.4 times compared to the control. In intact rats receiving simvastatin, the lag phase of oxidation in biomembranes from the liver decreased practically by 2 times. At the same time, in animals receiving simvastatin in combination with antioxidant vitamins (vitamins E and C, provitamin A) and selenium, the period of induction of oxidation increased by 3.3 times. Our results indicate that beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors produce a prooxidant effect on the liver, which can be prevented by administration of antioxidant agents.

Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase.

PubMed

Würtz, Peter; Wang, Qin; Soininen, Pasi; Kangas, Antti J; Fatemifar, Ghazaleh; Tynkkynen, Tuulia; Tiainen, Mika; Perola, Markus; Tillin, Therese; Hughes, Alun D; Mäntyselkä, Pekka; Kähönen, Mika; Lehtimäki, Terho; Sattar, Naveed; Hingorani, Aroon D; Casas, Juan-Pablo; Salomaa, Veikko; Kivimäki, Mika; Järvelin, Marjo-Riitta; Davey Smith, George; Vanhala, Mauno; Lawlor, Debbie A; Raitakari, Olli T; Chaturvedi, Nish; Kettunen, Johannes; Ala-Korpela, Mika

2016-03-15

Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R(2) = 0.94, slope 1.00 ± 0.03). Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects

Pediatric Statin Administration: Navigating a Frontier with Limited Data

PubMed Central

Abdel-Rahman, Susan M.

2016-01-01

Increasingly, children and adolescents with dyslipidemia qualify for pharmacologic intervention. As they are for adults, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are the mainstay of pediatric dyslipidemia treatment when lifestyle modifications have failed. Despite the overall success of these drugs, the magnitude of variability in dose-exposure-response profiles contributes to adverse events and treatment failure. In children, the cause of treatment failures remains unclear. This review describes the updated guidelines for screening and management of pediatric dyslipidemia and statin disposition pathway to assist the provider in recognizing scenarios where alterations in dosage may be warranted to meet patients' specific needs. PMID:27877092

Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening.

PubMed

Lin, Shih-Hung; Huang, Kao-Jean; Weng, Ching-Feng; Shiuan, David

2015-01-01

Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR). The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank) database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity) properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration) values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening.

Risk Factor for Diabetes Mellitus and High Blood Glucose With HMG-CoA Reductase Inhibitors Using a Postmarketing Surveillance Database in Japan.

PubMed

Hashiguchi, Masayuki; Maruyama, Junya; Shimizu, Mikiko; Takahashi, Daichi; Shiga, Tsuyoshi

2018-02-20

To investigate whether 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) use is associated with an increased risk of diabetes mellitus and hyperglycemia, we performed a nested case-control study using a postmarketing surveillance database in Japan. The database cohort included 26,849 cases of statin use and 5308 cases of other lipid-lowering drug use in patients with hyperlipidemia. Participants received at least 1 type of statin, had a clear medication history of statin use, and had no complications of diabetes mellitus. Cases were defined as onset of diabetes mellitus or hyperglycemia during statin intake. For each case, 20 controls were randomly selected and matched by time point. The factors associated with an increased risk of diabetes mellitus and hyperglycemia during statin intake examined included sex, age, body mass index, statin use duration, complications, concomitant medication, and clinical laboratory tests. Statin-associated diabetes mellitus or hyperglycemia was identified based on abnormal elevation of blood glucose concentrations beyond the reference range. A total of 19,868 patients met the inclusion criteria, of whom 24 were patients in the case group. Two complicating factors, fatty liver (adjusted odds ratio 16.10) and hyperuricemia (adjusted odds ratio 28.96), were extracted for onset of diabetes mellitus or hyperglycemia. Nonalcoholic fatty liver was associated with diabetes mellitus, obesity, and insulin resistance, and hyperuricemia was associated with lifestyle. This study suggested that the onset of diabetes mellitus or hyperglycemia might be increased with statin use in patients with complications of fatty liver and hyperuricemia. © 2018, The American College of Clinical Pharmacology.

'Muscle-sparing' statins: preclinical profiles and future clinical use.

PubMed

Pfefferkorn, Jeffrey A

2009-03-01

Coronary heart disease (CHD) is a leading cause of death in the US, and hypercholesterolemia is a key risk factor for this disease. The current standard of care for treating hypercholesterolemia is the use of HMG-CoA reductase inhibitors, also known as statins, which block the rate-limiting step of cholesterol biosynthesis. In widespread clinical use, statins have proven safe and effective for both primary prevention of CHD and secondary prevention of coronary events. Results from several recent clinical trials have demonstrated that increasingly aggressive cholesterol-lowering therapy might offer additional protection against CHD compared with less aggressive treatment standards. While higher doses of current statin therapies are capable of achieving these more aggressive treatment goals, in certain cases statin-induced myalgia, the muscle pain or weakness that sometimes accompanies high-dose statin therapy, limits patient compliance with a treatment regimen. To address this limitation, efforts have been undertaken to develop highly hepatoselective statins that are capable of delivering best-in-class efficacy with minimized risk of dose-limiting myalgia. In this review, the preclinical and early clinical data for these next generation statins are discussed.

Correlation of compliance to statin therapy with lipid profile and serum HMGCoA reductase levels in dyslipidemic patients.

PubMed

Grover, Abhinav; Rehan, Harmeet Singh; Gupta, Lalit Kumar; Yadav, Madhur

The efficacy of statin therapy may be lost or vary with reduction in compliance and intensity of statin therapy. To study and correlate the quantitative effect of compliance on lipid profile and 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMGCoA-R) levels in dyslipidemic patients. Compliance to different intensity of statin therapy assessed by pill count was correlated with serum levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and HMGCoA-R. Out of 200 patients, 160 received moderate intensity statin therapy whereas 40 were on high intensity statin therapy. The overall mean compliance of patients was 56.7%. The compliance of patients on moderate intensity statin therapy was higher (56.8%) than those on high intensity (56.4%) (p=0.92). There was significant inverse correlation (p<0.05) between compliance and TC, TG, LDL-C and HMGCoA-R levels and positive correlation (p<0.05) with HDL-C levels. The mean serum HMGCoA-R levels did not fall below 9-10ng/mL when compliance to either moderate or high intensity statin therapy was increased above 60%. It is appropriate to improve the compliance to existing statin therapy than switching over to higher intensity statin therapy. Estimation of HMGCoA-R levels may be explored as a surrogate marker to monitor and assess the compliance of patients to statin therapy. Copyright © 2016. Published by Elsevier B.V.

Synergistic effect of combined HMG-CoA reductase inhibitor and angiotensin-II receptor blocker therapy in patients with chronic heart failure: the HF-COSTAR trial.

PubMed

Maejima, Yasuhiro; Nobori, Kiyoshi; Ono, Yuichi; Adachi, Susumu; Suzuki, Jun-Ichi; Hirao, Kenzo; Isobe, Mitsuaki; Ito, Hiroshi

2011-01-01

It is known that HMG-CoA reductase inhibitors (statins) may have a therapeutic benefit in patients with heart failure (HF). However, no studies have yet evaluated the possible interaction of statins and angiotensin-II receptor blockers (ARBs) on left ventricular (LV) function in patients with HF. We hypothesized that statins might alter the effect of ARBs on cardiac function in patients with HF. We prospectively randomized patients with chronic HF who received the ARB, losartan (LOS group), or the statin, simvastatin (SIM), in combination with LOS (SIM+LOS group) at our hospitals and assessed before and after treatment for 6 months. Although no significant improvement of HF symptoms as evaluated by the New York Heart Association (NYHA) classification was observed in the LOS group, HF symptoms in the SIM+LOS group significantly improved. The percent increase of LV ejection fraction after treatment in the SIM+LOS group was significantly larger than in the LOS group. Furthermore, the plasma brain natriuretic peptide level was significantly lower after treatment in the SIM+LOS group than in the LOS group. Combined statin and ARB therapy significantly improves both symptoms and LV function over time in patients with HF. Thus, the combination of an ARB with a statin may be a useful therapeutic strategy for HF.

Effect of statin use on mobility disability and its prevention in at-risk older adults: the LIFE study

USDA-ARS?s Scientific Manuscript database

BACKGROUND: HMG-CoA reductase inhibitors (statins) are among the most commonly prescribed classes of medications. Although their cardiovascular benefits and myalgia risks are well documented, their effects on older adults initiating an exercise training program are less understood. METHODS: 1,635 s...

Role of Statin Drugs for Polycystic Ovary Syndrome.

PubMed

Cassidy-Vu, Lisa; Joe, Edwina; Kirk, Julienne K

2016-12-01

Objective: To review the potential role and specific impact of statin drugs in women with PCOS. The evidence for this use of statins in PCOS is limited and still under further investigation. Materials and methods: A search was conducted using PubMed, DynaMed and PubMedHealth databases through October 16, 2016 using the terms polycystic ovary syndrome, PCOS, hydroxymethylglutaryl-CoA reductase inhibitors, hydroxymethylglutaryl-CoA, statin, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin . English-language trials evaluating statins in PCOS were obtained and incorporated if they provided relevant data for providers. Results: We summarize twelve trials involving statins in PCOS. The trials were predominantly 12 weeks to 3 months in length (8 of the 12 trials) and low to moderate dose of statin drugs were used. The majority (10 of 12) of the trials show that statins reduce testosterone levels or other androgen hormones (DHEA-S and androstenedione), half of the trials evaluating LH/FSH ratio show an improvement, and all had positive effects on lipid profiles. Conclusion: Statins show promising improvements in serum levels of androgens and LH/FSH ratios translating to improved cardiovascular risk factors above and beyond simply lowering LDL levels. More investigation is needed to determine if statins can clinically impact women with PCOS long term, particularly those who are young and are not yet candidates for traditional preventative treatment with a statin medication.

Do statins have a role in the prevention of age-related macular degeneration?

PubMed

Tsao, Sean W; Fong, Donald S

2013-04-01

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide for which preventative therapies are few. Evidence suggesting shared common risk factors and mirrored pathophysiology between cardiovascular disease and AMD led to the hypothesis that hydroxymethylglutaryl-CoA reductase inhibitors (statins) could be helpful in preventing AMD. For over a decade, observational studies have repeatedly investigated this hypothesis with conflicting conclusions. Although many reports conclude that statin use has no effect on the risk of AMD, no randomized controlled trial has yet been completed. Furthermore, relatively few studies factor characteristics of statin use into their analysis. A few studies have observed an incompletely explained protective effect against drusen, a funduscopic finding associated with AMD. Although there is insufficient evidence for a preventive effect of statins on dry AMD, there does seem to be stronger evidence against any effect on the development of exudative AMD. Overall, we find that there is insufficient evidence to conclude whether statin use is helpful in preventing AMD.

Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge

PubMed Central

Majumdar, Gipsy; Mozhui, Khyobeni; Gerling, Ivan C.; Vera, Santiago R.; Fish-Trotter, Hannah; Williams, Robert W.; Childress, Richard D.

2017-01-01

Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of statin-treated patients experience myalgia symptoms, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels. Myalgia is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin myalgia are not clearly understood. To elucidate changes in gene expression associated with statin myalgia, we compared profiles of gene expression in skeletal muscle biopsies from patients with statin myalgia who were undergoing statin re-challenge (cases) versus those of statin-tolerant controls. A robust separation of case and control cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of patients with statin myalgia, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, cell senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals is genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario is further bolstered by the discovery that a number of single nucleotide

Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge.

PubMed

Elam, Marshall B; Majumdar, Gipsy; Mozhui, Khyobeni; Gerling, Ivan C; Vera, Santiago R; Fish-Trotter, Hannah; Williams, Robert W; Childress, Richard D; Raghow, Rajendra

2017-01-01

Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of statin-treated patients experience myalgia symptoms, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels. Myalgia is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin myalgia are not clearly understood. To elucidate changes in gene expression associated with statin myalgia, we compared profiles of gene expression in skeletal muscle biopsies from patients with statin myalgia who were undergoing statin re-challenge (cases) versus those of statin-tolerant controls. A robust separation of case and control cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of patients with statin myalgia, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, cell senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals is genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario is further bolstered by the discovery that a number of single nucleotide

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

Statin-induced necrotizing myositis - a discrete autoimmune entity within the "statin-induced myopathy spectrum".

PubMed

Hamann, Philip D H; Cooper, Robert G; McHugh, Neil J; Chinoy, Hector

2013-10-01

Statin-induced necrotizing myositis is increasingly being recognised as part of the "statin-induced myopathy spectrum". As in other immune-mediated necrotizing myopathies, statin-induced myositis is characterised by proximal muscle weakness with marked serum creatinine kinase elevations and histological evidence of myonecrosis, with little or no inflammatory cell infiltration. Unlike other necrotizing myopathies, statin-induced myopathy is associated with the presence of autoantibodies directed against 3-hydroxy-3-methylglutaryl- coenzyme A reductase (the enzyme target of statin therapies), and with Human Leukocyte Antigen-DRB1*11. This article summarises the clinical presentation, investigations and management of this rare, but serious complication of statin therapy. © 2013 Elsevier B.V. All rights reserved.

Pleiotropic Effects of Statins on the Cardiovascular System

PubMed Central

Oesterle, Adam; Laufs, Ulrich; Liao, James K

2017-01-01

The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors (statins), have been used for thirty years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol (LDL-C). Statins may exert cardiovascular protective effects that are independent of LDL-C lowering called “pleiotropic” effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small guanosine triphosphate binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of pro-inflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify since the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-C reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease. PMID:28057795

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.

Statins enhance efficacy of venetoclax in blood cancers.

PubMed

Lee, J Scott; Roberts, Andrew; Juarez, Dennis; Vo, Thanh-Trang T; Bhatt, Shruti; Herzog, Lee-Or; Mallya, Sharmila; Bellin, Richard J; Agarwal, Suresh K; Salem, Ahmed Hamed; Xu, Tu; Jia, Jia; Li, Lingxiao; Hanna, John R; Davids, Matthew S; Fleischman, Angela G; O'Brien, Susan; Lam, Lloyd T; Leverson, Joel D; Letai, Anthony; Schatz, Jonathan H; Fruman, David A

2018-06-13

Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells. By blocking mevalonate production, HMGCR inhibition suppressed protein geranylgeranylation, resulting in up-regulation of proapoptotic protein p53 up-regulated modulator of apoptosis (PUMA). In support of these findings, dynamic BH3 profiling confirmed that statins primed cells for apoptosis. Furthermore, in retrospective analyses of three clinical studies of chronic lymphocytic leukemia, background statin use was associated with enhanced response to venetoclax, as demonstrated by more frequent complete responses. Together, this work provides mechanistic justification and clinical evidence to warrant prospective clinical investigation of this combination in hematologic malignancies. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Statin Medications and the Risk of Gynecomastia.

PubMed

Skeldon, Sean C; Carleton, Bruce; Brophy, James; Sodhi, Mohit; Etminan, Mahyar

2018-06-19

Case reports have suggested an increased risk of gynecomastia with HMG-CoA reductase inhibitors (i.e. statins). A recent meta-analysis also found that statins decrease circulating testosterone levels in men. We investigated whether statin use was associated with an increased risk of gynecomastia. Case control study. A cohort of patients from a random sample of 9,053,240 US subjects from the PharMetrics Plus ™ health claims database from 2006 to 2016 was created. New cases of gynecomastia requiring at least two ICD-9 codes were identified from the cohort and matched to 10 controls by follow-up time and age using density-based sampling. Rate ratios (RRs) for past users of statins were computed using conditional logistic regression adjusting for alcoholic cirrhosis, hyperthyroidism, testicular cancer, Klinefelter syndrome, obesity, hypogonadism, hyperprolactinemia and use of spironolactone, ketoconazole, H 2 receptor antagonists (H 2 blockers), risperidone, testosterone and androgen deprivation therapy. Our cohort included 6,147 cases of gynecomastia and 61,470 corresponding matched controls. The adjusted RR for current, recent and past statin use with respect to gynecomastia was 1.19 (1.04-1.36), 1.38 (1.15-1.65) and 1.20 (1.03-1.40) respectively. Statin use is associated with an increased risk of developing gynecomastia. Clinicians should be cognizant of this effect and educate patients accordingly. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Statins Are Associated With Reduced Mortality in Multiple Myeloma

PubMed Central

Keller, Jesse; Gage, Brian F.; Luo, Suhong; Wang, Tzu-Fei; Moskowitz, Gerald; Gumbel, Jason; Blue, Brandon; O’Brian, Katiuscia; Carson, Kenneth R.

2016-01-01

Purpose The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have activity in one of the pathways influenced by nitrogen-containing bisphosphonates, which are associated with improved survival in multiple myeloma (MM). To understand the benefit of statins in MM, we evaluated the association between statin use and mortality in a large cohort of patients with MM. Patients and Methods From the Veterans Administration Central Cancer Registry, we identified patients diagnosed with MM between 1999 and 2013. We defined statin use as the presence of any prescription for a statin within 3 months before or any time after MM diagnosis. Cox proportional hazards regression assessed the association of statin use with mortality, while controlling for known MM prognostic factors. Results We identified a cohort of 4,957 patients, of whom 2,294 received statin therapy. Statin use was associated with a 21% decrease in all-cause mortality (adjusted hazard ratio, 0.79; 95% CI, 0.73 to 0.86; P < .001) as well as a 24% decrease in MM-specific mortality (adjusted hazard ratio, 0.76; 95% CI, 0.67 to 0.86; P < .001). This association remained significant across all sensitivity analyses. In addition to reductions in mortality, statin use was associated with a 31% decreased risk of developing a skeletal-related event. Conclusion In this cohort study of US veterans with MM, statin therapy was associated with a reduced risk of both all-cause and MM-specific mortality. Our findings suggest a potential role for statin therapy in patients with MM. The putative benefit of statin therapy in MM should be corroborated in prospective studies. PMID:27646948

Statins, Angiotensin-Converting Enzyme Inhibitors and Physical Performance in Older Women

PubMed Central

Gray, Shelly L.; Aragaki, Aaron K.; LaMonte, Michael J.; Cochrane, Barbara B.; Kooperberg, Charles; Robinson, Jennifer G.; Woods, Nancy F.; LaCroix, Andrea Z.

2012-01-01

OBJECTIVES Angiotensin-converting enzyme (ACE) inhibitor and statin medications may preserve skeletal muscle. We examined associations between each medication class and baseline and mean annual change in physical performance measures and muscle strength in older women. DESIGN Prospective cohort study PARTICIPANTS Participants from the Women’s Health Initiative Clinical Trials who were aged 65–79 at baseline and had physical performance measures, self-report of health insurance and no prior history of stroke or congestive heart failure were included (n=5777). Women were recruited between 1993 and 1998. MEASUREMENTS Medication use was ascertained through a baseline inventory. Physical performance measures (timed 6-meter walk, repeated chair stands in 15 seconds) and grip strength were assessed at baseline and follow-up years 1, 3 and 6. Multivariable adjusted linear repeated- measures models adjusted for demographic and health characteristics. RESULTS ACE inhibitor use was negatively associated with mean grip strength at baseline (22.40 kg, 95% confidence interval [CI] 21.89, 22.91 versus 23.18 kg, 95% CI 23.02, 23.34; P = .005) and a greater mean annual change in number of chair stands (−.182, 95% CI −.217, −.147 versus −.145, 95% CI −.156, −.133; P = .05) compared to non-use. Statin use was not significantly associated with baseline or mean annual change for any outcome. A subgroup analysis suggested that statin use was associated with less mean annual change in chair stands (P = .006) in the oldest women. CONCLUSION These results do not support an association of statin or ACE inhibitor use with slower decline in physical performance or muscle strength, and thus do not support the use of these medications for preserving functional status in older adults. PMID:23176078

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.

Association Between Statin Use and Endometrial Cancer Survival.

PubMed

Nevadunsky, Nicole S; Van Arsdale, Anne; Strickler, Howard D; Spoozak, Lori A; Moadel, Alyson; Kaur, Gurpreet; Girda, Eugenia; Goldberg, Gary L; Einstein, Mark H

2015-07-01

To evaluate the association of 3 hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) use and concordant polypharmacy with disease-specific survival from endometrial cancer. A retrospective cohort study was conducted of 985 endometrial cancer cases treated from January 1999 through December 2009 at a single institution. Disease-specific survival was estimated by Kaplan-Meier analyses. A Cox proportional hazards model was used to study factors associated with survival. All statistical tests were two-sided and performed using Stata. At the time of analysis, 230 patients (22% of evaluable patients) died of disease and median follow-up was 3.28 years. Disease-specific survival was greater (179/220 [81%]) for women with endometrial cancer taking statin therapy at the time of diagnosis and staging compared with women not using statins (423/570 [74%]) (log rank test, P=.03). This association persisted for the subgroup of patients with nonendometrioid endometrial tumors who were statin users (59/87 [68%]) compared with nonusers (93/193 [43%]) (log rank test, P=.02). The relationship remained significant (hazard ratio 0.63, 95% confidence interval [CI] 0.40-0.99) after adjusting for age, clinical stage, radiation, and other factors. Further evaluation of polypharmacy showed an association between concurrent statin and aspirin use with an especially low disease-specific mortality (hazard ratio 0.25, 95% CI 0.09-0.70) relative to those who used neither. Statin and aspirin use was associated with improved survival from nonendometrioid endometrial cancer.

The Impact of Exercise on Statin-Associated Skeletal Muscle Myopathy

PubMed Central

Chung, Hae R.; Vakil, Mayand; Munroe, Michael; Parikh, Alay; Meador, Benjamin M.; Wu, Pei T.; Jeong, Jin H.; Woods, Jeffrey A.; Wilund, Kenneth R.; Boppart, Marni D.

2016-01-01

HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p<0.05). Cholesterol, grip strength, and maximal isometric force were significantly lower in all groups following statin treatment (statin main effect, p<0.05). Mitochondrial content and myofiber size were increased and 4-HNE was decreased by exercise (statin x exercise interaction, p<0.05), and these beneficial effects were abrogated by statin treatment. Exercise (Acct and Nov) increased atrogin-1 mRNA in combination with statin treatment, yet enhanced fiber damage or atrophy was not observed. The results from this study suggest that exercise (Nov, Acct) does not exacerbate statin-induced myopathy in ApoE-/- mice, yet statin treatment reduces activity in a manner that prevents muscle from mounting a beneficial adaptive response to training. PMID:27936249

Effect of early statin therapy after acute coronary syndromes: a concise review of the recent data.

PubMed

Bybee, Kevin A; Wright, R Scott; Kopecky, Stephen L

2002-01-01

HMG Co-A reductase inhibitors(statins) have been shown, in three large randomized trials, to decrease adverse cardiac events in patients with clinically evident coronary artery disease. All of these trials have excluded patients with an acute coronary syndrome within the three months prior to enrollment. Statin therapy is thought to stabilize coronary plaque and decrease the risk of plaque rupture. Statins have been shown to quickly reduce levels of LDL-C in addition to altering systemic inflammatory responses, improving endothelial function, and reducing platelet aggregation and activation. These mechanisms are potentially beneficial in the setting of acute coronary syndromes, a time of profound plaque instability. There is a growing body of evidence supporting the early initiation of statin therapy in the setting of acute coronary syndromes. This paper reviews the available data from randomized-controlled trials and observational studies evaluating the effect of early statin initiation during, or soon following, an acute coronary syndrome.

Effect of statins on intracerebral hemorrhage outcome and recurrence.

PubMed

FitzMaurice, Emilie; Wendell, Lauren; Snider, Ryan; Schwab, Kristin; Chanderraj, Rishi; Kinnecom, Cathrine; Nandigam, Kaveer; Rost, Natalia S; Viswanathan, Anand; Rosand, Jonathan; Greenberg, Steven M; Smith, Eric E

2008-07-01

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved outcome after ischemic stroke and subarachnoid hemorrhage but an increased risk of incident intracerebral hemorrhage (ICH). We investigated (1) whether statin use before ICH was associated with functional independence at 90 days, and (2) whether survivors exposed to statins after ICH had an increased risk of recurrence. We analyzed 629 consecutive ICH patients with 90-day outcome data enrolled in a prospective cohort study between 1998 to 2005. Statin use was determined by patient interview at the time of ICH and supplemented by medical record review. Independent status was defined as Glasgow Outcome Scale 4 or 5. ICH survivors were followed by telephone interview every 6 months. Statins were used by 149/629 (24%) before ICH. There was no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%, P=0.84) or mortality (46% versus 45%, P=0.93). Medical comorbidities and warfarin use were more common in statin users. Hematoma volumes were similar (median 28 cm(3) in pre-ICH statin users compared to 22 cm(3) in nonusers, P=0.18). The multivariable-adjusted odds ratio for independent status in pre-ICH statin users was 1.16 (95% CI 0.65 to 2.10, P=0.62). ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34 to 1.99, P=0.66). Pre-ICH statin use is not associated with improved ICH functional outcome or mortality. Post-ICH statin use is not associated with an increased risk of ICH recurrence.

Skin cancer associated with commonly prescribed drugs: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and statins -weighing the evidence.

PubMed

Nardone, Beatrice; Orrell, Kelsey A; Vakharia, Paras P; West, Dennis P

2018-02-01

Skin cancers, including both malignant melanoma (MM) and nonmelanoma skin cancer (NMSC), are the most commonly diagnosed cancers in the US. The incidence of both MM and NMSC continues to rise. Areas covered: Current evidence for an association between four of the most commonly prescribed classes of drugs in the U.S. and risk for MM and NMSC is reported. Medline was searched (January 2000 to May 2017) for each drug in the classes and for 'basal cell carcinoma', 'squamous cell carcinoma', 'non-melanoma skin cancer', 'skin cancer' and 'melanoma'. Skin cancer risk information was reported for: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins). Expert opinion: Since skin cancer risk is associated with all four classes of these commonly prescribed drugs that represent nearly 20% of the Top 100 drugs in the U.S., these important findings warrant enhanced education, especially for prescribers and those patients at high risk for skin cancer.

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.

The demand for statin: the effect of copay on utilization and compliance.

PubMed

Thiebaud, Patrick; Patel, Bimal V; Nichol, Michael B

2008-01-01

Increasing drug costs in the US have prompted employers and insurers alike to turn to higher drug copays for cost containment. The effect of rising copays on compliance with statins (HMG-CoA reductase inhibitors) treatment has received surprisingly little attention in the applied literature. This paper uses pharmacy claims data from a commercially insured adult population to determine the effect of copay change on compliance at the individual level. Fixed effect logit and Poisson regressions estimate the effect of copays on monthly likelihood of high compliance and average monthly days of supply respectively. Higher copays reduce compliance among statin users, with less compliant patients responding more strongly to copay change than compliant patients. These results suggest that specific financial incentives given to less compliant patients could improve compliance with statin treatment at a relatively low cost. Copyright (c) 2007 John Wiley & Sons, Ltd.

Statins and cancer.

PubMed

Vallianou, Natalia G; Kostantinou, Alexandra; Kougias, Marios; Kazazis, Christos

2014-06-01

Statins have pleiotropic properties and might exert an effect even in the field of cancer. Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoA to mevalonic acid. Specifically, inhibition of HMG-CoA reductase by statins has been proved to prevent the synthesis of mevalonic acid, a precursor of non-steroidal isoprenoids, which are lipid attachment molecules for small G proteins, such as Ras, Rho and Rac. Thus, statins may inhibit the synthesis of isoprenoids and thereby suppress the activation of small G proteins. In addition, statins exert pro-apoptotic, anti-angiogenic, and immunomodulatory effects, which may prevent cancer growth. Statins may inhibit the growth of a variety of cancer cell types, including breast, gastric, pancreatic, and prostate carcinoma, neuroblastoma, melanoma, mesothelioma and acute myeloid leukemia cells. They exert pro-apoptotic effects in a wide range of cancer cell lines, but with many differences in the sensitivity to statin-induced cell death among different cancer cell types. Regarding anti-angiogenic effects, multiple statin effects on blood vessel formation by inhibition of angiogenesis through down-regulation of pro-angiogenic factors, such as vascular endothelial growth factor, inhibition of endothelial cell proliferation and inhibition of adhesion to extracellular matrix by blocking intercellular adhesion molecules have been suggested. The molecular mechanisms of statin immunomodulation often implicate multiple pathways, regarding the regulation of genes encoding key molecules, which are involved in antigen presentation and subsequent immunomodulation. Another mechanism involves the down-regulation of the nuclear factor-kappa-B, which is responsible for the transcription of many genes involved in immunologic mechanisms, such as interferon-inducible protein-10, monocyte chemo-attractant protein 1 and cyclooxygenase-2. Statins

Effect of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitor on Disease Activity in Patients With Rheumatoid Arthritis

PubMed Central

Xing, Bin; Yin, Yu-Feng; Zhao, Li-Dan; Wang, Li; Zheng, Wen-Jie; Chen, Hua; Wu, Qing-Jun; Tang, Fu-Lin; Zhang, Feng-Chun; Shan, Guangliang; Zhang, Xuan

2015-01-01

Abstract HMG-CoA reductase inhibitors (also known as statins) are widely used as lipid-lowering agents in patients with rheumatoid arthritis (RA) to reduce their cardiovascular risk. However, whether they have an effect on RA disease activity is controversial. This study aimed to investigate the effect of statins on disease activity in RA patients. A systematic literature review was performed using the MEDLINE, EMBASE, Cochrane Library, ISI WEB of Knowledge, Scopus, and Clinical Trials Register databases. Only prospective randomized controlled trials or controlled clinical trials comparing the efficacy of statins with placebo on adult RA patients were included. The efficacy was measured according to the ACR criteria, EULAR criteria, DAS28, HAQ score, ESR, or CRP. The Jadad score was used for quality assessment. The inverse variance method was used to analyze continuous outcomes. A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was used. For stability of results, we performed leave-one-study-out sensitivity analysis by omitting individual studies one at a time from the meta-analysis. Publication bias was assessed using Egger test. A total 13 studies involving 737 patients were included in the meta-analysis; 11 studies were included in the meta-analysis based on DAS28, while the other 2 studies were only included in the meta-analysis based on ESR or CRP. The standardized mean difference (SMD) in DAS28 between the statin group and the placebo group was −0.55 (95% CI [−0.83, −0.26], P = 0.0002), with an I2 value of 68%. Subgroup analysis showed that patients with more active disease tended to benefit more from statin therapy (SMD −0.73, P = 0.01) than patients with moderate or low disease activity (SMD −0.38, P = 0.03). Statin therapy also significantly reduced tender joint counts, swollen joint counts, ESR, and CRP compared with placebo, but the reduction in HAQ score and VAS was not

On the inhibitor effects of bergamot juice flavonoids binding to the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme.

PubMed

Leopoldini, Monica; Malaj, Naim; Toscano, Marirosa; Sindona, Giovanni; Russo, Nino

2010-10-13

Density functional theory was applied to study the binding mode of new flavonoids as possible inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), an enzyme that catalyzes the four-electron reduction of HMGCoA to mevalonate, the committed step in the biosynthesis of sterols. The investigated flavonoid conjugates brutieridin and melitidin were recently quantified in the bergamot fruit extracts and identified to be structural analogues of statins, lipids concentration lowering drugs that inhibit HMGR. Computations allowed us to perform a detailed analysis of the geometrical and electronic features affecting the binding of these compounds, as well as that of the excellent simvastatin drug, to the active site of the enzyme and to give better insight into the inhibition process.

Statin withdrawal: clinical implications and molecular mechanisms.

PubMed

Cubeddu, Luigi X; Seamon, Matthew J

2006-09-01

Retrospective analyses of data from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM), the National Registry of Myocardial Infarction 4, and the Global Registry of Acute Coronary Events (GRACE) trials revealed that the benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) on acute coronary outcomes are rapidly lost and outcomes worsened if statins are discontinued during a patient's hospitalization for an acute coronary syndrome. Withdrawal of statin therapy in the first 24 hours of hospitalization for non-ST-elevation myocardial infarction increased the hospital morbidity and mortality rate versus continued therapy (11.9% vs 5.7%, p<0.01). Data from the Treating New Targets (TNT) study, however, suggested that short-term discontinuation of statin therapy in patients with stable cardiac conditions may not substantially increase the risk of acute coronary syndromes. In patients with acute coronary syndromes who discontinue statins, the rapid increase in risk of an event may result not only from the lost benefits from the therapy, but also from rebound inhibition of vascular protective substances and activation of vascular deleterious substances. Statins inhibit cholesterol synthesis in vascular cells. By reducing levels of isoprenoid intermediates, statins increase the production of nitric oxide and downregulate angiotensin II AT(1) receptors, endothelin-1, vascular inflammatory adhesion molecules, and inflammatory cytokines. These benefits are rapidly lost and often transiently reversed when statins are acutely discontinued. Acute removal of pleiotropic effects and rebound vascular dysfunction may be more important in an acute coronary event, where inflammation promotes rupture of atherosclerotic plaques and inflammatory and prothrombosis markers are present in high concentration, than in stable chronic vascular disease. In the absence of data from randomized controlled trials, current information suggests that

HMG-CoA reductase inhibitory activity and phytocomponent investigation of Basella alba leaf extract as a treatment for hypercholesterolemia.

PubMed

Baskaran, Gunasekaran; Salvamani, Shamala; Ahmad, Siti Aqlima; Shaharuddin, Noor Azmi; Pattiram, Parveen Devi; Shukor, Mohd Yunus

2015-01-01

The enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase is the key enzyme of the mevalonate pathway that produces cholesterol. Inhibition of HMG-CoA reductase reduces cholesterol biosynthesis in the liver. Synthetic drugs, statins, are commonly used for the treatment of hypercholesterolemia. Due to the side effects of statins, natural HMG-CoA reductase inhibitors of plant origin are needed. In this study, 25 medicinal plant methanol extracts were screened for anti-HMG-CoA reductase activity. Basella alba leaf extract showed the highest inhibitory effect at about 74%. Thus, B. alba was examined in order to investigate its phytochemical components. Gas chromatography with tandem mass spectrometry and reversed phase high-performance liquid chromatography analysis revealed the presence of phenol 2,6-bis(1,1-dimethylethyl), 1-heptatriacotanol, oleic acid, eicosyl ester, naringin, apigenin, luteolin, ascorbic acid, and α-tocopherol, which have been reported to possess antihypercholesterolemic effects. Further investigation of in vivo models should be performed in order to confirm its potential as an alternative treatment for hypercholesterolemia and related cardiovascular diseases.

HMG-CoA reductase inhibitory activity and phytocomponent investigation of Basella alba leaf extract as a treatment for hypercholesterolemia

PubMed Central

Baskaran, Gunasekaran; Salvamani, Shamala; Ahmad, Siti Aqlima; Shaharuddin, Noor Azmi; Pattiram, Parveen Devi; Shukor, Mohd Yunus

2015-01-01

The enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase is the key enzyme of the mevalonate pathway that produces cholesterol. Inhibition of HMG-CoA reductase reduces cholesterol biosynthesis in the liver. Synthetic drugs, statins, are commonly used for the treatment of hypercholesterolemia. Due to the side effects of statins, natural HMG-CoA reductase inhibitors of plant origin are needed. In this study, 25 medicinal plant methanol extracts were screened for anti-HMG-CoA reductase activity. Basella alba leaf extract showed the highest inhibitory effect at about 74%. Thus, B. alba was examined in order to investigate its phytochemical components. Gas chromatography with tandem mass spectrometry and reversed phase high-performance liquid chromatography analysis revealed the presence of phenol 2,6-bis(1,1-dimethylethyl), 1-heptatriacotanol, oleic acid, eicosyl ester, naringin, apigenin, luteolin, ascorbic acid, and α-tocopherol, which have been reported to possess antihypercholesterolemic effects. Further investigation of in vivo models should be performed in order to confirm its potential as an alternative treatment for hypercholesterolemia and related cardiovascular diseases. PMID:25609924

A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro[S

PubMed Central

Wasko, Brian M.; Smits, Jacqueline P.; Shull, Larry W.; Wiemer, David F.; Hohl, Raymond J.

2011-01-01

Statins and nitrogenous bisphosphonates (NBP) inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR) and farnesyl diphosphate synthase (FDPS), respectively, leading to depletion of farnesyl diphosphate (FPP) and disruption of protein prenylation. Squalene synthase (SQS) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis. Herein, we have identified novel bisphosphonates as potent and specific inhibitors of SQS, including the tetrasodium salt of 9-biphenyl-4,8-dimethyl-nona-3,7-dienyl-1,1-bisphosphonic acid (compound 5). Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells. At high concentrations, lovastatin and zoledronate impaired protein prenylation and decreased cell viability, which limits their potential use for cholesterol depletion. When combined with lovastatin, compound 5 prevented lovastatin-induced FPP depletion and impairment of protein farnesylation. Compound 5 in combination with the NBP zoledronate completely prevented zoledronate-induced impairment of both protein farnesylation and geranylgeranylation. Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone. The combination of an SQS inhibitor with an HMGCR or FDPS inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion. PMID:21903868

Thioredoxin Reductase and its Inhibitors

PubMed Central

Saccoccia, Fulvio; Angelucci, Francesco; Boumis, Giovanna; Carotti, Daniela; Desiato, Gianni; Miele, Adriana E; Bellelli, Andrea

2014-01-01

Thioredoxin plays a crucial role in a wide number of physiological processes, which span from reduction of nucleotides to deoxyriboucleotides to the detoxification from xenobiotics, oxidants and radicals. The redox function of Thioredoxin is critically dependent on the enzyme Thioredoxin NADPH Reductase (TrxR). In view of its indirect involvement in the above mentioned physio/pathological processes, inhibition of TrxR is an important clinical goal. As a general rule, the affinities and mechanisms of binding of TrxR inhibitors to the target enzyme are known with scarce precision and conflicting results abound in the literature. A relevant analysis of published results as well as the experimental procedures is therefore needed, also in view of the critical interest of TrxR inhibitors. We review the inhibitors of TrxR and related flavoreductases and the classical treatment of reversible, competitive, non competitive and uncompetitive inhibition with respect to TrxR, and in some cases we are able to reconcile contradictory results generated by oversimplified data analysis. PMID:24875642

Randomized clinical trials and recent patterns in the use of statins.

PubMed

Wang, T J; Stafford, R S; Ausiello, J C; Chaisson, C E

2001-06-01

Three landmark trials involving 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) were published between 1994 and 1996 (the Scandinavian Simvastatin Survival Study [4S], the West of Scotland Coronary Prevention Study, and the Cholesterol and Recurrent Events trial). These trials provided evidence that lipid-lowering therapy decreases cardiovascular events, including mortality. Whether these recent data caused a shift toward statin use has not been evaluated. Data from the National Ambulatory Medical Care Survey in 1980, 1981, 1985, and 1989 through 1998 were used. We analyzed 5053 visits by patients taking lipid-lowering medications to office-based physicians selected by stratified random sampling. The main outcome measure was use of specific lipid-lowering medications, including statins. In 1980 resins and niacin were the most commonly used lipid-lowering medications. By 1985 rising use of fibrates caused reductions in niacin use and resin use. By 1989 statins replaced fibrates as the most heavily used medications. Statin use climbed continuously thereafter, accounting for 90% of visits by patients treated for hypercholesterolemia in 1998. In time series analyses, increases in overall statin use were temporally unrelated to the publication of clinical trials, although the 4S trial may have contributed to a shift from older statins to simvastatin. For patients receiving lipid-lowering therapy in 1993 to 1998, statin use was significantly more likely for female patients, white patients, and patients visiting cardiologists. Although the market for lipid-lowering medications is dominated by statins, the rise in statins predated the recent clinical trials supporting their use.

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia.

PubMed

Maxwell, Whitney D; Ramsey, Laura B; Johnson, Samuel G; Moore, Kate G; Shtutman, Michael; Schoonover, John H; Kawaguchi-Suzuki, Marina

2017-09-01

Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes-based studies are available. We also summarize the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy. © 2017 Pharmacotherapy Publications, Inc.

Statins: pros and cons.

PubMed

Pinal-Fernandez, Iago; Casal-Dominguez, Maria; Mammen, Andrew L

2018-05-23

Statins inhibit the critical step of cholesterol synthesis in which 3-hydroxy-3-methylglutaryl coenzyme A (HMGC) is transformed to mevalonate by the enzyme HMGC reductase. By doing so, they have a potent lipid-lowering effect that reduces cardiovascular risk and decreases mortality. Since the mevalonate pathway also influences endothelial function, the inflammatory response, and coagulation, the effects of statins reach well beyond their cholesterol lowering properties. As with all drugs, statins may have adverse effects; these include musculoskeletal symptoms, increased risk of diabetes, and higher rates of hemorrhagic stroke. However, the frequency of adverse effects is extremely low and, in selected patient populations, the benefits of statins considerably outweigh the potential risks. Published by Elsevier España, S.L.U.

Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review

PubMed Central

Hirshburg, Jason M.; Kelsey, Petra A.; Therrien, Chelsea A.; Gavino, A. Carlo; Reichenberg, Jason S.

2016-01-01

Finasteride and dutasteride, both 5-alpha reductase inhibitors, are considered first-line treatment for androgenetic hair loss in men and used increasingly in women. In each case, patients are expected to take the medications indefinitely despite the lack of research regarding long-term adverse effects. Concerns regarding the adverse effects of these medications has led the United States National Institutes of Health to add a link for post-finasteride syndrome to its Genetic and Rare Disease Information Center. Herein, the authors report the results of a literature search reviewing adverse events of 5-alpha reductase inhibitors as they relate to prostate cancer, psychological effects, sexual health, and use in women. Several large studies found no increase in incidence of prostate cancer, a possible increase of high-grade cancer when detected, and no change in survival rate with 5-alpha reductase inhibitor use. Currently, there is no direct link between 5-alpha reductase inhibitor use and depression; however, several small studies have led to depression being listed as a side effect on the medication packaging. Sexual effects including erectile dysfunction and decreased libido and ejaculate were reported in as many as 3.4 to 15.8 percent of men. To date, there are very few studies evaluating 5-alpha reductase inhibitor use in women. Risks include birth defects in male fetuses if used in pregnancy, decreased libido, headache, gastrointestinal discomfort, and isolated reports of changes in menstruation, acne, and dizziness. Overall, 5-alpha reductase inhibitors were well-tolerated in both men and women, but not without risk, highlighting the importance of patient education prior to treatment. PMID:27672412

Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy).

PubMed

Pezzini, Alessandro; Grassi, Mario; Iacoviello, Licia; Zedde, Marialuisa; Marcheselli, Simona; Silvestrelli, Giorgio; DeLodovici, Maria Luisa; Sessa, Maria; Zini, Andrea; Paciaroni, Maurizio; Azzini, Cristiano; Gamba, Massimo; Del Sette, Massimo; Toriello, Antonella; Gandolfo, Carlo; Bonifati, Domenico Marco; Tassi, Rossana; Cavallini, Anna; Chiti, Alberto; Calabrò, Rocco Salvatore; Musolino, Rossella; Bovi, Paolo; Tomelleri, Giampaolo; Di Castelnuovo, Augusto; Vandelli, Laura; Ritelli, Marco; Agnelli, Giancarlo; De Vito, Alessandro; Pugliese, Nicola; Martini, Giuseppe; Lanari, Alessia; Ciccone, Alfonso; Lodigiani, Corrado; Malferrari, Giovanni; Del Zotto, Elisabetta; Morotti, Andrea; Costa, Paolo; Poli, Loris; De Giuli, Valeria; Bonaiti, Silvia; La Spina, Paolo; Marcello, Norina; Micieli, Giuseppe; de Gaetano, Giovanni; Colombi, Marina; Padovani, Alessandro

2016-09-01

Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated. We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case-control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH. A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones. Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Coenzyme Q10 and statins: biochemical and clinical implications.

PubMed

Littarru, Gian Paolo; Langsjoen, Peter

2007-06-01

Statins are drugs of known and undisputed efficacy in the treatment of hypercholesterolemia, usually well tolerated by most patients. In some cases treatment with statins produces skeletal muscle complaints, and/or mild serum CK elevation; the incidence of rhabdomyolysis is very low. As a result of the common biosynthetic pathway Coenzyme Q (ubiquinone) and dolichol levels are also affected, to a certain degree, by the treatment with these HMG-CoA reductase inhibitors. Plasma levels of CoQ10 are lowered in the course of statin treatment. This could be related to the fact that statins lower plasma LDL levels, and CoQ10 is mainly transported by LDL, but a decrease is also found in platelets and in lymphocytes of statin treated patients, therefore it could truly depend on inhibition of CoQ10 synthesis. There are also some indications that statin treatment affects muscle ubiquinone levels, although it is not yet clear to which extent this depends on some effect on mitochondrial biogenesis. Some papers indicate that CoQ10 depletion during statin therapy might be associated with subclinical cardiomyopathy and this situation is reversed upon CoQ10 treatment. We can reasonably hypothesize that in some conditions where other CoQ10 depleting situations exist treatment with statins may seriously impair plasma and possible tissue levels of coenzyme Q10. While waiting for a large scale clinical trial where patients treated with statins are also monitored for their CoQ10 status, with a group also being given CoQ10, physicians should be aware of this drug-nutrient interaction and be vigilant to the possibility that statin drugs may, in some cases, impair skeletal muscle and myocardial bioenergetics.

Toward "pain-free" statin prescribing: clinical algorithm for diagnosis and management of myalgia.

PubMed

Jacobson, Terry A

2008-06-01

Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and post-marketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins.

Evaluation of protein C and protein S levels in patients with diabetes mellitus receiving therapy with statins and ACE inhibitors or angiotensin II receptor blockers.

PubMed

Aktaş, Şerife; Uçak, Sema; Kurt, Fatma; Taşdemir, Mehmet; Kutlu, Orkide; Eker, Pınar

2018-01-01

To evaluate protein C, protein S level in patients with diabetes mellitus receiving statin and ACE inhibitor/ARB therapy. 95 patients were included in the study and divided into four groups depending on the use of statin and ACE inhibitor/ARB therapy. Group 1 comprised of patients receiving statin therapy (n = 15), Group 2 comprised of patients receiving ACE inhibitor/ARB therapy (n = 31), Group 3 comprised of patients receiving statin and ACE inhibitor/ARB therapy (n = 23), and Group 4 comprised of patients who did not receive either statin or ACE inhibitor/ARB therapy (n = 26). These four groups were compared with respect to protein C, protein S, fibrinogen, D-dimer, INR, and aPTT levels. There were statistically significant differences with respect to protein C levels. Group 1 and group 2 had higher protein C levels compared with group 4. (p < .01). Similarly, Group 3 had higher protein C levels compared with group 4. (p < .01). There was no significant difference between the groups with respect to protein S, INR, aPTT, and D-dimer levels. Diabetic patients receiving statin or ACE inhibitor/ARB therapy had higher protein C levels. Use of statin and ACE inhibitor/ARB therapy in diabetic patients decrease hypercoagulability and therefore could reduce the occurrence of cardiovascular events. Copyright © 2017 Elsevier B.V. All rights reserved.

Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice.

PubMed

Rebalka, Irena A; Cao, Andrew W; Raleigh, Matthew J; Henriksbo, Brandyn D; Coleman, Samantha K; Schertzer, Jonathan D; Hawke, Thomas J

2017-01-01

Those with diabetes invariably develop complications including cardiovascular disease (CVD). To reduce their CVD risk, diabetics are generally prescribed cholesterol-lowering 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors (i.e., statins). Statins inhibit cholesterol biosynthesis, but also reduce the synthesis of a number of mevalonate pathway intermediates, leading to several cholesterol-independent effects. One of the pleiotropic effects of statins is the reduction of the anti-fibrinolytic hormone plasminogen activator inhibitor-1 (PAI-1). We have previously demonstrated that a PAI-1 specific inhibitor alleviated diabetes-induced delays in skin and muscle repair. Here we tested if statin administration, through its pleiotropic effects on PAI-1, could improve skin and muscle repair in a diabetic rodent model. Six weeks after diabetes onset, adult male streptozotocin-induced diabetic (STZ), and WT mice were assigned to receive control chow or a diet enriched with 600 mg/kg Fluvastatin. Tibialis anterior muscles were injured via Cardiotoxin injection to induce skeletal muscle injury. Punch biopsies were administered on the dorsal scapular region to induce injury of skin. Twenty-four days after the onset of statin therapy (10 days post-injury), tissues were harvested and analyzed. PAI-1 levels were attenuated in statin-treated diabetic tissue when compared to control-treated tissue, however no differences were observed in non-diabetic tissue as a result of treatment. Muscle and skin repair were significantly attenuated in Fluvastatin-treated STZ-diabetic mice as demonstrated by larger wound areas, less mature granulation tissue, and an increased presence of smaller regenerating muscle fibers. Despite attenuating PAI-1 levels in diabetic tissue, Fluvastatin treatment impaired cutaneous healing and skeletal muscle repair in STZ-diabetic mice.

Human skeletal muscle drug transporters determine local exposure and toxicity of statins.

PubMed

Knauer, Michael J; Urquhart, Bradley L; Meyer zu Schwabedissen, Henriette E; Schwarz, Ute I; Lemke, Christopher J; Leake, Brenda F; Kim, Richard B; Tirona, Rommel G

2010-02-05

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. Interindividual differences in the activities of hepatic membrane drug transporters and metabolic enzymes are known to influence statin plasma pharmacokinetics and risk for myopathy. Interestingly, little is known regarding the molecular determinants of statin distribution into skeletal muscle and its relevance to toxicity. We sought to identify statin transporters in human skeletal muscle and determine their impact on statin toxicity in vitro. We demonstrate that the uptake transporter OATP2B1 (human organic anion transporting polypeptide 2B1) and the efflux transporters, multidrug resistance-associated protein (MRP)1, MRP4, and MRP5 are expressed on the sarcolemmal membrane of human skeletal muscle fibers and that atorvastatin and rosuvastatin are substrates of these transporters when assessed using a heterologous expression system. In an in vitro model of differentiated, primary human skeletal muscle myoblast cells, we demonstrate basal membrane expression and drug efflux activity of MRP1, which contributes to reducing intracellular statin accumulation. Furthermore, we show that expression of human OATP2B1 in human skeletal muscle myoblast cells by adenoviral vectors increases intracellular accumulation and toxicity of statins and such effects were abrogated when cells overexpressed MRP1. These results identify key membrane transporters as modulators of skeletal muscle statin exposure and toxicity.

Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins.

PubMed

El Harchaoui, Karim; Akdim, Fatima; Stroes, Erik S G; Trip, Mieke D; Kastelein, John J P

2008-01-01

Low-density lipoprotein-cholesterol (LDL-C) lowering is the mainstay of the current treatment guidelines in the management of cardiovascular risk. HMG-CoA reductase inhibitors (statins) are currently the most effective LDL-C-lowering drugs. However, a substantial number of patients do not reach treatment targets with statins. Therefore, an unmet medical need exists for lipid-lowering drugs with novel mechanisms of action to reach the recommended cholesterol target levels, either by monotherapy or combination therapy. Upregulation of the LDL receptor with squalene synthase inhibitors has shown promising results in animal studies but the clinical development of the lead compound lapaquistat (TAK-475) has recently been discontinued. Ezetimibe combined with statins allowed significantly more patients to reach their LDL-C targets. Other inhibitors of intestinal cholesterol absorption such as disodium ascorbyl phytostanol phosphate (FM-VP4) and bile acid transport inhibitors have shown positive results in early development trials, whereas the prospect of acyl coenzyme A: cholesterol acyltransferase inhibition in cardiovascular prevention is dire. Selective inhibition of messenger RNA (mRNA) by antisense oligonucleotides is a new approach to modify cholesterol levels. The inhibition of apolipoprotein B mRNA is in advanced development and mipomersen sodium (ISIS 301012) has shown striking results in phase II studies both as monotherapy as well as in combination with statins.

Withdrawal of statins increases event rates in patients with acute coronary syndromes.

PubMed

Heeschen, Christopher; Hamm, Christian W; Laufs, Ulrich; Snapinn, Steven; Böhm, Michael; White, Harvey D

2002-03-26

HMG-CoA Reductase Inhibitors (statins) reduce cardiac event rates in patients with stable coronary heart disease. Withdrawal of chronic statin treatment during acute coronary syndromes may impair vascular function independent of lipid-lowering effects and thus increase cardiac event rate. We investigated the effects of statins on the cardiac event rate in 1616 patients of the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study who had coronary artery disease and chest pain in the previous 24 hours. We recorded death and nonfatal myocardial infarction during the 30-day follow-up. Baseline clinical characteristics did not differ among 1249 patients without statin therapy, 379 patients with continued statin therapy, and 86 patients with discontinued statin therapy after hospitalization. Statin therapy was associated with a reduced event rate at 30-day follow-up compared with patients without statins (adjusted hazard ratio, 0.49 [95% CI, 0.21 to 0.86]; P=0.004). If the statin therapy was withdrawn after admission, cardiac risk increased compared with patients who continued to receive statins (2.93 [95% CI, 1.64 to 6.27]; P=0.005) and tended to be higher compared with patients who never received statins (1.69 [95% CI, 0.92 to 3.56]; P=0.15). This was related to an increased event rate during the first week after onset of symptoms and was independent of cholesterol levels. In a multivariate model, troponin T elevation (P=0.005), ST changes (P=0.02), and continuation of statin therapy (P=0.008) were the only independent predictors of patient outcome. Statin pretreatment in patients with acute coronary syndromes is associated with improved clinical outcome. However, discontinuation of statins after onset of symptoms completely abrogates this beneficial effect.

Novel aldose reductase inhibitors: a patent survey (2006--present).

PubMed

Chatzopoulou, Maria; Alexiou, Polyxeni; Kotsampasakou, Eleni; Demopoulos, Vassilis J

2012-11-01

Initially studied for its central role in the pathogenesis of chronic diabetic complications, aldose reductase (ALR2) gains more attention over the years as its implication in inflammatory diseases is being established, along with the therapeutic potential of its inhibitors. Reviewing the patents that were published since 2006, it is getting clear that the search for new chemical entities has subsided, giving rise to natural products and plant extracts with ALR2 inhibitory activity. Other aspects that were prominent were the search for proper forms of known inhibitors, in a way to improve their impaired physicochemical profile, as well as potential combination therapies with other compounds of pharmaceutical interest. On the spotlight were patents enhancing the therapeutic usage of aldose reductase inhibitors (ARIs) to various pathological conditions including cancer and inflammation-mediated diseases such as sepsis, asthma, and cancer. Although new chemical entities are scarcely registered and patented after many years of inconclusive clinical trials, the involvement of ALR2 to inflammatory pathologies might renew the interest in the field of ARIs.

A Discrete Event Simulation Model to Assess the Economic Value of a Hypothetical Pharmacogenomics Test for Statin-Induced Myopathy in Patients Initiating a Statin in Secondary Cardiovascular Prevention.

PubMed

Mitchell, Dominic; Guertin, Jason R; Dubois, Anick; Dubé, Marie-Pierre; Tardif, Jean-Claude; Iliza, Ange Christelle; Fanton-Aita, Fiorella; Matteau, Alexis; LeLorier, Jacques

2018-04-01

Statin (HMG-CoA reductase inhibitor) therapy is the mainstay dyslipidemia treatment and reduces the risk of a cardiovascular (CV) event (CVE) by up to 35%. However, adherence to statin therapy is poor. One reason patients discontinue statin therapy is musculoskeletal pain and the associated risk of rhabdomyolysis. Research is ongoing to develop a pharmacogenomics (PGx) test for statin-induced myopathy as an alternative to the current diagnosis method, which relies on creatine kinase levels. The potential economic value of a PGx test for statin-induced myopathy is unknown. We developed a lifetime discrete event simulation (DES) model for patients 65 years of age initiating a statin after a first CVE consisting of either an acute myocardial infarction (AMI) or a stroke. The model evaluates the potential economic value of a hypothetical PGx test for diagnosing statin-induced myopathy. We have assessed the model over the spectrum of test sensitivity and specificity parameters. Our model showed that a strategy with a perfect PGx test had an incremental cost-utility ratio of 4273 Canadian dollars ($Can) per quality-adjusted life year (QALY). The probabilistic sensitivity analysis shows that when the payer willingness-to-pay per QALY reaches $Can12,000, the PGx strategy is favored in 90% of the model simulations. We found that a strategy favoring patients staying on statin therapy is cost effective even if patients maintained on statin are at risk of rhabdomyolysis. Our results are explained by the fact that statins are highly effective in reducing the CV risk in patients at high CV risk, and this benefit largely outweighs the risk of rhabdomyolysis.

The Influence of the Brain‐Derived Neurotropic Factor Val66Met ‐Genotype and HMG‐CoA Reductase Inhibitors on Insulin Resistance in the Schizophrenia and Bipolar Populations

PubMed Central

Burghardt, K.J.; Pop‐Busui, R.; Bly, M.J.; Grove, T.B.; Taylor, S.F.; Ellingrod, V.L.

2012-01-01

Abstract Introduction: The brain‐derived neurotrophic factor (BDNF) Val66Met variant and HMG‐COA reductase inhibitors (statins) have been implicated in insulin resistance with a possible increased risk of diabetes. We sought to determine the effect of the BDNF Met variant and statin medication use on insulin resistance in schizophrenia and bipolar disorder using the homeostasis model assessment of insulin resistance (HOMA‐IR). Methods: A cross‐sectional design was used and patients with diabetes or on any medications affecting glucose regulation were ‐excluded. Associations between insulin resistance and genotype were then analyzed by ANOVA and regression analysis. Subjects were grouped by BDNF genotype as well as presence of statin. Results: Two hundred fifty‐two subjects with a mean age of 44 years were included. The group was 53% male and 41% had a diagnosis of bipolar disorder; 78% and 19% were receiving atypical antipsychotics (AAPs) and statin medications, respectively. Analysis showed schizophrenia subjects with the BDNF met allele as well as schizophrenia subjects with both the BDNF met allele and were receiving a statin had significantly higher HOMA‐IR values compared to the other groups (p= 0.046 and p= 0.016, respectively). Conclusions: Our results suggest that in the metabolically high‐risk population of schizophrenia the BDNF met allele alone and in combination with statin medications is associated with higher insulin resistance values. This was not seen in the bipolar population. Further validation of these associations remains necessary. Clin Trans Sci 2012; Volume 5: 486–490 PMID:23253673

Statin-Associated Autoimmune Myopathy: A Systematic Review of 100 Cases.

PubMed

Nazir, Salik; Lohani, Saroj; Tachamo, Niranjan; Poudel, Dilliram; Donato, Anthony

2017-04-01

Statins are a group of drugs that reduce the levels of triglycerides and cholesterol in blood by inhibiting HMG-CoA reductase, an enzyme involved in rate limiting step in cholesterol synthesis. About 2-20% patients on statins develop toxic myopathies, which usually resolve on discontinuation of statin. More recently, an immune-mediated necrotizing myopathy has been found to be associated with statin use which in most cases requires treatment with immunosuppressants. To perform a systematic review on published case reports and case series of statin-associated autoimmune myopathy. A comprehensive search of PUBMED, EMBASE, Cochrane library and ClinicalTrials.gov databases was performed for relevant articles from inception until March 19, 2016 to identify cases of statin-associated necrotizing myopathy and characterize their symptoms, evaluation and response to treatment. A total of 16 articles describing 100 patients with statin-associated autoimmune myopathy were identified. The mean age of presentation was 64.72 years, and 54.44% were males. The main presenting clinical feature was proximal muscle weakness, which was symmetric in 83.33% of patients. The mean creatine kinase (CK) was 6853 IU/l. Anti-HMG-CoA reductase antibody was positive in all cases tested (n = 57/57, 100%). In patients with no anti-HMG-CoA antibody results, diagnosis was established by findings of necrotizing myopathy on biopsy. Among the 83 cases where muscle biopsy information was available, 81.48% had necrosis, while 18.51% had combination of necrosis and inflammation. Most (83.82%) patients received two or more immunosuppressants to induce remission. Ninety-one percent had resolution of symptoms after treatment. Statin-associated necrotizing myopathy is a symmetric proximal muscle weakness associated with extreme elevations of CK. It is common in males and can occur after months of statin use. It is associated with necrosis on muscle biopsy and the presence of anti-HMG-CoA reductase antibodies

Regulation of HMG-CoA reductase in MCF-7 cells by genistein, EPA, and DHA, alone and in combination with mevastatin.

PubMed

Duncan, Robin E; El-Sohemy, Ahmed; Archer, Michael C

2005-06-28

We investigated the regulation of HMG-CoA reductase in MCF-7 human breast cancer cells by genistein, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). All three compounds down-regulated reductase activity, primarily through post-transcriptional effects. In mevastatin-treated cells, only genistein and DHA abrogated the induction of reductase activity caused by this competitive inhibitor. Diets rich in soy isoflavones and fish oils, therefore, may exert anti-cancer effects through the inhibition of mevalonate synthesis in the breast. Genistein and DHA, in particular, may augment the efficacy of statins, increasing the potential for use of these drugs in adjuvant therapy for breast cancer.

Pleiotropic effects of statins on the treatment of chronic periodontitis--a systematic review.

PubMed

Estanislau, Ilanna Mara Gomes; Terceiro, Icrólio Ribeiro Colares; Lisboa, Mario Roberto Pontes; Teles, Patrícia de Barros; Carvalho, Rosimary de Sousa; Martins, Ricardo Souza; Moreira, Maria Mônica Studart Mendes

2015-06-01

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are an important group of hypolipidaemic drugs, widely used in the treatment of hypercholesterolaemia and cardiovascular disease. Some studies have shown that statins are able to modulate inflammation and alveolar bone loss. In order to evaluate whether statins could influence periodontal treatment, improving the clinical and radiographic parameters in chronic periodontitis, a systematic review was conducted in the databases PUBMED and BIREME, searching for articles in English and Portuguese, published between the years 2004 and 2014, using the combined keywords statin, periodontal disease, periodontitis and alveolar bone. Studies regarding the treatment of chronic periodontitis in humans, blind or double-blind, retrospective cohort or randomized controlled trials that used statins topically or systemically were selected. Statins have important anti-inflammatory and immune effects, reducing levels of C-reactive protein and matrix metalloproteinases and their intermediate products, such as tumour necrosis factor-α, and are also able to inhibit the adhesion and extravasation of leukocytes, which block the co-stimulation of T cells. Statins reduce bone resorption by inhibiting osteoclast formation and lead to increased apoptosis of these cells. The effect of statins on bone formation is related to the increased gene expression of bone morphogenetic protein in osteoblasts. Although we found biological mechanisms and clinical results that show lower alveolar bone loss and reduction of clinical signs of inflammation, further studies are needed to evaluate the clinical applicability of statins in the routine treatment of chronic periodontitis. © 2014 The British Pharmacological Society.

Statins Reduce Lipopolysaccharide-Induced Cytokine and Inflammatory Mediator Release in an In Vitro Model of Microglial-Like Cells

PubMed Central

McFarland, A. J.

2017-01-01

The anti-inflammatory effects of statins (HMG-CoA reductase inhibitors) within the cardiovascular system are well-established; however, their neuroinflammatory potential is unclear. It is currently unknown whether statins' neurological effects are lipid-dependent or due to pleiotropic mechanisms. Therefore, the assumption that all statin compounds will have the same effect within the central nervous system is potentially inappropriate, with no studies to date having compared all statins in a single model. Thus, the aim of this study was to compare the effects of the six statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) within a single in vitro model of neuroinflammation. To achieve this, PMA-differentiated THP-1 cells were used as surrogate microglial cells, and LPS was used to induce inflammatory conditions. Here, we show that pretreatment with all statins was able to significantly reduce LPS-induced interleukin (IL)-1β and tumour necrosis factor (TNF)-α release, as well as decrease LPS-induced prostaglandin E2 (PGE2). Similarly, global reactive oxygen species (ROS) and nitric oxide (NO) production were decreased following pretreatment with all statins. Based on these findings, it is suggested that more complex cellular models should be considered to further compare individual statin compounds, including translation into in vivo models of acute and/or chronic neuroinflammation. PMID:28546657

[Establishment of an in vitro screening model for steroid 5 alpha-reductase inhibitors with the microplate reader].

PubMed

Wu, Jian-Hui; Sun, Zu-Yue

2013-06-01

To establish an in vitro screening model for steroid 5 alpha-reductase inhibitors using the microplate reader. Steroid 5 alpha-reductase was obtained from the liver of female rats, an in vitro screening model for steroid 5 alpha-reductase inhibitors established using the 96-well plate and microplate reader after determination of the enzymatic activity, and the reliability of the model verified with the known 5 alpha-reductase inhibitors epristeride and finasteride. Added to the 96-well plate were the final concentrations of testosterone (0-40 micromol/L), NADPH (22 micromol/L), epristeride (0-60 nmol/L) or finasteride (0-60 nmol/ L) and steroid 5 alpha-reductase (20 microl), the total volume of each well adjusted to 200 microl with Tris-Hcl buffer. The 96-well plate was placed in the microplate reader, mixed and incubated at 37 degrees C, followed by detection of the A340nm value at 0 and 10 min and analysis of the data. The Km value of steroid 5 alpha-reductase was 3.794 micromol/L, with a Vmax of 0.271 micromol/(L. min). The Ki of epristeride was 148.2 nmol/L, with an IC50 of 31.5 nmol/L, and the enzymatic reaction kinetic curve suggested that epristeride was an uncompetitive enzyme inhibitor. The Ki of finasteride was 158. 8 nmol/L, with an IC50 of 13.6 nmol/L. The enzymatic reaction kinetic curve showed that both epristeride and finasteride were competitive enzyme inhibitors, similar to those reported in the published literature. A screening model was successfully established, which could rapidly and effectively screen steroid 5 alpha-reductase inhibitors in vitro.

Targeting New Pharmacological Approaches for Alzheimer's Disease: Potential for Statins and Phosphodiesterase Inhibitors.

PubMed

Sallustio, Fabrizio; Studer, Valeria

2016-01-01

Alzheimer's disease (AD) is the most common cause of dementia among the elderly. It is pathologically characterized by diffused extracellular deposits, senile plaques, and intracellular neurofibrillary tangles in the brain, responsible for neuronal dysfunction and cell death. Memory, language and other cognitive functions can be affected to a limited extent in the initial stage called mild cognitive impairment (MCI) or in a more severe and daily life interfering manner in the later stage called dementia. Currently no effective disease-modifying treatment exists for the majority of neurodegenerative diseases. Failure of therapy aimed at affecting beta amyloid pathology has led research to investigate alternative approaches. Recent findings address statins and phosphodiesterase (PDE) inhibitors as compounds able to affect different mechanisms underlying AD. Statins could exert several effects based on their lipid-lowering and cerebral blood flow increasing abilities but also pleiotropic/antinflammatory and neuroprotective properties have been claimed. PDEs act as regulators of intracellular signaling cascades through the control of two second messengers, cyclic adenosine monophosphate and cyclic guanosine monophosphate. PDE inhibitors effects in animal models of AD have been promising and their proven safety in clinical use create high expectations for the treatment of AD. In this review, we will report main data and evidence on: 1. Current pathophysiological theories of AD in order to better understand which mechanisms lead to pathological changes and can be affected by therapies; 2. The use of statins and PDE inhibitors in animal models of AD and in humans, analyzing their mechanisms of action.

The Association of Statin Therapy with the Risk of Recurrent Venous Thrombosis

PubMed Central

Smith, Nicholas L.; Harrington, Laura B.; Blondon, Marc; Wiggins, Kerri L.; Floyd, James S.; Sitlani, Colleen M.; McKnight, Barbara; Larson, Eric B.; Rosendaal, Frits R.; Heckbert, Susan R.; Psaty, Bruce M.

2016-01-01

Background Meta-analyses of randomized controlled trials suggest that treatment with HMG-CoA reductase inhibitors (statins) lowers the risk of incident venous thrombosis (VT), particularly among those without prevalent clinical cardiovascular disease (CVD). Whether this is true for the prevention of recurrent VT is debated. We used an observational inception cohort to estimate the association of current statin use with the risk of recurrent VT. Methods and Results The study setting was a large healthcare organization with detailed medical record and pharmacy information at cohort entry and throughout follow-up. We followed 2,798 subjects 18–89 years of age who experienced a validated incident VT between January 1, 2002 and December 31, 2010, for a first recurrent VT, validated by medical record review. During follow-up, 457 (16%) developed a first recurrent VT. In time-to-event models incorporating time-varying statin use and adjusting for potential confounders, current statin use was associated with a 26% lower risk of recurrent VT: HR=0.74; 95%CI: 0.59–0.94. Among cohort members free of CVD (n=2,134), current statin use was also associated with a lower risk (38%) of recurrent VT: HR=0.62; 95%CI: 0.45–0.85. We found similar results when restricting to new users of statins and in subgroups of different statin types and doses. Conclusions In a population-based cohort of subjects who had experienced an incident VT, statin use, compared with non-use, was associated with a clinically-relevant lower risk of recurrent VT. These findings suggest a potential secondary benefit of statins among patients who have experienced an incident VT. PMID:27061794

Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review

PubMed Central

Canestaro, William J.; Austin, Melissa A.; Thummel, Kenneth E.

2015-01-01

Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1. PMID:24810685

The Impact of 5α-Reductase Inhibitor Use for Male Pattern Hair Loss on Men's Health.

PubMed

Said, Mohammed A; Mehta, Akanksha

2018-06-16

Male pattern hair loss, mediated by dihydrotestosterone, is a common hair loss disorder, affecting over 50% of men over the age of 50. The 5-α reductase inhibitors, finasteride and dutasteride, are Food and Drug Administration-approved drugs for the treatment of this disorder. Several recent studies have reported adverse sexual and spermatogenic events among young men using 5-α reductase inhibitors, such as erectile dysfunction, decreased ejaculate volume, decreased libido, and infertility. In this review, we summarize and analyze the literature regarding the efficacy and safety of these medications, with an overall focus on men's health. Finasteride for the treatment of male pattern hair loss was considered safe according to many previous clinical trials. However, these trials have been recently criticized for inadequate safety reporting. Comprehensive review of the current literature reveals that there is a disproportionately high number of men with 5-α reductase inhibitor-associated sexual dysfunction and infertility. Although uncommon, the use of 5-α reductase inhibitors is associated with serious and persistent sexual and reproductive side effects, such as erectile dysfunction, decreased ejaculate volume, decreased libido, and infertility.

Interplay between statins and PPARs in improving cardiovascular outcomes: a double-edged sword?

PubMed Central

Balakumar, Pitchai; Mahadevan, Nanjaian

2012-01-01

Statins are best-selling medications in the management of high cholesterol and associated cardiovascular complications. They inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase in order to prevent disproportionate cholesterol synthesis. Statins slow the progression of atherosclerosis, prevent the secondary cardiovascular events and improve the cardiovascular outcomes in patients with elevated cholesterol levels. The underlying mechanisms pertaining to the cardioprotective role of statins are linked with numerous pleiotropic actions including inhibition of inflammatory events and improvement of endothelial function, besides an effective cholesterol-lowering ability. Intriguingly, recent studies suggest possible interplay between statins and nuclear transcription factors like PPARs, which should also be taken into consideration while analysing the potential of statins in the management of cardiovascular complications. It could be suggested that statins have two major roles: (i) a well-established cholesterol-lowering effect through inhibition of HMG-CoA-reductase; (ii) a newly explored PPAR-activating property, which could mediate most of cardiovascular protective pleiotropic effects of statins including anti-inflammatory, antioxidant and anti-fibrotic properties. The present review addressed the underlying principles pertaining to the modulatory role of statins on PPARs. PMID:21790534

Impact of Statin Use on Outcomes in Triple Negative Breast Cancer

PubMed Central

Shaitelman, Simona F.; Stauder, Michael C.; Allen, Pamela; Reddy, Sangeetha; Lakoski, Susan; Atkinson, Bradley; Reddy, Jay; Amaya, Diana; Guerra, William; Ueno, Naoto; Caudle, Abigail; Tereffe, Welela; Woodward, Wendy A.

2017-01-01

Purpose: We sought to investigate if the use of HMG Co-A reductase inhibitors (statins) has an impact on outcomes among patients with triple negative breast cancer (TNBC). Methods: We reviewed the cases of women with invasive, non-metastatic TNBC, diagnosed 1997-2012. Clinical outcomes were compared based on statin use (defined as ever use during treatment vs. never use). We identified a subset of women for whom a 5-value lipid panel (5VLP) was available, including total cholesterol, low density lipoprotein, high density lipoprotein, very low density lipoprotein, and triglycerides. The Kaplan-Meier method was used to estimate median overall survival (OS), distant metastases-free survival (DMFS), and local-regional recurrence-free survival (LRRFS). A Cox proportional hazards regression model was used to test the statistical significance of prognostic factors. Results: 869 women were identified who met inclusion criteria, with a median follow-up time of 75.1 months (range 2.4-228.9 months). 293 (33.7%) patients used statins and 368 (42.3%) had a 5VLP. OS, DMFS, and LRRFS were not significant based on statin use or type. Controlling for the 5VLP values, on multivariable analysis, statin use was significantly associated with OS (HR 0.10, 95% CI 0.01-0.76), but not with DMFS (HR 0.14, 95% CI 0.01-1.40) nor LRRFS (HR 0.10 95% CI 0.00-3.51). Conclusions: Statin use among patients with TNBC is not associated with improved OS, although it may have a benefit for a subset of patients. Prospective assessment would be valuable to better assess the potential complex correlation between clinical outcome, lipid levels, and statin use. PMID:28819403

Statin Exposure Is Associated with Decreased Asthma-related Emergency Department Visits and Oral Corticosteroid Use

PubMed Central

Li, Lingling; Butler, Melissa G.; Fung, Vicki; Kharbanda, Elyse O.; Larkin, Emma K.; Vollmer, William M.; Miroshnik, Irina; Rusinak, Donna; Weiss, Scott T.; Lieu, Tracy; Wu, Ann Chen

2013-01-01

Rationale: Statins, or HMG-CoA reductase inhibitors, may aid in the treatment of asthma through their pleiotropic antiinflammatory effects. Objectives: To examine the effect of statin therapy on asthma-related exacerbations using a large population-based cohort. Methods: Statin users aged 31 years or greater with asthma were identified from the Population-Based Effectiveness in Asthma and Lung population, which includes data from five health plans. Statin exposure and asthma exacerbations were assessed over a 24-month observation period. Statin users with a statin medication possession ratio greater than or equal to 80% were matched to non–statin users by age, baseline asthma therapy, site of enrollment, season at baseline, and propensity score, which was calculated based on patient demographics and Deyo-Charlson conditions. Asthma exacerbations were defined as two or more oral corticosteroid dispensings, asthma-related emergency department visits, or asthma-related hospitalizations. The association between statin exposure and each of the three outcome measures was assessed using conditional logistic regression. Measurements and Main Results: Of the 14,566 statin users, 8,349 statin users were matched to a nonuser. After adjusting for Deyo-Charlson conditions that remained unbalanced after matching, among statin users, statin exposure was associated with decreased odds of having asthma-related emergency department visits (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.53–0.77; P < 0.0001) and two or more oral corticosteroid dispensings (OR, 0.90; 95% CI, 0.81–0.99; P = 0.04). There were no differences in asthma-related hospitalizations (OR, 0.91; 95% CI, 0.66–1.24; P = 0.52). Conclusions: Among statin users with asthma, statin exposure was associated with decreased odds of asthma-related emergency department visits and oral corticosteroid dispensings. PMID:24093599

Effect of coenzyme q10 on myopathic symptoms in patients treated with statins.

PubMed

Caso, Giuseppe; Kelly, Patricia; McNurlan, Margaret A; Lawson, William E

2007-05-15

Treatment of hypercholesterolemia with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) is effective in the primary and secondary prevention of cardiovascular disease. However, statin use is often associated with a variety of muscle-related symptoms or myopathies. Myopathy may be related in part to statin inhibition of the endogenous synthesis of coenzyme Q10, an essential cofactor for mitochondrial energy production. The aim of this study is to determine whether coenzyme Q10 supplementation would reduce the degree of muscle pain associated with statin treatment. Patients with myopathic symptoms were randomly assigned in a double-blinded protocol to treatment with coenzyme Q10 (100 mg/day, n = 18) or vitamin E (400 IU/day, n = 14) for 30 days. Muscle pain and pain interference with daily activities were assessed before and after treatment. After a 30-day intervention, pain severity decreased by 40% (p <0.001) and pain interference with daily activities decreased by 38% (p <0.02) in the group treated with coenzyme Q10. In contrast, no changes in pain severity (+9%, p = NS) or pain interference with daily activities (-11%, p = NS) was observed in the group treated with vitamin E. In conclusion, results suggest that coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment. Thus, coenzyme Q10 supplementation may offer an alternative to stopping treatment with these vital drugs.

Reduced mitochondrial coenzyme Q10 levels in HepG2 cells treated with high-dose simvastatin: A possible role in statin-induced hepatotoxicity?

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

Tavintharan, S.; Ong, C.N.; Jeyaseelan, K.

2007-09-01

Lowering of low-density lipoprotein cholesterol is well achieved by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). Statins inhibit the conversion of HMG-CoA to mevalonate, a precursor for cholesterol and coenzyme Q10 (CoQ{sub 10}). In HepG2 cells, simvastatin decreased mitochondrial CoQ{sub 10} levels, and at higher concentrations was associated with a moderately higher degree of cell death, increased DNA oxidative damage and a reduction in ATP synthesis. Supplementation of CoQ{sub 10}, reduced cell death and DNA oxidative stress, and increased ATP synthesis. It is suggested that CoQ{sub 10} deficiency plays an important role in statin-induced hepatopathy, and that CoQ{sub 10} supplementation protectsmore » HepG2 cells from this complication.« less

[Organprotection in cardiac risk patients--rational of perioperative beta-adrenoceptor-antagonists and statins].

PubMed

Hanss, Robert; Bein, Berthold

2010-04-01

The number of patients with limited organ function is steadily increasing due to the aging of the population. Consequently, a growing number of patients needing surgery is accompanied by serious comorbidities. These patients are at high risk of perioperative organ dysfunction. In this context cardiac events (e.g. cardiac arrhythmias, angina or myocardial infarction) play a major role with significant impact on postoperative care, long term outcome and economic sequelae. Thus, anaesthesiologists must prevent such events in the perioperative period. Besides general measures such as adequate analgesia, protection from stressful events and sufficient volume replacement, medical intervention with beta-blockers or HMG-CoA-reductase-inhibitors (statins) are necessary to reduce the incidence of perioperative cardiac events. Both beta-blockers and HMG-CoA-reductase-inhibitors are known to exhibit pleiotropic effects (defined as additional cardioprotective effects) besides the primary blockade of the beta-adrenergic receptor or the inhibition of the synthesis of serum cholesterol, respectively. Both groups of drugs improve cardiac function, decrease inflammatory response, decrease activation of blood coagulation and stabilize endothelial plaques. Based on the current literature the following recommendations are published concerning the perioperative administration of beta-blockers: (i) Patients who are on beta-blockers on a regular basis following guidelines concerning chronic treatment of cardiovascular diseases should continue this medication throughout the perioperative period; (ii) a sufficient indicator of an adequate therapy is the baseline heart rate. It should not exceed 60-70bpm at rest; (iii) the Revised Cardiac Risk Index (RCRI) is a widely accepted score to estimate the patient's perioperative cardiac risk; (iv) patients with a RCRI > or =3 should not be scheduled for routine surgery without sufficient beta-adrenergic-receptor blockade; (v) in patients at high

Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

PubMed Central

Golomb, Beatrice A.; Evans, Marcella A.

2009-01-01

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 (CYP)3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many non-muscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity. PMID:19159124

Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes

PubMed Central

Hackett, Geoffrey; Jones, Peter W; Strange, Richard C; Ramachandran, Sudarshan

2017-01-01

AIM To determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men. METHODS We studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual. RESULTS Age was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality. CONCLUSION We show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men. PMID:28344753

Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century?

PubMed

Keen, Helen I; Krishnarajah, Janakan; Bates, Timothy R; Watts, Gerald F

2014-09-01

Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk. This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence. Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD.

A Randomized Clinical Trial to Assess the Effect of Statins on Skeletal Muscle Function and Performance: Rationale and Study Design

PubMed Central

Thompson, Paul D.; Parker, Beth A.; Clarkson, Priscilla M.; Pescatello, Linda S.; White, C. Michael; Grimaldi, Adam S.; Levine, Benjamin D.; Haller, Ronald G.; Hoffman, Eric P.

2014-01-01

Hydroxymethylglutaryl-coenzyme A reductase inhibitors or statins are the most effective medications for reducing elevated concentrations of low-density lipoprotein cholesterol (LDL-C). Statins reduce cardiac events in patients with coronary artery disease and previously healthy persons. Current recommendations for LDL-C treatment goals indicate that more patients will be treated with higher doses of these medications. Statins have been extremely well-tolerated in controlled clinical trials but are increasingly recognized to produce skeletal muscle myalgia, cramps, and weakness. The reported frequency of such mild symptoms is not clear, and muscle performance has not been examined with these medications. Accordingly, the present investigation, the Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study, will recruit approximately 440 healthy persons. Participants will be randomly assigned to treatment with atorvastatin 80 mg/d or placebo. Handgrip, elbow and knee isometric and isokinetic strength, knee extensor endurance, and maximal aerobic exercise performance will be determined at baseline. Participants will undergo repeat testing after 6 months of treatment or after meeting the study definition of statin myalgia. This study will determine the effect of statins on skeletal muscle strength, endurance, and aerobic exercise performance and may ultimately help clinicians better evaluate statin-related muscle and exercise complaints. PMID:20626664

Cost-Effectiveness of Statins for Primary Cardiovascular Prevention in Chronic Kidney Disease

PubMed Central

Erickson, Kevin F.; Japa, Sohan; Owens, Douglas K.; Chertow, Glenn M.; Garber, Alan M.; Goldhaber-Fiebert, Jeremy D.

2013-01-01

Objectives To evaluate the cost-effectiveness of statins for primary prevention of myocardial infarction (MI) and stroke in patients with chronic kidney disease (CKD). Background Patients with CKD have an elevated risk of MI and stroke. Although HMG Co-A reductase inhibitors (“statins”) may prevent cardiovascular events in patients with non-dialysis-requiring CKD, adverse drug effects and competing risks could materially influence net effects and clinical decision-making. Methods We developed a decision-analytic model of CKD and cardiovascular disease (CVD) to determine the cost-effectiveness of low-cost generic statins for primary CVD prevention in men and women with hypertension and mild-to-moderate CKD. Outcomes included MI and stroke rates, discounted quality adjusted life years (QALYs) and lifetime costs (2010 USD), and incremental cost-effectiveness ratios. Results For 65 year-old men with moderate hypertension and mild-to-moderate CKD, statins reduced the combined rate of MI and stroke, yielded 0.10 QALYs, and increased costs by $1,800 ($18,000 per QALY gained). For patients with lower baseline cardiovascular risks, health and economic benefits were smaller; for 65 year-old women, statins yielded 0.06 QALYs and increased costs by $1,900 ($33,400 per QALY gained). Results were sensitive to rates of rhabdomyolysis and drug costs. Statins are less cost-effective when obtained at average retail prices, particularly in patients at lower CVD risk. Conclusions While statins reduce absolute CVD risk in patients with CKD, increased risk of rhabdomyolysis, and competing risks associated with progressive CKD, partly offset these gains. Low-cost generic statins appear cost-effective for primary prevention of CVD in patients with mild-to-moderate CKD and hypertension. PMID:23500327

Cost-effectiveness of statins for primary cardiovascular prevention in chronic kidney disease.

PubMed

Erickson, Kevin F; Japa, Sohan; Owens, Douglas K; Chertow, Glenn M; Garber, Alan M; Goldhaber-Fiebert, Jeremy D

2013-03-26

The authors sought to evaluate the cost-effectiveness of statins for primary prevention of myocardial infarction (MI) and stroke in patients with chronic kidney disease (CKD). Patients with CKD have an elevated risk of MI and stroke. Although HMG Co-A reductase inhibitors (“statins”) may prevent cardiovascular events in patients with non–dialysis-requiring CKD, adverse drug effects and competing risks could materially influence net effects and clinical decision-making. We developed a decision-analytic model of CKD and cardiovascular disease (CVD) to determine the cost-effectiveness of low-cost generic statins for primary CVD prevention in men and women with hypertension and mild-to-moderate CKD. Outcomes included MI and stroke rates, discounted quality-adjusted life years (QALYs) and lifetime costs (2010 USD), and incremental cost-effectiveness ratios. For 65-year-old men with moderate hypertension and mild-to-moderate CKD, statins reduced the combined rate of MI and stroke, yielded 0.10 QALYs, and increased costs by $1,800 ($18,000 per QALY gained). For patients with lower baseline cardiovascular risks, health and economic benefits were smaller; for 65-year-old women, statins yielded 0.06 QALYs and increased costs by $1,900 ($33,400 per QALY gained). Results were sensitive to rates of rhabdomyolysis and drug costs. Statins are less cost-effective when obtained at average retail prices, particularly in patients at lower CVD risk. Although statins reduce absolute CVD risk in patients with CKD, the increased risk of rhabdomyolysis, and competing risks associated with progressive CKD, partly offset these gains. Low-cost generic statins appear cost-effective for primary prevention of CVD in patients with mild-to-moderate CKD and hypertension.

Angiotensin-converting enzyme inhibitor and statin use and incident mobility limitation in community-dwelling older adults: the Health, Aging and Body Composition study.

PubMed

Gray, Shelly L; Boudreau, Robert M; Newman, Anne B; Studenski, Stephanie A; Shorr, Ronald I; Bauer, Douglas C; Simonsick, Eleanor M; Hanlon, Joseph T

2011-12-01

To evaluate whether the use of angiotensin-converting enzyme (ACE) inhibitors and statins is associated with a lower risk of incident mobility limitation in older community dwelling adults. Longitudinal cohort study. Health, Aging and Body Composition (Health ABC) study. Three thousand fifty-five participants who were well functioning at baseline (no mobility limitations). Summated standardized daily doses (low, medium, high) and duration of ACE inhibitor and statin use were computed. Mobility limitation (two consecutive self-reports of having any difficulty walking one-quarter of a mile or climbing 10 steps without resting) was assessed every 6 months after baseline. Multivariable Cox proportional hazards analyses were conducted, adjusting for demographics, health status, and health behaviors. At baseline, 15.2% used ACE inhibitors and 12.9% used statins; use of both was greater than 25% by Year 6. Over 6.5 years of follow-up, 49.8% had developed mobility limitation. In separate multivariable models, neither ACE inhibitor (multivariate hazard ratio (HR) = 0.95, 95% confidence interval (CI) = 0.82-1.09) nor statin use (multivariate HR = 1.02, 95% CI = 0.87-1.17) was associated with lower risk of mobility limitation. Similar findings were seen in analyses examining dose-response and duration-response relationships and a sensitivity analysis restricted to those with hypertension. ACE inhibitors and statins widely prescribed to treat hypertension and hypercholesterolemia, respectively, do not lower risk of mobility limitation, an important indicator of quality of life. © 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society.

Discovery and quantitative structure-activity relationship study of lepidopteran HMG-CoA reductase inhibitors as selective insecticides.

PubMed

Zang, Yang-Yang; Li, Yuan-Mei; Yin, Yue; Chen, Shan-Shan; Kai, Zhen-Peng

2017-09-01

In a previous study we have demonstrated that insect 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) can be a potential selective insecticide target. Three series of inhibitors were designed on the basis of the difference in HMGR structures from Homo sapiens and Manduca sexta, with the aim of discovering potent selective insecticide candidates. An in vitro bioassay showed that gem-difluoromethylenated statin analogues have potent effects on JH biosynthesis of M. sexta and high selectivity between H. sapiens and M. sexta. All series II compounds {1,3,5-trisubstituted [4-tert-butyl 2-(5,5-difluoro-2,2-dimethyl-6-vinyl-4-yl) acetate] pyrazoles} have some effect on JH biosynthesis, whereas most of them are inactive on human HMGR. In particular, the IC 50 value of compound II-12 (37.8 nm) is lower than that of lovastatin (99.5 nm) and similar to that of rosuvastatin (24.2 nm). An in vivo bioassay showed that I-1, I-2, I-3 and II-12 are potential selective insecticides, especially for lepidopteran pest control. A predictable and statistically meaningful CoMFA model of 23 inhibitors (20 as training sets and three as test sets) was obtained with a value of q 2 and r 2 of 0.66 and 0.996 respectively. The final model suggested that a potent insect HMGR inhibitor should contain suitable small and non-electronegative groups in the ring part, and electronegative groups in the side chain. Four analogues were discovered as potent selective lepidopteran HMGR inhibitors, which can specifically be used for lepidopteran pest control. The CoMFA model will be useful for the design of new selective insect HMGR inhibitors that are structurally related to the training set compounds. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Dietary sources of aldose reductase inhibitors: prospects for alleviating diabetic complications.

PubMed

Saraswat, Megha; Muthenna, P; Suryanarayana, P; Petrash, J Mark; Reddy, G Bhanuprakash

2008-01-01

Activation of polyol pathway due to increased aldose reductase activity is one of the several mechanisms that have been implicated in the development of various secondary complications of diabetes. Though numerous synthetic aldose reductase inhibitors have been tested, these have not been very successful clinically. Therefore, a number of common plant/ natural products used in Indian culinary have been evaluated for their aldose reductase inhibitory potential in the present study. The aqueous extracts of 22 plant-derived materials were prepared and evaluated for the inhibitory property against rat lens and human recombinant aldose reductase. Specificity of these extracts towards aldose reductase was established by testing their ability to inhibit a closely related enzyme viz, aldehyde reductase. The ex vivo incubation of erythrocytes in high glucose containing medium was used to underscore the significance in terms of prevention of intracellular sorbitol accumulation. Among the 22 dietary sources tested, 10 showed considerable inhibitory potential against both rat lens and human recombinant aldose reductase. Prominent inhibitory property was found in spinach, cumin, fennel, lemon, basil and black pepper with an approximate IC50 of 0.2 mg/mL with an excellent selectivity towards aldose reductase. As against this, 10 to 20 times higher concentrations were required for 50% inhibition of aldehyde reductase. Reduction in the accumulation of intracellular sorbitol by the dietary extracts further substantiated their in vivo efficacy. The findings reported here indicate the scope of adapting life-style modifications in the form of inclusion of certain common sources in the diet for the management of diabetic complications.

Structure-based design of pteridine reductase inhibitors targeting African sleeping sickness and the leishmaniases.

PubMed

Tulloch, Lindsay B; Martini, Viviane P; Iulek, Jorge; Huggan, Judith K; Lee, Jeong Hwan; Gibson, Colin L; Smith, Terry K; Suckling, Colin J; Hunter, William N

2010-01-14

Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.

Association between statin use, the vaginal microbiome, and Gardnerella vaginalis vaginolysin-mediated cytotoxicity.

PubMed

Abdelmaksoud, Abdallah A; Girerd, Philippe H; Garcia, Erin M; Brooks, J Paul; Leftwich, Lauren M; Sheth, Nihar U; Bradley, Steven P; Serrano, Myrna G; Fettweis, Jennifer M; Huang, Bernice; Strauss, Jerome F; Buck, Gregory A; Jefferson, Kimberly K

2017-01-01

Bacterial vaginosis (BV) is the leading dysbiosis of the vaginal microbiome. The pathways leading towards the development of BV are not well understood. Gardnerella vaginalis is frequently associated with BV. G. vaginalis produces the cholesterol-dependent cytolysin (CDC), vaginolysin, which can lyse a variety of human cells and is thought to play a role in pathogenesis. Because membrane cholesterol is required for vaginolysin to function, and because HMG-CoA reductase inhibitors (statins) affect not only serum levels of cholesterol but membrane levels as well, we hypothesized that statins might affect the vaginal microbiome. To investigate the relationship between use of the statins and the vaginal microbiome, we analyzed 16S rRNA gene taxonomic surveys performed on vaginal samples from 133 women who participated in the Vaginal Human Microbiome Project and who were taking statins at the time of sampling, 152 women who reported high cholesterol levels but were not taking statins, and 316 women who did not report high cholesterol. To examine the effect of statins on the cytolytic effect of vaginolysin, the cholesterol-dependent cytolysin (CDC) produced by Gardnerella vaginalis, we assessed the effect of simvastatin pretreatment of VK2E6/E7 vaginal epithelial cells on vaginolysin-mediated cytotoxicity. The mean proportion of G. vaginalis among women taking statins was significantly lower relative to women not using statins. Women using statins had higher mean proportions of Lactobacillus crispatus relative to women with normal cholesterol levels, and higher levels of Lactobacillus jensenii relative to women with high cholesterol but not taking statins. In vitro, vaginal epithelial cells pretreated with simvastatin were relatively resistant to vaginolysin and this effect was inhibited by cholesterol. In this cross-sectional study, statin use was associated with reduced proportions of G. vaginalis and greater proportions of beneficial lactobacilli within the vaginal

Statin-Associated Muscle-Related Adverse Effects: A Case Series of 354 Patients

PubMed Central

Cham, Stephanie; Evans, Marcella A.; Denenberg, Julie O.; Golomb, Beatrice A.

2016-01-01

Study Objective To characterize the properties and natural history of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-associated muscle-related adverse effects (MAEs). Design Patient-targeted postmarketing adverse-effect surveillance approach coupling survey design with an open-ended narrative. Setting University-affiliated health care system. Subjects Three hundred fifty-four patients (age range 34–86 yrs) who self-reported muscle-related problems associated with statin therapy. Measurements and Main Results Patients with perceived statin-associated MAEs completed a survey assessing statin drugs and dosages; characteristics of the MAEs; time course of onset, resolution, or recurrence; and impact on quality of life (QOL). Cases were assessed for putative drug adverse-effect causality by using the Naranjo adverse drug reaction probability scale criteria and were evaluated for inclusion in groups for which mortality benefit with statins has been shown. Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p<0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p<0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and QOL domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy. Conclusion This study complements available information on the properties and natural history of statin

Statin-associated muscle-related adverse effects: a case series of 354 patients.

PubMed

Cham, Stephanie; Evans, Marcella A; Denenberg, Julie O; Golomb, Beatrice A

2010-06-01

To characterize the properties and natural history of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-associated muscle-related adverse effects (MAEs). Patient-targeted postmarketing adverse-effect surveillance approach coupling survey design with an open-ended narrative. University-affiliated health care system. Three hundred fifty-four patients (age range 34-86 yrs) who self-reported muscle-related problems associated with statin therapy. Patients with perceived statin-associated MAEs completed a survey assessing statin drugs and dosages; characteristics of the MAEs; time course of onset, resolution, or recurrence; and impact on quality of life (QOL). Cases were assessed for putative drug adverse-effect causality by using the Naranjo adverse drug reaction probability scale criteria and were evaluated for inclusion in groups for which mortality benefit with statins has been shown. Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p<0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p<0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and QOL domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy. This study complements available information on the properties and natural history of statin-associated MAEs, affirming dose dependence and strong QOL impact. The data indicating a dose

[In vitro study over statins effects on cellular growth curves and its reversibility with mevalonate].

PubMed

Millan Núñez-Cortés, Jesús; Alvarez Rodriguez, Ysmael; Alvarez Novés, Granada; Recarte Garcia-Andrade, Carlos; Alvarez-Sala Walther, Luis

2014-01-01

HMG-CoA-Reductase inhibitors, also known as statins, are currently the most powerful cholesterol-lowering drugs available on the market. Clinical trials and experimental evidence suggest that statins have heavy anti-atherosclerotic effects. These are in part consequence of lipid lowering but also result from pleiotropic actions of the drugs. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL-c reduction or via a direct effect on cellular functions. Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certain agents and account for differences in their pharmacological activity. So, although statins typically have similar effects on LDL-c levels, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects. In this paper we analize the in vitro effects of different statins over different cell lines from cells implicated in atherosclerotic process: endothelial cells, fibroblasts, and vascular muscular cells. In relation with our results we can proof that the effects of different dosis of different statins provides singular effects over growth curves of different cellular lines, a despite of a class-dependent effects. So, pleiotropic effects and its reversibility with mevalonate are different according with the molecule and the dosis. Copyright © 2013 Elsevier España, S.L. y SEA. All rights reserved.

Angiotensin-converting Enzyme Inhibitor and Statin Medication Use and Incident Mobility Limitation in Community Older Adults. The Health, Aging and Body Composition Study

PubMed Central

Gray, Shelly L.; Boudreau, Robert M.; Newman, Anne B.; Studenski, Stephanie A.; Shorr, Ronald I; Bauer, Douglas C.; Simonsick, Eleanor M.; Hanlon, Joseph T

2012-01-01

Objective Angiotensin-converting enzyme (ACE) inhibitors and statin medications have been proposed as potential agents to prevent or delay physical disability; yet limited research has evaluated whether such use in older community dwelling adults is associated with a lower risk of incident mobility limitation. Design Longitudinal cohort study Setting Health, Aging and Body Composition (Health ABC) Participants 3055 participants who were well functioning at baseline (e.g., no mobility limitations). Measurements Summated standardized daily doses (low, medium and high) and duration of ACE inhibitor and statin use was computed. Mobility limitation (two consecutive self-reports of having any difficulty walking 1/4 mile or climbing 10 steps without resting) was assessed every 6 months after baseline. Multivariable Cox proportional hazard analyses were conducted adjusting for demographics, health status, and health behaviors. Results At baseline, ACE inhibitors and statins were used by 15.2% and 12.9%, respectively and both increased to over 25% by year 6. Over 6.5 years of follow-up, 49.8% had developed mobility limitation. In separate multivariable models, neither ACE inhibitor (multivariate hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.82–1.09) nor statin use (multivariate HR 1.02; 95% CI 0.87–1.17) was associated with a lower risk for mobility limitation. Similar findings were seen in analyses examining dose- and duration-response relationships and sensitivity analyses restricted to those with hypertension. Conclusions These findings indicate that ACE inhibitors and statins widely prescribed to treat hypertension and hypercholesterolemia, respectively do not lower risk of mobility limitation, an important life quality indicator. PMID:22092102

Identification of new potent inhibitor of aldose reductase from Ocimum basilicum.

PubMed

Bhatti, Huma Aslam; Tehseen, Yildiz; Maryam, Kiran; Uroos, Maliha; Siddiqui, Bina S; Hameed, Abdul; Iqbal, Jamshed

2017-12-01

Recent efforts to develop cure for chronic diabetic complications have led to the discovery of potent inhibitors against aldose reductase (AKR1B1, EC 1.1.1.21) whose role in diabetes is well-evident. In the present work, two new natural products were isolated from the ariel part of Ocimum basilicum; 7-(3-hydroxypropyl)-3-methyl-8-β-O-d-glucoside-2H-chromen-2-one (1) and E-4-(6'-hydroxyhex-3'-en-1-yl)phenyl propionate (2) and confirmed their structures with different spectroscopic techniques including NMR spectroscopy etc. The isolated compounds (1, 2) were evaluated for in vitro inhibitory activity against aldose reductase (AKR1B1) and aldehyde reductase (AKR1A1). The natural product (1) showed better inhibitory activity for AKR1B1 with IC 50 value of 2.095±0.77µM compare to standard sorbinil (IC 50 =3.14±0.02µM). Moreover, the compound (1) also showed multifolds higher activity (IC 50 =0.783±0.07µM) against AKR1A1 as compared to standard valproic acid (IC 50 =57.4±0.89µM). However, the natural product (2) showed slightly lower activity for AKR1B1 (IC 50 =4.324±1.25µM). Moreover, the molecular docking studies of the potent inhibitors were also performed to identify the putative binding modes within the active site of aldose/aldehyde reductases. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in human myocytes.

PubMed

Nishimoto, Tomoyuki; Tozawa, Ryuichi; Amano, Yuichiro; Wada, Takeo; Imura, Yoshimi; Sugiyama, Yasuo

2003-12-01

TAK-475 is a squalene synthase inhibitor, rapidly metabolized to T-91485 in vivo. We investigated the myotoxicities of T-91485 and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in a human rhabdomyosarcoma cell line, RD, and in human skeletal myocytes. In differentiated RD cells, T-91485, atorvastatin (ATV) and simvastatin acid (SIM) inhibited cholesterol biosynthesis, with IC(50) values of 36, 2.8 and 3.8 nM, respectively. ATV and SIM decreased the intracellular ATP content, with IC(25) values (concentrations giving a 25% decrease in intracellular ATP content) of 0.61 and 0.44 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis in RD cells, the IC(25) value exceeded 100 microM. In human skeletal myocytes, T-91485, ATV and SIM concentration-dependently inhibited cholesterol biosynthesis, with IC(50) values of 45, 8.6 and 8.4 nM, respectively. ATV and SIM decreased intracellular ATP content, with IC(25) values of 2.1 and 0.72 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis, the IC(25) value exceeded 100 microM. Myotoxicity induced by ATV was prevented by mevalonate or geranylgeranyl-PP, but not by squalene in skeletal cells. Furthermore, T-91485 attenuated the myotoxicity of ATV. These findings suggest that TAK-475 and T-91485 may not only be far from myotoxic, they may also decrease statin-induced myotoxicity in lipid-lowering therapy.

Statins and myositis: the role of anti-HMGCR antibodies.

PubMed

Selva-O'Callaghan, Albert; Alvarado-Cardenas, Marcelo; Marin, Ana; Pinal-Fernandez, Iago

2015-01-01

Muscle toxicity is a recognized adverse effect of statin use. Recently, a new myositis syndrome was described in association with antibodies directed against the pharmacologic target of statins, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR antibody). The patient's genetic background, characteristic histologic patterns (immune-mediated necrotizing myopathy), and presence of anti-HMGCR antibodies define the syndrome. In most patients, statin discontinuation is insufficient to reverse the myositis symptoms, and immunosuppressive therapy is needed. The mechanisms by which these antibodies may lead to disease are not fully elucidated. Several important questions remain unsolved and warrant further research.

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

The association of statin therapy with the risk of recurrent venous thrombosis.

PubMed

Smith, N L; Harrington, L B; Blondon, M; Wiggins, K L; Floyd, J S; Sitlani, C M; McKnight, B; Larson, E B; Rosendaal, F R; Heckbert, S R; Psaty, B M

2016-07-01

Essentials A lowered risk of recurrent venous thrombosis (VT) with statin treatment is controversial. Among observational inception cohort of 2,798 adults with incident VT, 457 had recurrent VT. Time-to-event models with time-varying statin use and adjustment for potential confounders was used for analysis. Compared to nonuse, current statin use was associated with 26% lower risk of recurrent VT. Click to hear Prof. Büller's perspective on Anticoagulant Therapy in the Treatment of Venous Thromboembolism Background Meta-analyses of randomized controlled trials suggest that treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) lowers the risk of incident venous thrombosis (VT), particularly among those without prevalent clinical cardiovascular disease (CVD). Whether this is true for the prevention of recurrent VT is debated. We used an observational inception cohort to estimate the association of current statin use with the risk of recurrent VT. Methods and Results The study setting was a large healthcare organization with detailed medical record and pharmacy information at cohort entry and throughout follow-up. We followed 2798 subjects 18-89 years of age who experienced a validated incident VT between January 1, 2002, and December 31, 2010, for a first recurrent VT, validated by medical record review. During follow-up, 457 (16%) developed a first recurrent VT. In time-to-event models incorporating time-varying statin use and adjusting for potential confounders, current statin use was associated with a 26% lower risk of recurrent VT: hazard ratio 0.74, 95% confidence interval 0.59-0.94. Among cohort members free of CVD (n = 2134), current statin use was also associated with a lower risk (38%) of recurrent VT: hazard ratio 0.62, 95% confidence interval 0.45-0.85. We found similar results when restricting to new users of statins and in subgroups of different statin types and doses. Conclusions In a population-based cohort of subjects who had

Statin Drugs Markedly Inhibit Testosterone Production by Rat Leydig Cells In Vitro: Implications for Men

EPA Science Inventory

Statin drugs lower blood cholesterol by inhibiting hepatic 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase. During drug development it was shown that statins inhibit production of cholesterol in the testis. We evaluated testosterone production in vitro, using highly purified rat ...

Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in The Health Improvement Network

PubMed Central

Rowan, Christopher G.; Brunelli, Steven M.; Munson, Jeffrey; Flory, James; Reese, Peter P.; Hennessy, Sean; Lewis, James; Mines, Daniel; Barrett, Jeffrey S.; Bilker, Warren; Strom, Brian L.

2014-01-01

Objective To compare the relative hazard of muscle toxicity, renal dysfunction, and hepatic dysfunction associated with the drug interaction between statins and concomitant medications that inhibit the CYP3A4 isoenzyme. Background Although statins provide important clinical benefits related to mitigating the risk of cardiovascular events, this class of medications also has the potential for severe adverse reactions. The risk for adverse events may be potentiated by concomitant use of medications that interfere with statin metabolism. Methods Data from The Health Improvement Network (THIN) from 1990 to 2008 were used to conduct a retrospective cohort study. Cohorts were created to evaluate each outcome (muscle toxicity, renal dysfunction, and hepatic dysfunction) independently. Each cohort included new statin initiators and compared the relative hazard of the outcome. The interaction ratio (I*R) was the primary contrast of interest. The I*R represents the relative effect of each statin type (statin 3A4 substrate vs. statin non-3A4 substrate) with a CYP3A4 inhibitor, independent of the effect of the statin type without a CYP3A4 inhibitor. We adjusted for confounding variables using the multinomial propensity score. Results The median follow-up time per cohort was 1.5 years. There were 7889 muscle toxicity events among 362 809 patients and 792 665 person-years. The adjusted muscle toxicity I*R was 1.22 (95% confidence interval [CI] = 0.90–1.66). There were 1449 renal dysfunction events among 272,099 patients and 574 584 person-years. The adjusted renal dysfunction I*R was 0.91 (95%CI = 0.58–1.44). There were 1434 hepatic dysfunction events among 367 612 patients and 815 945 person-years. The adjusted hepatic dysfunction I*R was 0.78 (95%CI = 0.45–1.31). Conclusions Overall, this study found no difference in the relative hazard of muscle toxicity, renal dysfunction, or hepatic dysfunction for patients prescribed a statin 3A4 substrate versus a statin non-3A4

1,8-Dihydroxynaphthalene (DHN)-Melanin Biosynthesis Inhibitors Increase Erythritol Production in Torula corallina, and DHN-Melanin Inhibits Erythrose Reductase

PubMed Central

Lee, Jung-Kul; Jung, Hyung-Moo; Kim, Sang-Yong

2003-01-01

The yeast Torula corallina is a strong erythritol producer that is used in the industrial production of erythritol. However, melanin accumulation during culture represents a serious problem for the purification of erythritol from the fermentation broth. Melanin biosynthesis inhibitors such as 3,4-dihydroxyphenylalanine and 1,8-dihydroxynaphthalene (DHN)-melanin inhibitors were added to the T. corallina cultures. Only the DHN-melanin inhibitors showed an effect on melanin production, which suggests that the melanin formed during the culturing of T. corallina is derived from DHN. This finding was confirmed by the detection of a shunt product of the pentaketide pathway, flaviolin, and elemental analysis. Among the DHN-melanin inhibitors, tricyclazole was the most effective. Supplementation with tricyclazole enhanced the production of erythritol while significantly inhibiting the production of DHN-melanin and DHN-melanin biosynthetic enzymes, such as trihydroxynaphthalene reductase. The erythrose reductase from T. corallina was purified to homogeneity by ion-exchange and affinity chromatography. Purified erythrose reductase was significantly inhibited in vitro in a noncompetitive manner by elevated levels of DHN-melanin. In contrast, the level of erythrose reductase activity was unaffected by increasing concentrations of tricyclazole. These results suggest that supplemental tricyclazole reduces the production of DHN-melanin, which may lead to a reduction in the inhibition of erythrose reductase and a higher yield of erythritol. This is the first report to demonstrate that melanin biosynthesis inhibitors increase the production of a sugar alcohol in T. corallina. PMID:12788746

Identification of an anti-MRSA dihydrofolate reductase inhibitor from a diversity-oriented synthesis.

PubMed

Wyatt, Emma E; Galloway, Warren R J D; Thomas, Gemma L; Welch, Martin; Loiseleur, Olivier; Plowright, Alleyn T; Spring, David R

2008-10-28

The screening of a diversity-oriented synthesis library followed by structure-activity relationship investigations have led to the discovery of an anti-MRSA agent which operates as an inhibitor of Staphylococcus aureus dihydrofolate reductase.

Statins: the holy grail of Abdominal Aortic Aneurysm (AAA) growth attenuation? A systematic review of the literature.

PubMed

Dunne, Jonathan A; Bailey, Marc A; Griffin, Kathryn J; Sohrabi, Soroush; Coughlin, Patrick A; Scott, D Julian A

2014-01-01

In the era of Abdominal Aortic Aneurysm (AAA) screening, pharmacotherapies to attenuate AAA growth are sought. HMG Co-A reductase inhibitors (statins) have pleiotropic actions independent of their lipid lowering effects and have been suggested as potential treatment for small AAAs. We systematically review the clinical evidence for this effect. Medline, EMBASE and the Cochrane Central Register of Controlled Trials (1950-2011) were searched for studies reporting data on the role of statin therapy on AAA growth rate. No language restrictions were placed on the search. References of retrieved articles and pertinent journals were hand searched. Included studies were reviewed by 2 independent observers. The search retrieved 164 papers, 100 were irrelevant based on their title, 47 were reviews and 1 was a letter. 8 studies were excluded based on review of their abstract leaving 8 for inclusion in the study. Eight observational clinical studies with a total of 4,466 patients were reviewed. Four studies demonstrated reduced AAA expansion in statin users while 4 studies failed to demonstrate this effect. The method of determining AAA growth rates varied significantly between the studies and the ability of many studies to control for misclassification bias was poor. The claim that statins attenuate AAA growth remains questionable. Further prospective studies with stringent identification and verification of statin usage and a standardised method of estimating AAA growth rates are required. Statin type and dose also merit consideration.

CoQ10 and L-carnitine for statin myalgia?

PubMed

DiNicolantonio, James J

2012-10-01

Statins are a standard of care in many clinical settings such as acute myocardial infarction and for patients having or at risk of cardiovascular (CV) disease. This is based on a plethora of data showing reductions in CV events and mortality. The CV benefit of statins can be partly explained by their ability to inhibit of HMG-CoA reductase, which subsequently lowers cholesterol and decreases the formation of mevalonate. However, the inhibition of the mevalonate pathway decreases the formation of coenzyme Q10 (CoQ10) within the body. It has been a long-standing theory that statin-associated muscle pain (myalgia) is caused, or at least partly contributed by, a reduction in CoQ10 levels in muscle mitochondria. One of the main side effects of statins is myalgia, which causes the patient to either stop their statin or significantly reduce the dose of their statin. The question of whether CoQ10 can help treat statin myopathy is a common one encountered by clinicians in current day practice.

Statin intolerance: diagnosis and remedies.

PubMed

Pirillo, Angela; Catapano, Alberico Luigi

2015-05-01

Despite the efficacy of statins in reducing cardiovascular events in both primary and secondary prevention, the adherence to statin therapy is not optimal, mainly due to the occurrence of muscular adverse effects. Several risk factors may concur to the development of statin-induced myotoxicity, including patient-related factors (age, sex, and race), statin properties (dose, lipophilicity, and type of metabolism), and the concomitant administration of other drugs. Thus, the management of patients intolerant to statins, particularly those at high or very high cardiovascular risk, involves alternative therapies, including the switch to another statin or the use of intermittent dosage statin regimens, as well as nonstatin lipid lowering drugs (ezetimibe and fibrates) or new hypolipidemic drugs such as PCSK9 monoclonal antibodies, the antisense oligonucleotide against the coding region of human apolipoprotein B mRNA (mipomersen), and microsomal triglyceride transfer protein inhibitor lomitapide. Ongoing clinical trials will reveal whether the lipid-lowering effects of alternative therapies to statins can also translate into a cardiovascular benefit.

PLEIOTROPIC EFFECTS OF STATINS

PubMed Central

Liao, James K.; Laufs, Ulrich

2009-01-01

Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins. PMID:15822172

Statins for cardiovascular prevention according to different strategies: a cost analysis.

PubMed

Ito, Marcia K; Nanchen, David; Rodondi, Nicolas; Paccaud, Fred; Waeber, Gérard; Vollenweider, Peter; Marques-Vidal, Pedro

2011-01-01

Several studies have shown that treatment with HMG-CoA reductase inhibitors (statins) can reduce coronary heart disease (CHD) rates. However, the cost effectiveness of statin treatment in the primary prevention of CHD has not been fully established. To estimate the costs of CHD prevention using statins in Switzerland according to different guidelines, over a 10-year period. The overall 10-year costs, costs of one CHD death averted, and of 1 year without CHD were computed for the European Society of Cardiology (ESC), the International Atherosclerosis Society (IAS), and the US Adult Treatment Panel III (ATP-III) guidelines. Sensitivity analysis was performed by varying number of CHD events prevented and costs of treatment. Using an inflation rate of medical costs of 3%, a single yearly consultation, a single total cholesterol measurement per year, and a generic statin, the overall 10-year costs of the ESC, IAS, and ATP-III strategies were 2.2, 3.4, and 4.1 billion Swiss francs (SwF [SwF1 = $US0.97]). In this scenario, the average cost for 1 year of life gained was SwF352, SwF421, and SwF485 thousand, respectively, and it was always higher in women than in men. In men, the average cost for 1 year of life without CHD was SwF30.7, SwF42.5, and SwF51.9 thousand for the ESC, IAS, and ATP-III strategies, respectively, and decreased with age. Statin drug costs represented between 45% and 68% of the overall preventive cost. Changing the cost of statins, inflation rates, or number of fatal and non-fatal cases of CHD averted showed ESC guidelines to be the most cost effective. The cost of CHD prevention using statins depends on the guidelines used. The ESC guidelines appear to yield the lowest costs per year of life gained free of CHD.

Pharmacokinetic Interactions between Nelfinavir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Simvastatin

PubMed Central

Hsyu, Poe-Hirr; Schultz-Smith, Melissa D.; Lillibridge, James H.; Lewis, Ronald H.; Kerr, Bradley M.

2001-01-01

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are effective agents in lowering cholesterol and triglycerides and are being used by human immunodeficiency virus-positive patients to treat the lipid elevation that may be associated with antiretroviral therapy. Many HMG-CoA reductase inhibitors and protease inhibitors are metabolized by the same cytochrome P450 enzyme 3A4 (CYP3A4). In addition, many protease inhibitors are potent inhibitors of CYP3A4. Therefore, coadministration of these two classes of drugs may cause significant drug interactions. This open-label, multiple-dose study was performed to determine the interactions between nelfinavir, a protease inhibitor, and two HMG-CoA reductase inhibitors, atorvastatin and simvastatin, in healthy volunteers. Thirty-two healthy subjects received either atorvastatin calcium (10 mg once a day) or simvastatin (20 mg once a day) for the first 14 days of the study. Nelfinavir (1,250 mg twice a day) was added on days 15 to 28. Pharmacokinetic assessment was performed on days 14 and 28. The study drugs were well tolerated. Nelfinavir increased the steady-state area under the plasma concentration-time curve during one dosing period (AUCτ) of atorvastatin 74% and the maximum concentration (Cmax) of atorvastatin 122% and increased the AUCτ of simvastatin 505% and the Cmax of simvastatin 517%. Neither atorvastatin nor simvastatin appeared to alter the pharmacokinetics of nelfinavir. It is recommended that coadministration of simvastatin with nelfinavir should be avoided, whereas atorvastatin should be used with nelfinavir with caution. PMID:11709322

The pleotropic role of statins: Could it be the imminent host modulation agent in periodontics?

PubMed

Grover, Harpreet Singh; Luthra, Shailly; Maroo, Shruti; Maroo, Niteeka

2013-03-01

Periodontal disease is a chronic inflammatory disease which represents a primarily anaerobic Gram-negative oral infection that results in gingival inflammation, loss of attachment, bone destruction. Bacterial endotoxins in the form of lipopolysaccharides (LPS) that are instrumental in generating a host-mediated tissue destructive immune response by mobilizing their defensive cells and releasing cytokines like Interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), and Interleukin-6 (IL-6), which lead to tissue destruction by stimulating the production of the collagenolytic enzymes: Matrix metalloproteinases (MMPs). Since the host-mediated tissue destruction is to be controlled, various means have been employed for modulating this response. Statins, 3-hydroxy-3-methylglutarylcoenzyme A (HMG CoA) reductase inhibitors, besides having lipid-lowering abilities also have antioxidant, antithrombotic, anti-inflammatory, immunomodulatory and osteomodulatory properties. All of these pleiotropic effects of statins point out to it perhaps becoming the novel host modulation agent in periodontics.

The pleotropic role of statins: Could it be the imminent host modulation agent in periodontics?

PubMed Central

Grover, Harpreet Singh; Luthra, Shailly; Maroo, Shruti; Maroo, Niteeka

2013-01-01

Periodontal disease is a chronic inflammatory disease which represents a primarily anaerobic Gram-negative oral infection that results in gingival inflammation, loss of attachment, bone destruction. Bacterial endotoxins in the form of lipopolysaccharides (LPS) that are instrumental in generating a host-mediated tissue destructive immune response by mobilizing their defensive cells and releasing cytokines like Interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), and Interleukin-6 (IL-6), which lead to tissue destruction by stimulating the production of the collagenolytic enzymes: Matrix metalloproteinases (MMPs). Since the host-mediated tissue destruction is to be controlled, various means have been employed for modulating this response. Statins, 3-hydroxy-3-methylglutarylcoenzyme A (HMG CoA) reductase inhibitors, besides having lipid-lowering abilities also have antioxidant, antithrombotic, anti-inflammatory, immunomodulatory and osteomodulatory properties. All of these pleiotropic effects of statins point out to it perhaps becoming the novel host modulation agent in periodontics. PMID:23946727

Statin-associated immune-mediated myopathy: biology and clinical implications.

PubMed

Christopher-Stine, Lisa; Basharat, Pari

2017-04-01

In the last 6 years, our understanding of statin-associated myopathy expanded to include not only a toxic myopathy with limited and reversible side-effects but also an autoimmune variety in which statins likely induce an autoimmune myopathy that is both associated with a specific autoantibody and responsive to immunosuppression and immune modulation. This review widens the reader's understanding of statin myopathy to include an autoimmune process. Statin-associated immune-mediated myopathy provides an example of an environmental trigger (statins) directly implicated in an autoimmune disease associated with a genetic predisposition as well as potential risk factors including concomitant diseases and specific statins. Given a median exposure to statins of 38 months, providers should be aware that anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy may occur even after several years of statin exposure. It is important for the reader to understand the clinical presentation of statin-associated immune-mediated myopathy and the difference in its clinical presentation to that of statins as direct myotoxins. Prompt recognition of such an entity allows the clinician to immediately stop the offending agent if it has not already been discontinued as well as to recognize that statin rechallenge is not a likely option, and that prompt treatment with immunosuppression and/or immunomodulation is usually of enormous benefit to the patient in restoring muscle strength and physical function. VIDEO ABSTRACT.

Improved Biochemical Outcomes With Statin Use in Patients With High-Risk Localized Prostate Cancer Treated With Radiotherapy

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

Kollmeier, Marisa A.; Katz, Matthew S.; Mak, Kimberley

Purpose: To investigate the association between 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and biochemical and survival outcomes after high-dose radiotherapy (RT) for prostate cancer. Methods and Materials: A total of 1711 men with clinical stage T1-T3 prostate cancer were treated with conformal RT to a median dose of 81 Gy during 1995-2007. Preradiotherapy medication data were available for 1681 patients. Three hundred eighty-two patients (23%) were taking a statin medication at diagnosis and throughout RT. Nine hundred forty-seven patients received a short-course of neoadjuvant and concurrent androgen-deprivation therapy (ADT) with RT. The median follow-up was 5.9 years. Results: The 5-more » and 8-year PSA relapse-free survival (PRFS) rates for statin patients were 89% and 80%, compared with 83% and 74% for those not taking statins (p = 0.002). In a multivariate analysis, statin use (hazard ratio [HR]0.69, p = 0.03), National Comprehensive Cancer Network (NCCN) low-risk group, and ADT use were associated with improved PRFS. Only high-risk patients in the statin group demonstrated improvement in PRFS (HR 0.52, p = 0.02). Across all groups, statin use was not associated with improved distant metastasis-free survival (DMFS) (p = 0.51). On multivariate analysis, lower NCCN risk group (p = 0.01) and ADT use (p = 0.005) predicted improved DMFS. Conclusions: Statin use during high-dose RT for clinically localized prostate cancer was associated with a significant improvement in PRFS in high-risk patients. These data suggest that statins have anticancer activity and possibly provide radiosensitization when used in conjunction with RT in the treatment of prostate cancer.« less

Anti-HMG-CoA Reductase, Antioxidant, and Anti-Inflammatory Activities of Amaranthus viridis Leaf Extract as a Potential Treatment for Hypercholesterolemia

PubMed Central

Salvamani, Shamala; Gunasekaran, Baskaran; Shukor, Mohd Yunus; Shaharuddin, Noor Azmi; Sabullah, Mohd Khalizan

2016-01-01

Inflammation and oxidative stress are believed to contribute to the pathology of several chronic diseases including hypercholesterolemia (elevated levels of cholesterol in blood) and atherosclerosis. HMG-CoA reductase inhibitors of plant origin are needed as synthetic drugs, such as statins, which are known to cause adverse effects on the liver and muscles. Amaranthus viridis (A. viridis) has been used from ancient times for its supposedly medically beneficial properties. In the current study, different parts of A. viridis (leaf, stem, and seed) were evaluated for potential anti-HMG-CoA reductase, antioxidant, and anti-inflammatory activities. The putative HMG-CoA reductase inhibitory activity of A. viridis extracts at different concentrations was determined spectrophotometrically by NADPH oxidation, using HMG-CoA as substrate. A. viridis leaf extract revealed the highest HMG-CoA reductase inhibitory effect at about 71%, with noncompetitive inhibition in Lineweaver-Burk plot analysis. The leaf extract showed good inhibition of hydroperoxides, 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), and ferric ion radicals in various concentrations. A. viridis leaf extract was proven to be an effective inhibitor of hyaluronidase, lipoxygenase, and xanthine oxidase enzymes. The experimental data suggest that A. viridis leaf extract is a source of potent antioxidant and anti-inflammatory agent and may modulate cholesterol metabolism by inhibition of HMG-CoA reductase. PMID:27051453

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

PubMed Central

Hanai, Jun-ichi; Cao, Peirang; Tanksale, Preeti; Imamura, Shintaro; Koshimizu, Eriko; Zhao, Jinghui; Kishi, Shuji; Yamashita, Michiaki; Phillips, Paul S.; Sukhatme, Vikas P.; Lecker, Stewart H.

2007-01-01

Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1α, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins. PMID:17992259

Mechanisms and assessment of statin-related muscular adverse effects

PubMed Central

Moßhammer, Dirk; Schaeffeler, Elke; Schwab, Matthias; Mörike, Klaus

2014-01-01

Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers. PMID:25069381

Effectiveness of statin prescribing on reducing mortality in South Asian, Chinese, and White patients with diabetes.

PubMed

Brunner, Nathan W; Ramanathan, Krishnan; Wang, Hong; Quan, Hude; Khan, Nadia A

2013-08-01

Clinical trials have shown that 3-hydroxy-3-methylgutaryl coenzyme A reductase inhibitors (statins) reduce mortality in patients with diabetes. However, as these trials were conducted in largely white populations, it is unknown whether the benefits of statins can be extended to other ethnic populations in which the incidence of diabetes is rising sharply. We investigated associations between statin prescription and outcomes in a multiethnic population with diabetes. We identified all patients with newly diagnosed diabetes in British Columbia, Canada (1993-2006), using administrative data. Validated surname analysis was used to identify South Asian and Chinese patients. Statin prescribing was defined as any prescription filled within 1 year of diabetes diagnosis according to a provincial pharmacy database. Median length of follow-up was 4 years. Cox proportional hazards models were constructed for each ethnic group to determine the association of statin prescribing with time to death, adjusting for covariates including age, sex, socioeconomic status, and comorbid conditions. There were 143,630 white, 9529 South Asian, and 14,084 Chinese persons with newly diagnosed diabetes. White patients were older and had more comorbidity than the other groups. Statin prescribing was associated with lower mortality compared with no prescribing within each ethnic group: South Asian (Hazard Ratio [HR], 0.69; 95% confidence interval [CI], 0.55-0.86; P = 0.001), Chinese (HR, 0.60; 95% CI, 0.49-0.72; P < 0.0001), and white (HR, 0.65; 95% CI, 0.63-0.67; P < 0.0001). Statin prescribing is associated with lower mortality in white, Chinese, and South Asian patients with newly diagnosed diabetes, confirming the benefits of statins across these ethnic groups. Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Effects of direct-to-consumer advertising of hydroxymethylglutaryl coenzyme a reductase inhibitors on attainment of LDL-C goals.

PubMed

Bradford, W David; Kleit, Andrew N; Nietert, Paul J; Ornstein, Steven

2006-12-01

Although highly controversial, directto-consumer (DTC) television advertising for prescription drugs is an established practice in the US health care industry. While the US Food and Drug Administration is currently reexamining its regulatory stance, little evidence exists regarding the impact of DTC advertising on patient health outcomes. The objective of this research was to study the relationship between heavy television promotion of 3 major hydroxymethylglutaryl coenzyme A reductase inhibitors ("statins") and the frequency with which patients are able to attain low-density lipoprotein cholesterol (LDL-C) blood-level goals after treatment with any statin. We used logistic regression to determine achievement of LDL-C goals at 6 months after statin treatment, using electronic medical record extract data from patients from geographically dispersed primary care practices in the United States. We identified LDL-C blood levels as being at or less than goal, as defined by risk-adjusted guidelines published by the National Heart, Lung, and Blood Institute from the Adult Treatment Panel III (ATP III) data. A total of 50,741 patients, identified from 88 practices, were diagnosed with hyperlipidemia and had begun therapy with any statin medication during the 1998-2004 time period. In addition, total dollars spent each month on television advertising at the national and local levels for atorvastatin, pravastatin, and simvastatin were obtained. DTC advertising data were merged by local media market where the physician practice was located and by the month in which the patient was first prescribed a statin. The models were run for all patients who initiated therapy, and also on a subsample of patients who continued to receive prescriptions for the drugs for at least 6 months. Logistic regressions were used to predict the likelihood that each patient attained the ATP III LDL-C blood-level goals as a function of DTC advertising and other factors. High levels of national DTC

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

Evaluating an implementation strategy in cardiovascular prevention to improve prescribing of statins in Germany: an intention to treat analysis

PubMed Central

2013-01-01

Background The prescription of statins is an evidence-based treatment to reduce the risk of cardiovascular events in patients with elevated cardiovascular risk or with a cardiovascular disorder (CVD). In spite of this, many of these patients do not receive statins. Methods We evaluated the impact of a brief educational intervention in cardiovascular prevention in primary care physicians’ prescribing behaviour regarding statins beyond their participation in a randomised controlled trial (RCT). For this, prescribing data of all patients > 35 years who were counselled before and after the study period were analysed (each n > 75000). Outcome measure was prescription of Hydroxymethylglutaryl-CoA Reductase Inhibitors (statins) corresponding to patients’ overall risk for CVD. Appropriateness of prescribing was examined according to different risk groups based on the Anatomical Therapeutic Chemical Classification System (ATC codes). Results There was no consistent association between group allocation and statin prescription controlling for risk status in each risk group before and after study participation. However, we found a change to more significant drug configurations predicting the prescription of statins in the intervention group, which can be regarded as a small intervention effect. Conclusion Our results suggest that an active implementation of a brief evidence-based educational intervention does not lead to prescription modifications in everyday practice. Physician’s prescribing behaviour is affected by an established health care system, which is not easy to change. Trial registration ISRCTN71348772 PMID:23819600

Pharmacological Characterization of a Novel Bifunctional Aldo-Keto Reductase 1C3 Inhibitor and Androgen Receptor Antagonist

DTIC Science & Technology

2013-10-01

Novel Bifunctional Aldo -Keto Reductase 1C3 Inhibitor and Androgen Receptor Antagonist” PRINCIPAL INVESTIGATOR: ADEGOKE ADENIJI, Ph.D...therapeutic benefit relative to targeting either mechanism alone. Aldo -keto reductase 1C3 (AKR1C3) is highly upregulated in APC and is localized within...therapy of Abi with MDV3100 has been proposed as a way to reduce resistance. 14, 15 Aldo -keto reductase IC3 (AKR1C3, type 5 17β hydroxysteroid

Statins - a role in breast cancer therapy?

PubMed

Borgquist, Signe; Bjarnadottir, Olöf; Kimbung, Siker; Ahern, Thomas P

2018-06-20

Statin drugs have been used for more than two decades to treat hypercholesterolemia and as cardio-preventive drugs, resulting in a marked decrease in cardiovascular morbidity and mortality worldwide. Statins halt hepatic cholesterol biosynthesis by inhibiting the rate-limiting enzyme in the mevalonate pathway, hydroxymethylglutaryl-coenzyme A reductase (HMGCR). The mevalonate pathway regulates a host of biochemical processes in addition to cholesterol production. Attenuation of these pathways is likely responsible for the myriad benefits of statin therapy beyond cholesterol reduction-the so-called pleiotropic effects of statins. Chief among these purported effects is anti-cancer activity. A considerable body of preclinical, epidemiologic, and clinical evidence shows that statins impair proliferation of breast cancer cells and reduce the risk of breast cancer recurrence. Potential mechanisms for this effect have been explored in laboratory models, but remain poorly understood and require further investigation. The number of clinical trials assessing the putative clinical benefit of statins in breast cancer is increasing. Currently, a total of 30 breast cancer/statin trials are listed at the global trial identifier website clinicaltrials. gov.Given the compelling evidence from performed trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant breast cancer setting. It would be imperative for such a trial to incorporate tumor biomarkers predictive of statin response in its design and analysis plan. Ongoing translational clinical trials aimed at biomarker discovery will help identify, which breast cancer patients are most likely to benefit from adjuvant statin therapy, and will add valuable clinical knowledge to the field. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effects of statins on the recovery of olfactory function in a 3-methylindole-induced anosmia mouse model.

PubMed

Kim, Hyo Yeol; Kim, Joon Ho; Dhong, Hun-Jong; Kim, Ki Ryung; Chung, Seung-Kyu; Chung, Soo-Chan; Kang, Jeong Min; Jung, Yong Gi; Jang, Seong Yun; Hong, Sang Duk

2012-01-01

Despite the importance of olfactory function, no effective medications have been identified to treat olfactory disorders. This study was performed to evaluate the functional recovery of olfaction damaged by 3-methylindole (3MI) in a mouse model with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins). In a randomized placebo-controlled trial, 24 healthy female BALB/c mice (aged 9-10 weeks and weighing 18-20 g each) were randomly allocated to statin-treated or control groups. Olfactory loss was induced by i.p. injections of 3MI. Atorvastatin (10 mg/kg) or normal saline was then administered per os with a gastric tube for 3 weeks. The effects of treatment were evaluated by food-finding tests and Western blot analysis. Both groups showed complete losses of olfactory function 1 week after 3MI injection. Three weeks after 3MI injection, 9 of the 12 mice in the statin-treated group (75%) passed a food-finding test, in which they were able to find the food within 3 minutes, at least two times out of three trials. However, only two mice in the control group (16.6%) passed the food-finding test, and this difference was statistically significant (p = 0.004; chi-square test). The expression level of the olfactory marker protein was also elevated in the statin-treated group (p = 0.030; Wilcoxon rank sum test). Statins are associated with recovery of olfaction after 3MI injection in a mouse model.

Sources of heterogeneity in case-control studies on associations between statins, ACE-inhibitors, and proton pump inhibitors and risk of pneumonia.

PubMed

de Groot, Mark C H; Klungel, Olaf H; Leufkens, Hubert G M; van Dijk, Liset; Grobbee, Diederick E; van de Garde, Ewoudt M W

2014-10-01

The heterogeneity in case-control studies on the associations between community-acquired pneumonia (CAP) and ACE-inhibitors (ACEi), statins, and proton pump inhibitors (PPI) hampers translation to clinical practice. Our objective is to explore sources of this heterogeneity by applying a common protocol in different data settings. We conducted ten case-control studies using data from five different health care databases. Databases varied on type of patients (hospitalised vs. GP), level of case validity, and mode of exposure ascertainment (prescription or dispensing based). Identified CAP patients and controls were matched on age, gender, and calendar year. Conditional logistic regression was used to calculate odds ratios (OR) for the associations between the drugs of interest and CAP. Associations were adjusted by a common set of potential confounders. Data of 38,742 cases and 118,019 controls were studied. Comparable patterns of variation between case-control studies were observed for ACEi, statins and PPI use and pneumonia risk with adjusted ORs varying from 1.04 to 1.49, 0.82 to 1.50 and 1.16 to 2.71, respectively. Overall, higher ORs were found for hospitalised CAP patients matched to population controls versus GP CAP patients matched to population controls. Prevalence of drug exposure was higher in dispensing data versus prescription data. We show that case-control selection and methods of exposure ascertainment induce bias that cannot be adjusted for and to a considerable extent explain the heterogeneity in results obtained in case-control studies on statins, ACEi and PPIs and CAP. The common protocol approach helps to better understand sources of variation in observational studies.

Associations of Statin Use With Colorectal Cancer Recurrence and Mortality in a Danish Cohort.

PubMed

Lash, Timothy L; Riis, Anders H; Ostenfeld, Eva B; Erichsen, Rune; Vyberg, Mogens; Ahern, Thomas P; Thorlacius-Ussing, Ole

2017-09-15

In earlier studies of the influence of hydroxymethylglutaryl-coenzyme A reductase inhibitors (also known as statins) on colorectal cancer prognosis, investigators reported a reduced rate of cancer-specific mortality. Studies of recurrence are few and small. Using data from Danish registries, we followed 21,152 patients diagnosed with stage I-III colorectal cancer from 2001 to 2011. We estimated the association between statin use in the preceding year and cancer recurrence, cancer-specific mortality, and all-cause mortality rates. We identified 5,036 recurrences, 7,084 deaths from any cause, and 4,066 deaths from colorectal cancer. After adjustment for potential confounders, statin use was not associated with recurrence (adjusted hazard ratio (aHR) = 1.01, 95% confidence interval (CI): 0.93, 1.09), but it was associated with death from colorectal cancer (aHR = 0.72, 95% CI: 0.65, 0.79) and death from any cause (aHR = 0.72, 95% CI: 0.67, 0.76). Statin use in the year preceding recurrence was associated with a reduced risk of cancer-specific mortality (aHR = 0.83, 95% CI: 0.74, 0.92) but also a reduced risk of death from any other cause (aHR = 0.78, 95% CI: 0.61, 1.00). Statin use was not associated with a reduced rate of colorectal cancer recurrence, but it was associated with a reduced rate of cancer-specific mortality, which suggests that there is no cancer-directed benefit; therefore, there is no basis to prescribe statins to colorectal cancer patients who do not have cardiovascular indications. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Footprinting of Inhibitor Interactions of In Silico Identified Inhibitors of Trypanothione Reductase of Leishmania Parasite

PubMed Central

Venkatesan, Santhosh K.; Dubey, Vikash Kumar

2012-01-01

Structure-based virtual screening of NCI Diversity set II compounds was performed to indentify novel inhibitor scaffolds of trypanothione reductase (TR) from Leishmania infantum. The top 50 ranked hits were clustered using the AuPoSOM tool. Majority of the top-ranked compounds were Tricyclic. Clustering of hits yielded four major clusters each comprising varying number of subclusters differing in their mode of binding and orientation in the active site. Moreover, for the first time, we report selected alkaloids and dibenzothiazepines as inhibitors of Leishmania infantum TR. The mode of binding observed among the clusters also potentiates the probable in vitro inhibition kinetics and aids in defining key interaction which might contribute to the inhibition of enzymatic reduction of T[S] 2. The method provides scope for automation and integration into the virtual screening process employing docking softwares, for clustering the small molecule inhibitors based upon protein-ligand interactions. PMID:22550471

Effects of Statins on Renal Outcome in Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis

PubMed Central

Sanguankeo, Anawin; Upala, Sikarin; Cheungpasitporn, Wisit; Ungprasert, Patompong; Knight, Eric L.

2015-01-01

Background HMG CoA reductase inhibitors (statins) are known to prevent cardiovascular disease and improve lipid profiles. However, the effects of statins on renal outcomes, including decline in estimated glomerular filtration rate (eGFR) and proteinuria in patients with chronic kidney disease (CKD), are controversial. This meta-analysis evaluated the impact of statins on renal outcomes in patients with CKD. Materials and Methods We comprehensively searched the databases of MEDLINE, EMBASE, and Cochrane Databases. The inclusion criteria were published RCT and cohort studies comparing statin therapy to placebo or active controls in patients with CKD (eGFR <60 ml/min/1.73 m2) not requiring dialysis. The primary outcome was the differences in the change of eGFR. We also examined change of protein concentration in urine as a secondary outcome. A meta-analysis comparing statin and its control groups and a subgroup analysis examining intensity of statin were performed. Results From 142 full-text articles, 10 studies were included in the meta-analysis. Overall, there was a significant difference in rate of eGFR change per year favoring statin group (mean difference (MD) = 0.10 ml/min/1.73 m2, 95% CI: 0.09 to 0.12). In our subgroup analysis, those who received high-intensity statins had a significant difference in eGFR with a MD of 3.35 (95% CI: 0.91 to 5.79) ml/min/1.73 m2 compared to control. No significant change in eGFR was found with moderate- and low-intensity statin therapy. Compared with the control group, the statin group did not have a difference in reduction of proteinuria with MD in change of proteinuria of 0.19 gm/day (95% CI: -0.02 to 0.40). Conclusion Overall, there was a difference in change of eGFR between the statin and control group. High-intensity statins were found to improve a decline in eGFR in population with CKD not requiring dialysis compared with control, but moderate- and low-intensity statins were not. Statins were not found to decrease

Proton Pump Inhibitors and Risk of Rhabdomyolysis.

PubMed

Duncan, Scott J; Howden, Colin W

2017-01-01

Proton pump inhibitors (PPIs) have been associated with a variety of adverse events, although the level of evidence for many of these is weak at best. Recently, one national regulatory authority has mandated a change to the labeling of one PPI based on reports of possible associated rhabdomyolysis. Thus, in this review we summarize the available evidence linking PPI use with rhabdomyolysis. The level of evidence is insufficient to establish a causal relationship and is largely based on sporadic case reports. In general, patients with suspected PPI-associated rhabdomyolysis have not been re-challenged with a PPI after recovery. The mechanism whereby PPIs might have been associated with rhabdomyolysis is unclear but possibly related to interaction with concomitantly administered drugs such as HMG-CoA reductase inhibitors (statins). For patients with rhabdomyolysis, a careful search must be made for possible etiological factors. In patients who recover from an episode of possible PPI-related rhabdomyolysis but do not have a genuine requirement for PPI treatment, the PPI should not be re-introduced. For those with a definite indication for ongoing PPI treatment, the PPI can be re-introduced but should preferably not be administered with a statin.

Characterization of Statin-Associated Myopathy Case Reports in Thailand Using the Health Product Vigilance Center Database.

PubMed

Boonmuang, Pornwalai; Nathisuwan, Surakit; Chaiyakunapruk, Nathorn; Suwankesawong, Wimon; Pokhagul, Pattreya; Teerawattanapong, Nattawat; Supsongserm, Pairin

2013-09-01

HMG-CoA reductase inhibitors [statins], a widely prescribed cholesterol-lowering therapy, are associated with muscle-related adverse events. While characteristics of such events are well documented in Western countries, little data exists for the Thai population. The aim of this study was to determine the characteristics of patients, type and dosing of statin, and to identify patterns of drug use that may be associated with such adverse events using the national pharmacovigilance database known as Thai Vigibase. Muscle-related adverse events involving statins in the Thai Vigibase from 1996 to December 2009 were identified. For each report, the following information was extracted: patient demographics, co-morbidities, detailed information of adverse event, detailed information of suspected drug, treatment and outcome, as well as causality assessment and quality of reports. Descriptive statistics were performed for all study variables. A total of 198 cases of statin-associated muscle-related adverse events were identified. Mean age was 61.4 ± 12.4 years of age and 59.6% were female. Simvastatin, atorvastatin, rosuvastatin and cerivastatin were implicated as the suspected drug in 163 (82.3%), 24 (12.1%), 10 (5.1%) and 1 (0.5%) cases, respectively. Rhabdomyolysis accounted for 55.6% of all muscle-related adverse events. Drug interactions known to enhance such toxicity of statins were identified in 40.9% of the total set of reports. Similar to studies from Western countries, fibrates, HIV protease inhibitors, non-dihydropyridine calcium channel blockers, azole antifungals and macrolides were commonly found in such cases. Interestingly, colchicine has been identified as the second most common drug interaction in our database. Case fatality rates were 0.9, 1.6 and 16.7%, when there were 0, 1 and ≥2 interacting drugs, respectively. Characteristics of muscle-related adverse events with statins in the Thai population showed some similarities and differences compared with

Effect of Statin Use on Mobility Disability and its Prevention in At-risk Older Adults: The LIFE Study

PubMed Central

Lovato, Laura; Miller, Michael E.; Fielding, Roger A.; Church, Tim S.; Newman, Anne B.; Buford, Thomas W.; Pahor, Marco; McDermott, Mary M.; Stafford, Randall S.; Lee, David S. H.; Kritchevsky, Stephen B.

2016-01-01

Background: HMG-CoA reductase inhibitors (statins) are among the most commonly prescribed classes of medications. Although their cardiovascular benefits and myalgia risks are well documented, their effects on older adults initiating an exercise training program are less understood. Methods: 1,635 sedentary men and women aged 70–89 years with Short Physical Performance Battery (SPPB) score of 9 or below and were able to walk 400 m were randomized to a structured, moderate-intensity physical activity (PA) program consisting of both center-based (twice/wk) and home-based (3–4 times/wk) aerobic, resistance, and flexibility training or to a health education (HE) program combined with upper extremity stretching. Results: Overall, the PA intervention was associated with lower risk of major mobility disability (hazard ratio [HR] = 0.82; 95% confidence interval [CI] = 0.69–0.98). The effect was similar (p value for interaction = .62) in both statin users (PA n = 415, HE n = 412; HR = 0.86, 95% CI = 0.67–1.1) and nonusers (PA n = 402, HE n = 404; HR = 0.78, 95% CI = 0.61–1.01). Attendance was similar for statin users (65%) and nonusers (63%). SPPB at 12 months was slightly greater for PA (8.35±0.10) than for HE (7.94±0.10) in statin users but not in nonusers (PA 8.25±0.10, HE 8.16±0.10), though the interaction effect was not statistically significant. Self-reported PA levels were not different between statin users and nonusers. Conclusions: Although statins have been associated with adverse effects on muscle, data from the LIFE Study show that statin users and nonusers both benefit from PA interventions. Older adults who require statin medications to manage chronic medical conditions and are sedentary will be able to benefit from interventions to increase PA. PMID:26988662

Serum levels of lipoprotein(a) and homocysteine in patients on hemodialysis who take hydroxymethylglutaryl-CoA reductase inhibitors, vitamin B6, and folic acid.

PubMed

Shojaei, Mir Hatef; Djalali, Mamhmoud; Siassi, Fereydoun; Khatami, Mohammad Reza; Boroumand, Mohammad Ali; Eshragian, Mohammad Reza

2009-07-01

High serum levels of lipoprotein(a) and homocysteine are risk factors of cardiovascular disease which are prevalent in patients on hemodialysis. Controversy exists about the effects of hydroxymethylglutaryl-CoA reductase inhibitors on serum lipoprotein(a) levels in patients on hemodialysis. Also, deficiency of some water soluble vitamins and administration of statins may raise serum levels of homocysteine in these patients. This study was designed to investigate serum levels of lipoprotein(a) and homocysteine in patients on hemodialysis who were taking a statin, vitamin B6, and folic acid. We investigated on 152 patients with maintenance hemodialysis who were taking atorvastatin or lovastatin, vitamin B6, and folic acid for at least 6 months. Their serum levels were obtained to measure lipoprotein(a) and homocysteine levels, as well as triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The mean serum values of total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol and triglyceride were significantly less than the maximum reference values (P < .001). The mean serum level of lipoprotein(a) was also less than the reference value (P = .009), but homocysteine level was 33% higher on average than the reference value (P < .001). Our study demonstrated that in our patients on hemodialysis, the mean serum level of homocysteine was about 30% higher than the reference value although they were receiving vitamin B6 and folic acid. Hence, they were still exposed to the risk of cardiovascular disease.

New Drugs for Treating Dyslipidemia: Beyond Statins

PubMed Central

Ahn, Chang Ho

2015-01-01

Statins have been shown to be very effective and safe in numerous randomized clinical trials, and became the implacable first-line treatment against atherogenic dyslipidemia. However, even with optimal statin treatment, 60% to 80% of residual cardiovascular risk still exists. The patients with familial hypercholesterolemia which results in extremely high level of low density lipoprotein cholesterol (LDL-C) level and the patients who are intolerant or unresponsive to statins are the other hurdles of statin treatment. Recently, new classes of lipid-lowering drugs have been developed and some of them are available for the clinical practice. The pro-protein convertase subtilisin/kexintype 9 (PCSK9) inhibitor increases the expression of low density lipoprotein (LDL) receptor in hepatocytes by enhancing LDL receptor recycling. The microsomal triglyceride transport protein (MTP) inhibitor and antisense oligonucleotide against apolipoprotein B (ApoB) reduce the ApoB containing lipoprotein by blocking the hepatic very low density lipoprotein synthesis pathway. The apolipoprotein A1 (ApoA1) mimetics pursuing the beneficial effect of high density lipoprotein cholesterol and can reverse the course of atherosclerosis. ApoA1 mimetics had many controversial clinical data and need more validation in humans. The PCSK9 inhibitor recently showed promising results of significant LDL-C lowering in familial hypercholesterolemia (FH) patients from the long-term phase III trials. The MTP inhibitor and antisesnse oligonucleotide against ApoB were approved for the treatment of homozygous FH but still needs more consolidated evidences about hepatic safety such as hepatosteatosis. We would discuss the benefits and concerns of these new lipid-lowering drugs anticipating additional benefits beyond statin treatment. PMID:25922802

Likely gains in life expectancy of patients with coronary artery disease treated with HMG-CoA reductase inhibitors, as predicted by a decision analysis model.

PubMed

Kellett, J

1997-07-01

To estimate the likely gains in life expectancy of patients with coronary artery disease treated with HMG-CoA reductase inhibitors based on published reports and the results of the 4S and the West of Scotland Study. Decision analysis. Four likely scenarios of the effect of treatment with HMG-CoA reductase inhibitors on the life expectancy of medically and surgically managed coronary artery disease were modelled. Regardless of the scenario, treatment with HMG-CoA reductase inhibitors was estimated to provide a gain in life expectancy for medically managed patients of all ages with coronary artery disease, ranging from 4.6 to 10.1 quality adjusted life years (QALYs) for a 40 year old with three vessel disease (depending on the scenario assumed), to 0.2 QALYs for a 80 year old with two vessel disease. These gains were always greater than those predicted after bypass alone. If the use of HMG-CoA reductase inhibitors produces the same reduction in cardiac mortality after bypass as it does in medically managed patients it will increase the benefits of operation except for patients with two vessel disease over 70 years of age. Conversely, if HMG-CoA reductase inhibitors do not influence the course of coronary artery disease after bypass, the benefits of operation over medical treatment with HMG-CoA reductase inhibitors are either reduced or lost completely, ranging from a loss of -5.6 QALYs for a 40 year old with two vessel disease to a gain of 1.5 QALYs for 55 to 60 year old patients with left main stem disease. Although their effect on the progression of coronary artery disease after bypass must be defined, it is probable that HMG-CoA reductase inhibitors will produce considerable gains in life expectancy for patients with coronary artery disease.

Inhibition of 3-Hydroxy-3-Methylglutaryl–Coenzyme A Reductase and Application of Statins as a Novel Effective Therapeutic Approach against Acanthamoeba Infections

PubMed Central

Lorenzo-Morales, Jacob; Machin, Rubén P.; López-Arencibia, Atteneri; García-Castellano, José Manuel; de Fuentes, Isabel; Loftus, Brendan; Maciver, Sutherland K.; Valladares, Basilio; Piñero, José E.

2013-01-01

Acanthamoeba is an opportunistic pathogen in humans, whose infections most commonly manifest as Acanthamoeba keratitis or, more rarely, granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of Acanthamoeba, they are generally lengthy and/or have limited efficacy. Therefore, there is a requirement for the identification, validation, and development of novel therapeutic targets against these pathogens. Recently, RNA interference (RNAi) has been widely used for these validation purposes and has proven to be a powerful tool for Acanthamoeba therapeutics. Ergosterol is one of the major sterols in the membrane of Acanthamoeba. 3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, one of the precursors for the production of cholesterol in humans and ergosterol in plants, fungi, and protozoa. Statins are compounds which inhibit this enzyme and so are promising as chemotherapeutics. In order to validate whether this enzyme could be an interesting therapeutic target in Acanthamoeba, small interfering RNAs (siRNAs) against HMG-CoA were developed and used to evaluate the effects induced by the inhibition of Acanthamoeba HMG-CoA. It was found that HMG-CoA is a potential drug target in these pathogenic free-living amoebae, and various statins were evaluated in vitro against three clinical strains of Acanthamoeba by using a colorimetric assay, showing important activities against the tested strains. We conclude that the targeting of HMG-CoA and Acanthamoeba treatment using statins is a novel powerful treatment option against Acanthamoeba species in human disease. PMID:23114753

Low plasma vitamin D levels and muscle-related adverse effects in statin users.

PubMed

Eisen, Alon; Lev, Eli; Iakobishvilli, Zaza; Porter, Avital; Brosh, David; Hasdai, David; Mager, Aviv

2014-01-01

Treatment with HMG-CoA reductase inhibitors (statins) is often complicated by muscle-related adverse effects (MAEs). Studies of the association between low plasma vitamin D levels and MAEs have yielded conflicting results. To determine if low plasma vitamin D level is a risk factorfor MAEs in statin users. Plasma levels of 25(OH) vitamin D were measured as part of the routine evaluation of unselected statin-treated patients attending the coronary and lipid clinics at our hospital during the period 2007-2010. Medical data on muscle complaints and statin use were retrieved from the medical files. Creatine kinase (CK) levels were derived from the hospital laboratory database. The sample included 272 patients (141 men) aged 33-89 years. Mean vitamin D level was 48.04 nmol/L. Levels were higher in men (51.0 +/- 20.5 versus 44.7 +/- 18.9 nmol/L, P = 0.001) and were unaffected by age. MAEs were observed in 106 patients (39%): myalgia in 95 (35%) and CK elevation in 20 (7%); 9 patients (3%) had both. There was no difference in plasma vitamin D levels between patients with and without myalgia (46.3 +/- 17.7 versus 48.9 +/- 21.0 nmol/L, P = 0.31), with and without CK elevation (50.2 +/- 14.6 versus 47.8 +/- 20.3 nmol/L, P = 0.60), or with or without any MAE (50.4 +/- 15.0 versus 47.8 +/- 10.2 nmol/L, P = 0.27). These findings were consistent when analyzed by patient gender and presence/absence of coronary artery disease, and when using a lower vitamin D cutoff (< 25 nmol/L). There is apparently no relationship between plasma vitamin D level and risk of MAEs in statin users.

Muscle symptoms in statin users, associations with cytochrome P450, and membrane transporter inhibitor use: a subanalysis of the USAGE study.

PubMed

Ito, Matthew K; Maki, Kevin C; Brinton, Eliot A; Cohen, Jerome D; Jacobson, Terry A

2014-01-01

Drug interactions have been identified as a risk factor for muscle-related side effects in statin users. The aim was to assess whether use of medications that inhibit cytochrome P450 (CYP450) isozymes, organic anion transporting polypeptide 1B1 (OATP1B1), or P-glycoprotein (P-gp) are associated with muscle-related symptoms among current and former statin users. Persons (n = 10,138) from the Understanding Statin Use in America and Gaps in Education (USAGE) internet survey were categorized about whether they ever reported new or worsening muscle pain while taking a statin (n = 2935) or ever stopped a statin because of muscle pain (n = 1516). Univariate and multivariate logistic regression models were used to assess associations between use of concomitant therapies that inhibit CYP450 isozymes, OATP1B1, P-gp, or a combination and muscle-related outcomes. In multivariate analyses, concomitant use of a CYP450 inhibitor was associated with increased odds for new or worse muscle pain (odds ratio [OR] = 1.42; P < .001) or ever having stopped a statin because of muscle pain (OR = 1.28; P = .037). Concomitant use of medication known to inhibit both OATP1B1 and P-gp was also associated with increased odds (OR = 1.80; P = .030) of ever having stopped a statin because of muscle pain. Concomitant use of medication(s) that inhibit statin metabolism was associated with increased odds of new or worse muscle pain while taking a statin and having previously stopped a statin because of muscle symptoms. These data emphasize the importance of enhancing the capabilities of clinicians and health systems for identifying and reducing statin drug interactions. Copyright © 2014 National Lipid Association. All rights reserved.

Association of statin and nonsteroidal anti-inflammatory drug use with prostate cancer outcomes: results from CaPSURE.

PubMed

Katz, Matthew S; Carroll, Peter R; Cowan, Janet E; Chan, June M; D'Amico, Anthony V

2010-09-01

To determine whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with the risk of prostate cancer and improved survival in men with prostate cancer. We retrospectively examined the association between NSAID and statin use among 7042 men who underwent radical prostatectomy (RP, 4611) or radiotherapy (RT, 2431) for prostate cancer between 1990 and 2003 identified in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a primarily community-based national prostate cancer registry. We compared clinical and sociodemographic variables by statin and NSAID use, using chi-square tests and multinomial logistic regression. We examined associations between medications and comorbid illness with mortality using unadjusted and adjusted Cox proportional hazard models. The median (range) follow-up from treatment was 4 (0-16) years. In multivariate survival analysis, statin 'ever-use' was associated with a reduced risk of all-cause mortality (ACM) after RP (hazard ratio, HR, 0.35, 95% confidence interval, CI, 0.21-0.58) and RT (0.59, 0.37-0.94). NSAID ever-use was also associated with a reduced risk of ACM after RP (HR 0.47, 95% CI 0.30-0.75) and RT (0.39, 0.25-0.59). In a population of men with prostate cancer, statin and NSAID ever-use were associated with a reduced risk of ACM. Our study highlights the importance of multidisciplinary survivorship care for men with prostate cancer. © 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.

Statins enhance cognitive performance in object location test in albino Swiss mice: involvement of beta-adrenoceptors.

PubMed

Vandresen-Filho, Samuel; França, Lucas Moreira; Alcantara-Junior, José; Nogueira, Lucas Caixeta; de Brito, Thiago Marques; Lopes, Lousã; Junior, Fernando Mesquita; Vanzeler, Maria Luzinete; Bertoldo, Daniela Bohn; Dias, Paula Gomes; Colla, André R S; Hoeller, Alexandre; Duzzioni, Marcelo; Rodrigues, Ana Lúcia S; de Lima, Thereza C M; Tasca, Carla Inês; Viola, Giordano Gubert

2015-05-01

Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby inhibiting cell synthesis of cholesterol and isoprenoids. Moreover, several studies have been evaluating pleiotropic effects of statins, mainly because they present neuroprotective effects in various pathological conditions. However, knowledge about behavioral effects of statins per se is relatively scarce. Considering these facts, we aimed to analyze behavioral responses of atorvastatin or simvastatin-treated mice in the open field test, elevated plus maze and object location test. Atorvastatin treatment for 7 consecutive days at 1 mg/kg or 10 mg/kg (v.o.) or simvastatin 10 mg/kg or 20 mg/kg enhanced cognitive performance in object location test when compared to control group (saline-treated mice). Simvastatin effects on mice performance in the object location test was abolished by post-training infusion of the beta-adrenoceptor antagonist propranolol. Atorvastatin and simvastatin did not change the behavioral response in open field and elevated plus-maze (EPM) tests in any of the used doses. These data demonstrate the positive effects of both statins in cognitive processes in mice, without any alteration in locomotor parameters in the open field test or anxiolytic-like behavior in EPM. In conclusion, we demonstrate that atorvastatin and simvastatin per se improve the cognitive performance in a rodent model of spatial memory and this effect is related to beta-adrenergic receptors modulation. Copyright © 2015 Elsevier Inc. All rights reserved.

In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors

NASA Astrophysics Data System (ADS)

Lindert, Steffen; Tallorin, Lorillee; Nguyen, Quynh G.; Burkart, Michael D.; McCammon, J. Andrew

2015-01-01

The need for novel therapeutics against Plasmodium falciparum is urgent due to recent emergence of multi-drug resistant malaria parasites. Since fatty acids are essential for both the liver and blood stages of the malarial parasite, targeting fatty acid biosynthesis is a promising strategy for combatting P. falciparum. We present a combined computational and experimental study to identify novel inhibitors of enoyl-acyl carrier protein reductase ( PfENR) in the fatty acid biosynthesis pathway. A small-molecule database from ChemBridge was docked into three distinct PfENR crystal structures that provide multiple receptor conformations. Two different docking algorithms were used to generate a consensus score in order to rank possible small molecule hits. Our studies led to the identification of five low-micromolar pyrimidine dione inhibitors of PfENR.

Liquid chromatography-tandem mass spectrometry method for the measurement of serum mevalonic acid: a novel marker of hydroxymethylglutaryl coenzyme A reductase inhibition by statins.

PubMed

Waldron, Jenna; Webster, Craig

2011-05-01

Mevalonic acid (MVA) is synthesized at an early and rate-limiting step in the biosynthesis of cholesterol by the enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, and is a useful measure of statin efficacy or treatment. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the measurement of serum MVA has been developed. Following the in vitro conversion of MVA to mevalonic acid lactone (MVAL) in the serum, MVAL and a deuterated internal standard were extracted using an online solid-phase extraction procedure. Chromatographic separation was achieved using a Luna PFP column (Phenomenex), with enhanced selectivity and improved resolution for polar compounds. A gradient system was used, with mobile phase comprising methanol and water (5 mmol/L ammonium formate buffer, pH 2.5). Analysis was performed using an API 5000 tandem mass spectrometer (Applied Biosystems) in positive electrospray ionization mode. The method showed excellent recoveries (98 ± 8%) and imprecision (intra-assay coefficient of variation of 2.2% [6.5 ng/mL] and 2.6% [10.5 ng/mL], and inter-assay coefficient of variation of 9% [10.5 ng/mL]). The assay provides a calibration range up to 50 ng/mL with a limit of detection at 0.1 ng/mL. A simple, rapid and analytically specific method has been developed for the measurement of serum MVA, in the form of MVAL. The high analytical sensitivity of the method allows for accurate quantitation of MVAL in serum samples, both at the endogenous levels found in healthy individuals and in statin-treated patients where normal levels are expected to be greatly reduced through the inhibition of HMG-CoA reductase.

Statin Intolerance: A Literature Review and Management Strategies.

PubMed

Saxon, David R; Eckel, Robert H

Statin intolerance is a commonly encountered clinical problem for which useful management strategies exist. Although many patients report statin-related muscle symptoms, studies indicate that the majority of these patients can tolerate a statin upon re-challenge. Alternative statin dosing strategies are an effective way to modify and reintroduce statin therapy for patients reporting adverse symptoms. Correction of vitamin D deficiency and hypothyroidism may improve statin tolerability in some patients. CoQ10 supplementation has been found to be of no benefit for statin-related muscle symptoms in most recent clinical trials. PCSK9 inhibitors are a new therapeutic option that if confirmed as safe and effective by outcomes trials may be of substantial benefit to select patients at high ASCVD risk who are unable to achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on maximally tolerated statin therapy. Other available medications to lower LDL-C in statin intolerant patients include ezetimibe, bile acid sequestrants, niacin, and fibrates. Published by Elsevier Inc.

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

Lepidopteran HMG-CoA reductase is a potential selective target for pest control

PubMed Central

Li, Yuan-mei; Huang, Juan; Tobe, Stephen S.

2017-01-01

As a consequence of the negative impacts on the environment of some insecticides, discovery of eco-friendly insecticides and target has received global attention in recent years. Sequence alignment and structural comparison of the rate-limiting enzyme HMG-CoA reductase (HMGR) revealed differences between lepidopteran pests and other organisms, which suggested insect HMGR could be a selective insecticide target candidate. Inhibition of JH biosynthesis in vitro confirmed that HMGR inhibitors showed a potent lethal effect on the lepidopteran pest Manduca sexta, whereas there was little effect on JH biosynthesis in Apis mellifera and Diploptera punctata. The pest control application of these inhibitors demonstrated that they can be insecticide candidates with potent ovicidal activity, larvicidal activity and insect growth regulatory effects. The present study has validated that Lepidopteran HMGR can be a potent selective insecticide target, and the HMGR inhibitors (especially type II statins) could be selective insecticide candidates and lead compounds. Furthermore, we demonstrated that sequence alignment, homology modeling and structural comparison may be useful for determining potential enzymes or receptors which can be eco-friendly pesticide  targets. PMID:28133568

Lepidopteran HMG-CoA reductase is a potential selective target for pest control.

PubMed

Li, Yuan-Mei; Kai, Zhen-Peng; Huang, Juan; Tobe, Stephen S

2017-01-01

As a consequence of the negative impacts on the environment of some insecticides, discovery of eco-friendly insecticides and target has received global attention in recent years. Sequence alignment and structural comparison of the rate-limiting enzyme HMG-CoA reductase (HMGR) revealed differences between lepidopteran pests and other organisms, which suggested insect HMGR could be a selective insecticide target candidate. Inhibition of JH biosynthesis in vitro confirmed that HMGR inhibitors showed a potent lethal effect on the lepidopteran pest Manduca sexta , whereas there was little effect on JH biosynthesis in Apis mellifera and Diploptera punctata . The pest control application of these inhibitors demonstrated that they can be insecticide candidates with potent ovicidal activity, larvicidal activity and insect growth regulatory effects. The present study has validated that Lepidopteran HMGR can be a potent selective insecticide target, and the HMGR inhibitors (especially type II statins) could be selective insecticide candidates and lead compounds. Furthermore, we demonstrated that sequence alignment, homology modeling and structural comparison may be useful for determining potential enzymes or receptors which can be eco-friendly pesticide  targets.

Quantifying the use of the statin antilipemic drugs: comparisons and contrasts between Nova Scotia, Canada, and Queensland, Australia.

PubMed

Cooke, Charmaine; Nissen, Lisa; Sketris, Ingrid; Tett, Susan E

2005-04-01

Jurisdictions are developing public drug insurance systems to improve access to pharmaceuticals, cost-effective prescribing, and patient health and well-being. We compared 2 jurisdictions with different pharmaceutical policies to determine prescribing patterns for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (ie, statins). The aim of this work was to investigate the feasibility of using available prescription administrative databases to compare the use of statins in Queensland, Australia, and in Nova Scotia, Canada. Data from the Nova Scotia Pharmacare Program and the Health Insurance Commission in Australia were used to obtain dispensing data. Utilization was compared for the 5-year period from 1997 through 2001, using the World Health Organization anatomic therapeutic chemical/defined daily dose (DDD) system. In the year 2001, there were 177,000 beneficiaries in the public drug plan in Nova Scotia (62% aged > or = 65 years old) and 960,000 concession beneficiaries (pensioners and social security recipients, 61 aged > or = 65 years) in Queensland. These 2 groups were comparable. The overall utilization of statin medications increased steadily in both areas over the study period, from 50 to 205 DDD/1000 beneficiaries per day. Comparison of the 2 growth lines showed no statistically significant differences in overall statin use despite differences in brand availabilities and policies about prescribing. In the year 2001, atorvastatin was the most commonly prescribed statin in both areas, comprising 46% of statin use in Nova Scotia and 51% in Queensland. Mean doses of each statin prescribed were slightly above the DDDs. Expenditure on statins per 1000 beneficiaries and per DDD were similar in each jurisdiction, being slightly higher in Nova Scotia. Despite differences in pharmaceutical reimbursement systems, use of the statins was similar in Nova Scotia and Queensland. The feasibility of the methodology was demonstrated. Future studies, including

Changes to the statin prescribing policy in Belgium: potential impact in clinical and economic terms.

PubMed

Liew, Danny; Webb, Kate; Marbaix, Sophie; Annemans, Lieven

2012-08-01

New policies in Belgium encourage prescribing of generic HMG-CoA reductase inhibitors (statins), but may lead to non-equivalent switching of patients from more potent second generation statins, as has occurred elsewhere. We sought to assess the potential health economic impact of the new policies. This was a cost-effectiveness analysis. A Markov model was constructed to simulate the onset of cardiovascular disease (CVD) and death among a representative cohort of 80 Belgian patients initially free of CVD and taking atorvastatin. Cardiovascular risks were estimated from calibrated Framingham equations, and utilities and costs from published data. Decision analysis assessed the potential impact of switching all 80 patients to simvastatin. Changes in lipid levels expected to arise from switching were based on a published meta-analysis. If the 80 patients remained on atorvastatin, the model predicted that 23 (29%) would develop CVD over 20 years. If they were switched to simvastatin, the predicted number was 25 (31%), equating to a 'number needed to harm' of 52. Switching would lead to a net cost saving of €131 (2012) per subject, but also a loss of 0.03 quality-adjusted life-years (QALYs) per subject. These equated to a decremental cost-effectiveness ratio of €4777 per QALY lost. Sensitivity analyses indicated this result to be robust. Recently introduced statin prescribing policies in Belgium are likely, as intended, to reduce statin costs, but also increase the burden of CVD due to non-equivalent switching. It would be cost effective to maintain patients on atorvastatin for primary prevention rather than switch them to simvastatin.

Synergistic effect of statins and postmenopausal hormone therapy in the prevention of skeletal fractures in elderly women.

PubMed

Bakhireva, Ludmila N; Shainline, Michael R; Carter, Shelley; Robinson, Scott; Beaton, Sarah J; Nawarskas, James J; Gunter, Margaret J

2010-09-01

To examine the role of concurrent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) use and postmenopausal hormone therapy on osteoporosis-related fractures. Case-control study. Data Source. Large integrated health plan in New Mexico. Patients. Case patients were 1001 women with incident fractures of the hip, wrist, forearm, or spine that occurred between January 1, 2000, and December 31, 2005, and controls were 2607 women without fractures during the same time frame; both groups were selected from the same population of women aged 50 years or older who utilized health plan services during the study time frame. Postmenopausal hormone therapy use was classified as "current" (12 mo before index date) or "never or past." The risk of fractures was ascertained among continuous (> or = 80% medication possession ratio during 12 mo before the index date) and current (3 mo before index date) statin users relative to patients without hyperlipidemia who did not use lipid-lowering drugs. The interaction between statins and hormone therapy was examined in multivariable logistic regression. The association between statin use and fractures was examined separately among current and never or past hormone therapy users after controlling for other risk factors. Nineteen percent of the study participants were current hormone therapy users; 9.5% were current and 4.8% were continuous statin users. No association between continuous statin use and fractures was observed among never or past hormone therapy users (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.53-1.22). In contrast, a strong protective effect (OR 0.19, 95% CI 0.04-0.87) was observed among women who concurrently used statins and hormone therapy for 1 year, independent of age; corticosteroid, bisphosphonate, thiazide diuretic, calcitonin, methotrexate, or antiepileptic drug use; chronic kidney disease; and Charlson comorbidity index. Concurrent statin use and hormone therapy may have a synergistic

Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase

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

Beierlein, J.; Frey, K; Bolstad, D

2008-01-01

Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structuremore » of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 A resolution. The structure reveals several features that can be exploited for further development of this lead series.« less

Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis

PubMed Central

Begley, Darren W.; Edwards, Thomas E.; Raymond, Amy C.; Smith, Eric R.; Hartley, Robert C.; Abendroth, Jan; Sankaran, Banumathi; Lorimer, Donald D.; Myler, Peter J.; Staker, Bart L.; Stewart, Lance J.

2011-01-01

Babesiosis is a tick-borne disease caused by eukaryotic Babesia parasites which are morphologically similar to Plasmodium falciparum, the causative agent of malaria in humans. Like Plasmodium, different species of Babesia are tuned to infect different mammalian hosts, including rats, dogs, horses and cattle. Most species of Plasmodium and Babesia possess an essential bifunctional enzyme for nucleotide synthesis and folate metabolism: dihydrofolate reductase-thymidylate synthase. Although thymidylate synthase is highly conserved across organisms, the bifunctional form of this enzyme is relatively uncommon in nature. The structural characterization of dihydrofolate reductase-thymidylate synthase in Babesia bovis, the causative agent of babesiosis in livestock cattle, is reported here. The apo state is compared with structures that contain dUMP, NADP and two different antifolate inhibitors: pemetrexed and raltitrexed. The complexes reveal modes of binding similar to that seen in drug-resistant malaria strains and point to the utility of applying structural studies with proven cancer chemotherapies towards infectious disease research. PMID:21904052

Reduction of Brain β-Amyloid (Aβ) by Fluvastatin, a Hydroxymethylglutaryl-CoA Reductase Inhibitor, through Increase in Degradation of Amyloid Precursor Protein C-terminal Fragments (APP-CTFs) and Aβ Clearance*

PubMed Central

Shinohara, Mitsuru; Sato, Naoyuki; Kurinami, Hitomi; Takeuchi, Daisuke; Takeda, Shuko; Shimamura, Munehisa; Yamashita, Toshihide; Uchiyama, Yasuo; Rakugi, Hiromi; Morishita, Ryuichi

2010-01-01

Epidemiological studies suggest that statins (hydroxymethylglutaryl-CoA reductase inhibitors) could reduce the risk of Alzheimer disease. Although one possible explanation is through an effect on β-amyloid (Aβ) metabolism, its effect remains to be elucidated. Here, we explored the molecular mechanisms of how statins influence Aβ metabolism. Fluvastatin at clinical doses significantly reduced Aβ and amyloid precursor protein C-terminal fragment (APP-CTF) levels among APP metabolites in the brain of C57BL/6 mice. Chronic intracerebroventricular infusion of lysosomal inhibitors blocked these effects, indicating that up-regulation of the lysosomal degradation of endogenous APP-CTFs is involved in reduced Aβ production. Biochemical analysis suggested that this was mediated by enhanced trafficking of APP-CTFs from endosomes to lysosomes, associated with marked changes of Rab proteins, which regulate endosomal function. In primary neurons, fluvastatin enhanced the degradation of APP-CTFs through an isoprenoid-dependent mechanism. Because our previous study suggests additive effects of fluvastatin on Aβ metabolism, we examined Aβ clearance rates by using the brain efflux index method and found its increased rates at high Aβ levels from brain. As LRP1 in brain microvessels was increased, up-regulation of LRP1-mediated Aβ clearance at the blood-brain barrier might be involved. In cultured brain microvessel endothelial cells, fluvastatin increased LRP1 and the uptake of Aβ, which was blocked by LRP1 antagonists, through an isoprenoid-dependent mechanism. Overall, the present study demonstrated that fluvastatin reduced Aβ level by an isoprenoid-dependent mechanism. These results have important implications for the development of disease-modifying therapy for Alzheimer disease as well as understanding of Aβ metabolism. PMID:20472556

Technological advances and proteomic applications in drug discovery and target deconvolution: identification of the pleiotropic effects of statins.

PubMed

Banfi, Cristina; Baetta, Roberta; Gianazza, Erica; Tremoli, Elena

2017-06-01

Proteomic-based techniques provide a powerful tool for identifying the full spectrum of protein targets of a drug, elucidating its mechanism(s) of action, and identifying biomarkers of its efficacy and safety. Herein, we outline the technological advancements in the field, and illustrate the contribution of proteomics to the definition of the pharmacological profile of statins, which represent the cornerstone of the prevention and treatment of cardiovascular diseases (CVDs). Statins act by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, thus reducing cholesterol biosynthesis and consequently enhancing the clearance of low-density lipoproteins from the blood; however, HMG-CoA reductase inhibition can result in a multitude of additional effects beyond lipid lowering, known as 'pleiotropic effects'. The case of statins highlights the unique contribution of proteomics to the target profiling of a drug molecule. Copyright © 2017 Elsevier Ltd. All rights reserved.

Investigation of the Plausibility of 5-Alpha-Reductase Inhibitor Syndrome

PubMed Central

Fertig, Raymond; Shapiro, Jerry; Bergfeld, Wilma; Tosti, Antonella

2017-01-01

Postfinasteride syndrome (PFS) is a term recently coined to characterize a constellation of reported undesirable side effects described in postmarketing reports and small uncontrolled studies that developed during or after stopping finasteride treatment, and persisted after drug discontinuation. Symptoms included decreased libido, erectile dysfunction, sexual anhedonia, decreased sperm count, gynecomastia, skin changes, cognitive impairment, fatigue, anxiety, depression, and suicidal ideation. The aim of this study is to review the existing medical literature for evidence-based research of permanent sexual dysfunction and mood changes during treatment with 5-alpha-reductase inhibitors including finasteride and dutasteride. PMID:28232919

Nafuredin, a novel inhibitor of NADH-fumarate reductase, produced by Aspergillus niger FT-0554.

PubMed

Ui, H; Shiomi, K; Yamaguchi, Y; Masuma, R; Nagamitsu, T; Takano, D; Sunazuka, T; Namikoshi, M; Omura, S

2001-03-01

A novel compound, nafuredin, was isolated as an inhibitor of anaerobic electron transport (NADH-fumarate reductase). It was obtained from culture broth of Aspergillus niger FT-0554 isolated from a marine sponge. The structure was elucidated as an epoxy-delta-lactone with an attached methylated olefinic side chain on the basis of spectral analysis.

Biological evaluation of some uracil derivatives as potent glutathione reductase inhibitors

NASA Astrophysics Data System (ADS)

Güney, Murat; Ekinci, Deniz; Ćavdar, Huseyin; Şentürk, Murat; Zilbeyaz, Kani

2016-04-01

Discovery of glutathione reductase (GR) inhibitors has become very popular recently due to antimalarial and anticancer activities. In this study, GR inhibitory capacities of some uracil derivatives (UDCs) (1-4) were reported. Some commercially available molecules (5-6) were also tested for comparison reasons. The novel UDCs were obtained in high yields using simple chemical procedures and exhibited much potent inhibitory activities against GR at low nanomolar concentrations with IC50 values ranging from 2.68 to 166.6 nM as compared with well-known agents.

A Pilot Study: The Beneficial Effects of Combined Statin-exercise Therapy on Cognitive Function in Patients with Coronary Artery Disease and Mild Cognitive Decline.

PubMed

Toyama, Kensuke; Sugiyama, Seigo; Oka, Hideki; Hamada, Mari; Iwasaki, Yuri; Horio, Eiji; Rokutanda, Taku; Nakamura, Shinichi; Spin, Joshua M; Tsao, Philip S; Ogawa, Hisao

2017-01-01

Objective Hypercholesterolemia, a risk factor in cognitive impairment, can be treated with statins. However, cognitive decline associated with "statins" (HMG-CoA reductase inhibitors) is a clinical concern. This pilot study investigated the effects of combining statins and regular exercise on cognitive function in coronary artery disease (CAD) patients with prior mild cognitive decline. Methods We recruited 43 consecutive CAD patients with mild cognitive decline. These patients were treated with a statin and weekly in-hospital aerobic exercise for 5 months. We measured serum lipids, exercise capacity, and cognitive function using the mini mental state examination (MMSE). Results Low-density lipoprotein cholesterol levels were significantly decreased, and maximum exercise capacity (workload) was significantly increased in patients with CAD and mild cognitive decline after treatment compared with before. Combined statin-exercise therapy significantly increased the median (range) MMSE score from 24 (22-25) to 25 (23-27) across the cohort (p<0.01). Changes in body mass index (BMI) were significantly and negatively correlated with changes in the MMSE. After treatment, MMSE scores in the subgroup of patients that showed a decrease in BMI were significantly improved, but not in the BMI-increased subgroup. Furthermore, the patients already on a statin at the beginning of the trial displayed a more significant improvement in MMSE score than statin-naïve patients, implying that exercise might be the beneficial aspect of this intervention as regards cognition. In a multivariate logistic regression analysis adjusted for age >65 years, sex, and presence of diabetes mellitus, a decrease in BMI during statin-exercise therapy was significantly correlated with an increase in the MMSE score (odds ratio: 4.57, 95% confidence interval: 1.05-20.0; p<0.05). Conclusion Statin-exercise therapy may help improve cognitive dysfunction in patients with CAD and pre-existing mild cognitive

Overcoming 'ageism' bias in the treatment of hypercholesterolaemia : a review of safety issues with statins in the elderly.

PubMed

Jacobson, Terry A

2006-01-01

Atherosclerosis is a progressive, lifelong condition that is the leading cause of death among middle-aged and elderly individuals aged > or =65 years. Up to 80% of elderly patients are found to have evidence of obstructive coronary heart disease at autopsy. Demographic trends, including the advancing median age and life expectancy of Western societies, suggest that a large share of the burden of atherosclerotic plaque is likely to be borne by elderly individuals. These trends are in part due to increases in a number of chronic diseases associated with adverse cardiovascular outcomes, including metabolic syndrome, diabetes mellitus and chronic kidney disease. Because the elderly have a higher attributable risk of coronary heart disease as a result of hypercholesterolaemia, more coronary deaths and overall events can be prevented via treatment in this age group compared with younger persons with hypercholesterolaemia. The efficacy, safety and tolerability of HMG-CoA reductase inhibitors (statins) have been confirmed in randomised, controlled, multicentre trials involving large numbers of patients aged > or =65 years. Although muscle symptoms such as myalgia are relatively common adverse events, more severe signs of myolysis such as myopathy and rhabdomyolysis are rare, but their risk is elevated by conditions (e.g. concomitant medications) that increase the systemic exposure of these agents. Statins differ in their susceptibility to increases in systemic exposure, but most statins have been demonstrated to be well tolerated and safe when administered to elderly patients. These favourable clinical findings should help clinicians counter highly prevalent 'ageism' bias in statin prescribing, whereby elderly patients, particularly those at highest cardiovascular risk, are often denied the benefits of statins without any meaningful foundation.

Proprotein convertase subtilisin/kexin 9 inhibitors: an emerging lipid-lowering therapy?

PubMed

Dragan, Simona; Serban, Maria-Corina; Banach, Maciej

2015-03-01

Proprotein convertase subtilisin/kexin 9 (PCSK9) is part of the proteinase K subfamily of subtilases and plays a key role in lipid metabolism. It increases degradation of the low-density lipoprotein receptor (LDL-R), modulates cholesterol metabolism and transport, and contributes to the production of apolipoprotein B (apoB) in intestinal cells. Exogenous PCSK9 modifies the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase and enhances secretion of chylomicrons by modulating production of lipids and apoB-48. Statins increase PCSK9 messenger RNA expression and attenuate the capacity to increase LDL-R levels. Therefore, the inhibition of PCSK9 in combination with statins provides a promising approach for lowering low-density lipoprotein cholesterol (LDL-C) concentrations. This review will address new therapeutic strategies targeting PCSK9, including monoclonal antibodies, antisense oligonucleotides, small interfering RNAs, and other small molecule inhibitors. Further studies are still needed to determine the efficacy and safety of the PCSK9 inhibitors not only to decrease LDL-C but also to investigate the potential underlying mechanisms involved and to test whether these compounds actually reduce cardiovascular end points and mortality. © The Author(s) 2014.

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.

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.

[The effects of combination therapy with 5-reductase inhibitor and -blocker on the prognosis of BPH].

PubMed

Neimark, A I; Davydov, A V; Aliev, R T

2018-05-01

Benign prostatic hyperplasia (BPH) is a polyethological disease of elderly and old men. The symptomatic pharmacological treatment of BPH involves the use of drugs that reduce either the dynamic component of obstruction or the size of the prostate (a mechanical component of obstruction). 5-reductase inhibitors (5-ARI) and -blockers are considered first-line therapy in the management of prostate adenoma. To investigate the efficacy of combination therapy with Fokusin and Penester in BPH patients. The study is based on the analysis of medical records of 67 BPH patients aged over 50 years. All patients included in the study were randomized to 3 groups and had comparable age, sex, clinical manifestations and severity of the disease. Group 1 comprised 21 patients (mean age 63.8+/-9.7 years), who received a 5-reductase inhibitor (5-ARI) Pentester (Sanofi, France) 5 mg once daily. Group 2 included 22 patients (mean age 65.2+/-7.8 years), who received an -blocker Fokusin (Sanofi, France) 0.4 mg once a day. Group 3 comprised 24 patients (mean age 64.2+/-8.6 years) who received combination therapy with 5-reductase inhibitor (5-ARI) (Penester 5 mg once daily) and blocker (Fokusin 0.4 mg once daily). The study findings showed that in comparison with monotherapy, the concurrent administration of Fokusin and Penester was more effective in reducing the clinical manifestations of BPH, slowing the growth of adenomatous tissue thus reducing the size of the enlarged prostate. Combination therapy with Fokusin and Penester can be recommended to improve the treatment results of BPH patients.

Autoantibodies against 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase (HMGCR) in Patients with Statin-Associated Autoimmune Myopathy

PubMed Central

Mammen, Andrew L.; Chung, Tae; Christopher-Stine, Lisa; Rosen, Paul; Rosen, Antony; Casciola-Rosen, Livia A.

2010-01-01

Objective In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing (IMNM) myopathy with autoantibodies recognizing ~ 200 and ~100 kDa autoantigens. Identifying these molecules will clarify disease mechanism and facilitate diagnosis. Methods The effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using patient sera. The identity of the ~100 kDa autoantigen was confirmed by immunoprecipitating in vitro-translated HMGCR protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by ELISA and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy. Results Statin exposure induced expression of the ~200/~100 kDa autoantigens in cultured cells. HMGCR was identified as the ~100 kDa autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the ~200 kDa protein. In muscle biopsies from anti-HMGCR positive patients, HMGCR expression was up-regulated in cells expressing NCAM, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients age 50 or older, 92% were exposed to statins. The prevalence of the rs4149056 C allele was not increased in anti-HMGCR subjects. Conclusion Statins up-regulate expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy. PMID:21360500

The association of statin therapy with the primary patency of femoral and popliteal artery stents.

PubMed

de Grijs, Derek; Teixeira, Pedro; Katz, Steven

2018-05-01

It has long been known that hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) broadly reduce cardiovascular events in patients with peripheral vascular disease. It was the goal of this study to determine whether there is an association between statin therapy and primary patency after stenting of superficial femoral and popliteal arteries. The records of all patients undergoing primary nitinol stenting of the femoral and popliteal arteries at a single institution and by a single surgeon during a 10-year period were reviewed. Demographic characteristics of the patients and risk factors were identified. TransAtlantic Inter-Society Consensus (TASC II) classifications were determined for all stented lesions. Analysis was performed to determine whether the use of statins at the time of stent placement was associated with a change in rates of primary patency. Loss of primary patency was said to have occurred when an intrastent occlusion or a ≥70% stenosis was identified by arterial duplex ultrasound or angiography. Kaplan-Meier survival curves were plotted, and differences between groups were tested by log-rank method. Between 2004 and 2014, primary femoral or popliteal stenting was performed on 308 limbs in 250 patients. At the time of intervention, 52.4% of these patients were being treated with statin therapy; 137 interventions were done for claudication and 113 for critical limb ischemia. Of the lesions treated, 165 were TASC A or B and 85 were TASC C or D. Primary patency rates for all stented lesions were 75%, 54%, and 35% at 12, 24, and 36 months. The patency rates at 12, 24, and 36 months, respectively, were 80%, 55%, and 40% for those taking statins and 68%, 49%, and 28% for those not taking statins (P = .178). Statin therapy demonstrated a trend toward an association with improved primary patency rates in TASC A/B lesions but had no association in TASC C/D lesions (TASC A/B, P = .056; TASC C/D, P = .537). Statin compliance was found to be

A novel therapeutic effect of statins on nephrogenic diabetes insipidus

PubMed Central

Bonfrate, Leonilde; Procino, Giuseppe; Wang, David Q-H; Svelto, Maria; Portincasa, Piero

2015-01-01

Statins competitively inhibit hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase, resulting in reduced plasma total and low-density lipoprotein cholesterol levels. Recently, it has been shown that statins exert additional ‘pleiotropic’ effects by increasing expression levels of the membrane water channels aquaporin 2 (AQP2). AQP2 is localized mainly in the kidney and plays a critical role in determining cellular water content. This additional effect is independent of cholesterol homoeostasis, and depends on depletion of mevalonate-derived intermediates of sterol synthetic pathways, i.e. farnesylpyrophosphate and geranylgeranylpyrophosphate. By up-regulating the expression levels of AQP2, statins increase water reabsorption by the kidney, thus opening up a new avenue in treating patients with nephrogenic diabetes insipidus (NDI), a hereditary disease that yet lacks high-powered and limited side effects therapy. Aspects related to water balance determined by AQP2 in the kidney, as well as standard and novel therapeutic strategies of NDI are discussed. PMID:25594563

[Incremental effect and mechanism of cyclosporine on blood concentration of statins and statin package insert information in Japan].

PubMed

Hirata-Koizumi, Mutsuko; Saito, Mitsuo; Miyake, Shinji; Hasegawa, Ryuichi

2005-01-01

Cyclosporine is an indispensable immunosuppressant used in organ transplant patients, who frequently manifest hyperlipidemia. Statins, which are cholesterol-lowering agents, are often combined with cyclosporine in the treatment of hyperlipidemia of organ transplant patients. Since cyclosporine is a substrate and inhibitor of CYP3A4, researchers suspect that the immunosuppressant inhibits CYP3A4-mediated metabolism of statins, leading to an increase in statin plasma concentration and infrequently resulting in rhabdomyolysis. However, a number of clinical trials have shown cyclosporine to increase the plasma concentration of all developed statins, including those not metabolized by CYP3A4. Furthemore, recent mechanistic studies have shown organic anion transporting peptides (OATP) C to mediate the uptake of some statins and cyclosporine has been shown to inhibit the uptake via OATP-C in cultured cells. Therefore, the inhibition of hepatic uptake of statins is considered to be one of the mechanisms by which cyclosporine incrementally increases statin blood concentration. However, most current Japanese package inserts of statins give no information on change in pharmacokinetic parameters such as AUC and Cmax in the combined medication with cyclosporine. Furthermore, in the Japanese package inserts, it is either stated that cyclosporine inhibits CYP3A4-mediated metabolism or no comment is made on the mechanism. The package insert should properly provide available quantitative information on the change of pharmacokinetic parameters and the probable mechanism of action.

Use of Statins to Augment Progenitor Cell Function in Preclinical and Clinical Studies of Regenerative Therapy: a Systematic Review.

PubMed

Park, Angela; Barrera-Ramirez, Juliana; Ranasinghe, Indee; Pilon, Sophie; Sy, Richmond; Fergusson, Dean; Allan, David S

2016-06-01

Mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) are used in cell-based regenerative therapy. HMG CoA reductase inhibitors (statins) appear promising in blocking apoptosis, prolonging progenitor cell survival and improving their capacity to repair organ function. We performed a systematic review of preclinical and clinical studies to clarify whether statins can improve cell-based repair of organ injury. MEDLINE, EMBASE, and PUBMED databases were searched (1947 to June 25, 2013). Controlled clinical and pre-clinical studies were included that evaluated statin therapy used alone or in combination with MSCs or EPCs in patients or animals with organ injury. After screening 771 citations, 100 records underwent full eligibility screening of which 38 studies met eligibility and were included in the review: Studies were grouped into pre-clinical studies that involved statin treatment in combination with cell therapy (18 studies), preclinical studies of statin therapy alone (13 studies) and clinical studies of statin therapy (7 studies). Studies addressed cardiac injury (14 studies), vascular disorders (15 studies), neurologic conditions (8 studies) and bone fractures (1 study). Pre-clinical studies of statins in combination with MSC infusion (15 studies) or EPC therapy (3 studies) were described and despite marked heterogeneity in reporting outcomes of cellular analysis and organ function, all of these cell-based pre-clinical studies reported improved organ recovery with the addition of statin therapy. Moreover, 13 pre-clinical studies involved the administration of a statin drug alone to animals. An increase in EPC number and/or function (no studies of MSCs) was reported in 11 of these studies (85 %) and improved organ function in 12 studies (92 %). We also identified 7 clinical studies and none involved the administration of cells but described an increased number and/or function of EPCs (no studies of MSCs) and improved organ function with

Statins and protein prenylation in cancer cell biology and therapy.

PubMed

Garcia-Ruiz, Carmen; Morales, Albert; Fernandez-Checa, Jose C

2012-05-01

The use of statins has scaled up to become one of the most prescribed medicines in the world and have been very useful in the manegement of cardiovascular diseases and related mortality. The disclosure of their chemical structure similar to that of hydroxy methyl glutaryl-CoA (HMG-CoA) revealed their ability to compete with and inhibit the rate-limiting enzyme HMG-CoA reductase that catalyzes the synthesis of mevalonate, which then serves as the precursor for isoprenoids and cholesterol in the mevalonate pathway. While most of the effects of statins are associated with the lowering of cellular cholesterol levels, it is clear that they also blunt the non-sterol branch of the mevalonate pathway, decreasing formation of isoprenoids and altering protein-prenylation, a critical event in the posttranslational modulation of proteins involved in the regulation of cell cycle progression, proliferation and signaling pathways. Randomized controlled trials for the prevention of cardiovascular diseases indicated that statins elicited provocative and unexpected benefits for reducing a number of different types of cancers, including colorectal carcinoma, melanoma, prostate and hepatocellular carcinoma, although in other cancer types the preclinical expectations of statins were dissapointing. In this review, we will describe the evidence and mechanisms underlying the potential beneficial use of statins and the role of protein prenylation in cancer prevention. Of relevance, the combination of statins with other anti cancer drugs may be a significant asset in malignancies resistant to current therapy.

Cyclohex-1-ene carboxylic acids: synthesis and biological evaluation of novel inhibitors of human 5 alpha reductase.

PubMed

Baston, Eckhard; Salem, Ola I A; Hartmann, Rolf W

2003-03-01

In search of novel nonsteroidal mimics of steroidal inhibitors of 5 alpha reductase, 4-(2-phenylethyl)cyclohex-1-ene carboxylic acids 1-5 were synthesized with different substituents in para position of the phenyl ring (1: N, N-diisopropylcarbamoyl, 2: phenyl, 3: phenoxy, 4: benzoyl, and 5: benzyl). The principal synthetic approach for the desired compounds consisted of a Wittig olefination between 1, 4-dioxaspiro [4.5]-decane-8-carbaldehyde (4g and the appropriate phosphonium salts. The compounds were tested for inhibition of human 5 alpha reductase isozymes 1 and 2 using DU 145 cells and preparations from prostatic tissue, respectively. They turned out to be good inhibitors of the prostatic isozyme 2 with compound 1 being the most potent one (IC(50) = 760 nM). Isozyme 1 was only slightly inhibited. It is concluded that the novel structures are appropriate for being further optimized, aiming at the development of a novel drug for the treatment of benign prostatic hyperplasia.

A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor

PubMed Central

Kerr, Alastair G.; Tam, Lawrence C. S.; Hale, Ashley B.; Cioroch, Milena; Douglas, Gillian; Agkatsev, Sarina; Hibbitt, Olivia; Mason, Joseph; Holt-Martyn, James; Bataille, Carole J. R.; Wynne, Graham M.; Channon, Keith M.; Russell, Angela J.

2017-01-01

Hypercholesterolemia remains one of the leading risk factors for the development of cardiovascular disease. Many large double-blind studies have demonstrated that lowering low-density lipoprotein (LDL) cholesterol using a statin can reduce the risk of having a cardiovascular event by approximately 30%. However, despite the success of statins, some patient populations are unable to lower their LDL cholesterol to meet the targeted lipid levels, due to compliance or potency issues. This is especially true for patients with heterozygous familial hypercholesterolemia who may require additional upregulation of the low-density lipoprotein receptor (LDLR) to reduce LDL cholesterol levels below those achievable with maximal dosing of statins. Here we identify a series of small molecules from a genomic DNA reporter screen that upregulate the LDLR in mouse and human liver cell lines at nanomolar potencies (EC50 = 39 nM). Structure-activity relationship studies carried out on the lead compound, OX03771 [(E)-N,N-dimethyl-3-(4-styrylphenoxy)propan-1-amine], led to the identification of compound OX03050 [(E)-3-(4-styrylphenoxy)propan-1-ol], which had similar potency (EC50 = 26 nM) but a much-improved pharmacokinetic profile and showed in vivo efficacy. Compounds OX03050 and OX03771 were found to inhibit squalene synthase, the first committed step in cholesterol biosynthesis. These squalene synthase inhibitors were shown to act cooperatively with statins to increase LDLR expression in vitro. Overall, we demonstrated here a novel series of small molecules with the potential to be further developed to treat patients either alone or in combination with statins. PMID:28360334

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

Effects of statins on bone mineral density: a meta-analysis of clinical studies.

PubMed

Uzzan, Bernard; Cohen, Régis; Nicolas, Patrick; Cucherat, Michel; Perret, Gérard-Yves

2007-06-01

Statins inhibit HMG-CoA reductase, preventing synthesis of mevalonate but also of isoprenoids, which affect osteoclast activity. Amino-bisphosphonates share this effect. In vitro and in vivo, statins show convincing anabolic and anti-resorptive bone effects. However, in a clinical meta-analysis (MA), they did not prevent hip fractures. Our meta-analysis studied the impact of statins on bone mineral density (BMD) at various sites and compared the effects of lipophilic and more hydrophilic statins. Our PubMed and Embase queries using two keywords (statins, BMD) were updated to October 2006. Two readers independently collected BMDs from studies. Twenty-one studies, mostly observational (three randomized controlled trials and one pseudo-randomized study), were assessed. Two studies were excluded (no control groups). Three studies could not be analyzed. The sixteen studies analyzed mainly included postmenopausal osteopenic women (2971 patients under statins). Statins significantly increased BMD at total hip (TH) and femoral neck (FN). Effect sizes (ESs) were modest: 0.21 at TH (95% confidence interval [CI]: 0.16-0.25) and 0.20 at FN (CI: 0.08-0.28). Among women, statins acted similarly (ES: 0.20 for TH and 0.18 for FN; CI: 0.14-0.25 and 0.06-0.31 respectively); lipophilic statins (simvastatin, lovastatin) almost entirely caused this effect, at both TH (ES: 0.20; CI: 0.15-0.26) and FN (ES: 0.22; CI: 0.06-0.37). Our findings of modest but statistically significant beneficial effects of statins on hip BMD should promote large double-blind randomized controlled trials on their bone effects, in view of their major beneficial cardiovascular effects with excellent safety profile.

Statins, inflammation and deep vein thrombosis: a systematic review

PubMed Central

Rodriguez, April L.; Wojcik, Brandon M.; Wrobleski, Shirley K.; Myers, Daniel D.; Wakefield, Thomas W.

2012-01-01

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism. The 2009 JUPITER trial showed a significant decrease in DVT in non-hyperlipidemic patients, with elevated C-reactive protein (CRP) levels, treated with rosuvastatin. The effects of statins on thrombosis are unclear, prompting this literature review. A literature search was performed (1950 to February 2011) with MEDLINE, EMBASE, and PUBMED databases including the following keywords: “statins”, “hydroxymethylglutaryl-CoA reductase inhibitors”, “VTE”, “PE”, “DVT”, and either “anti-coagulation” or “inflammation”. Editorials, reviews, case reports, meta-analysis and duplicates were excluded. Inflammatory biomarkers of DVT, include interleukin (IL)-6, CRP, IL-8, and monocyte chemotactic protein 1 (MCP-1). Statin therapy reduces IL-6 expression of CRP and MCP-1, usually elevated in VTE. Reduction of IL-6 induced MCP-1 has been linked to vein wall fibrosis, promoting post thrombotic syndrome (PTS) and recurrent DVT in patients. Also, our review suggests that the anti-thrombotic effects are likely exhibited through the anti-inflammatory properties of statins. This work supports that statin therapy has the ability to decrease the incidence and recurrence of VTE and the potential to decrease PTS. This is mainly due to the anti-inflammatory effects of statins and may explain why normolipidemic patients, with elevated CRP, appear to have the greatest reduction in VTE. Given their low risk of bleeding, statins have the potential to serve as a safe adjunctive pharmacological therapy to current treatments in select patients with VTE, however further investigations into this concept are needed and essential. PMID:22278047

Statins Inhibit Monocyte Chemotactic Protein 1 Expression in Endometriosis

PubMed Central

Cakmak, Hakan; Basar, Murat; Seval-Celik, Yasemin; Osteen, Kevin G.; Duleba, Antoni J.; Taylor, Hugh S.; Lockwood, Charles J.; Arici, Aydin

2012-01-01

Statins are potent inhibitors of the endogenous mevalonate pathway. Besides inhibiting cholesterol biosynthesis, statins may also demonstrate anti-inflammatory properties. Inflammation is implicated in the attachment and invasion of endometrial cells to the peritoneal surface and growth of ectopic endometrium by inducing proliferation and angiogenesis. In this study, the effect of statins on monocyte chemotactic protein 1 (MCP-1) expression in endometriotic implants in nude mouse model and in cultured endometriotic cells was evaluated. In mouse model, simvastatin decreased MCP-1 expression in a dose-dependent manner in endometriotic implants (P < .05). Similarly, both simvastatin and mevastatin revealed a dose-dependent inhibition of MCP-1 production in cultured endometriotic cells (P < .01). This inhibitory effect of the statins on MCP-1 production was reversed by the downstream substrates of the mevalonate pathway. Moreover, statins decreased MCP-1 messenger RNA expression in cultured endometriotic cells (P < .05). In conclusion, statins exert anti-inflammatory effect in endometriotic cells and could provide a potential treatment of endometriosis in the future. PMID:22267540

Long-term benefit of statin therapy initiated during hospitalization for an acute coronary syndrome: a systematic review of randomized trials.

PubMed

Bavry, Anthony A; Mood, Girish R; Kumbhani, Dharam J; Borek, Peter P; Askari, Arman T; Bhatt, Deepak L

2007-01-01

This study sought to determine if the initiation of statin (HMG-CoA reductase inhibitor) therapy during acute coronary syndromes reduces long-term mortality and other adverse cardiac outcomes. Initiation of statin therapy during acute coronary syndromes has not been shown to reduce mortality, myocardial infarction or stroke within 4 months of follow-up. Clinical trials that randomized patients with acute coronary syndromes to early statin therapy compared with less intensive lipid reduction (placebo/lower-dose statin/usual care), and reported long-term outcomes were included for analysis. In all, there were seven studies (L-CAD, PTT, FLORIDA, Colivicchi et al., PROVE-IT, ESTABLISH, and A-to-Z) with 9553 patients who started statin therapy within 12 days of hospital presentation. The incidence of all-cause mortality was 3.4% in the statin group versus 4.6% in the less intensive lipid reduction group over a weighted mean follow-up of 22.9 months (relative risk [RR] 0.74; 95% CI 0.61, 0.90; p = 0.003). The number of patients needed to treat to prevent one death was 84 patients. Similarly, the incidence of cardiovascular mortality in the statin versus the less intensive lipid reduction group was 2.4% versus 3.3% (RR 0.74; 95% CI 0.58, 0.93; p = 0.010), unstable angina 4.1% versus 5.0% (RR 0.81; 95% CI 0.68, 0.98; p = 0.027), revascularization 11.2% versus 12.9% (RR 0.86; 95% CI 0.78, 0.96; p = 0.006), stroke 1.1% versus 1.2% (RR 0.90; 95% CI 0.62, 1.30; p = 0.56), and myocardial infarction 6.6% versus 7.0% (RR 0.94; 95% CI 0.81, 1.09; p = 0.41). The benefit of early initiation of statin therapy during acute coronary syndromes slowly accrues over time so that a survival advantage is seen around 24 months. Relatively few patients need to be treated to prevent one death over this time period. Furthermore, this approach significantly reduces unstable angina and the need for revascularization.

Loss of HMG-CoA reductase in C. elegans causes defects in protein prenylation and muscle mitochondria.

PubMed

Ranji, Parmida; Rauthan, Manish; Pitot, Christophe; Pilon, Marc

2014-01-01

HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway and the target of cholesterol-lowering statins. We characterized the C. elegans hmgr-1(tm4368) mutant, which lacks HMG-CoA reductase, and show that its phenotypes recapitulate that of statin treatment, though in a more severe form. Specifically, the hmgr-1(tm4368) mutant has defects in growth, reproduction and protein prenylation, is rescued by exogenous mevalonate, exhibits constitutive activation of the UPRer and requires less mevalonate to be healthy when the UPRmt is activated by a constitutively active form of ATFS-1. We also show that different amounts of mevalonate are required for different physiological processes, with reproduction requiring the highest levels. Finally, we provide evidence that the mevalonate pathway is required for the activation of the UPRmt.

Natural products with hypoglycemic, hypotensive, hypocholesterolemic, antiatherosclerotic and antithrombotic activities.

PubMed

Wang, H X; Ng, T B

1999-01-01

This article reviews compounds of botanical origin which are capable of lowering plasma levels of glucose and cholesterol and blood pressure, as well as compounds inhibiting atherosclerosis and thrombosis. Hypoglycemic natural products comprise flavonoids, xanthones, triterpenoids, alkaloids, glycosides, alkyldisulfides, aminobutyric acid derivatives, guanidine, polysaccharides and peptides. Hypotensive compounds include flavonoids, diterpenes, alkaloids, glycosides, polysaccharides and proteins. Among natural products with hypocholesterolemic activity are beta-carotene, lycopene, cycloartenol, beta-sitosterol, sitostanol, saponin, soybean protein, indoles, dietary fiber, propionate, mevinolin (beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor) and polysaccharides. Heparins, flavonoids, tocotrienols, beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors (statins), garlic compounds and fungal proteases exert antithrombotic action. Statins and garlic compounds also possess antiatherosclerotic activity.

An electronic health record based model predicts statin adherence, LDL cholesterol, and cardiovascular disease in the United States Military Health System

PubMed Central

Lucas, Joseph E.; Bazemore, Taylor C.; Alo, Celan; Monahan, Patrick B.

2017-01-01

HMG-CoA reductase inhibitors (or “statins”) are important and commonly used medications to lower cholesterol and prevent cardiovascular disease. Nearly half of patients stop taking statin medications one year after they are prescribed leading to higher cholesterol, increased cardiovascular risk, and costs due to excess hospitalizations. Identifying which patients are at highest risk for not adhering to long-term statin therapy is an important step towards individualizing interventions to improve adherence. Electronic health records (EHR) are an increasingly common source of data that are challenging to analyze but have potential for generating more accurate predictions of disease risk. The aim of this study was to build an EHR based model for statin adherence and link this model to biologic and clinical outcomes in patients receiving statin therapy. We gathered EHR data from the Military Health System which maintains administrative data for active duty, retirees, and dependents of the United States armed forces military that receive health care benefits. Data were gathered from patients prescribed their first statin prescription in 2005 and 2006. Baseline billing, laboratory, and pharmacy claims data were collected from the two years leading up to the first statin prescription and summarized using non-negative matrix factorization. Follow up statin prescription refill data was used to define the adherence outcome (> 80 percent days covered). The subsequent factors to emerge from this model were then used to build cross-validated, predictive models of 1) overall disease risk using coalescent regression and 2) statin adherence (using random forest regression). The predicted statin adherence for each patient was subsequently used to correlate with cholesterol lowering and hospitalizations for cardiovascular disease during the 5 year follow up period using Cox regression. The analytical dataset included 138 731 individuals and 1840 potential baseline predictors

STATINS MORE THAN CHOLESTEROL LOWERING AGENTS IN ALZHEIMER DISEASE: THEIR PLEIOTROPIC FUNCTIONS AS POTENTIAL THERAPEUTIC TARGETS

PubMed Central

Barone, Eugenio; Domenico, Fabio Di; Butterfield, D. Allan

2013-01-01

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including AD. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. The aim of this review is to provide an overview on the new discoveries about the effects of statin therapy on the oxidative ad nitrosative stress levels as well as on the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system in the brain. We propose a novel mechanism of action for atorvastatin which, through the activation of HO/BVR-A system, may contribute to the neuroprotective effects thus suggesting a potential therapeutic role in AD and potentially accounting for the observation of decreased AD incidence with persons on statin. PMID:24231510

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.

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.

Loss of HMG-CoA Reductase in C. elegans Causes Defects in Protein Prenylation and Muscle Mitochondria

PubMed Central

Ranji, Parmida; Rauthan, Manish; Pitot, Christophe; Pilon, Marc

2014-01-01

HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway and the target of cholesterol-lowering statins. We characterized the C. elegans hmgr-1(tm4368) mutant, which lacks HMG-CoA reductase, and show that its phenotypes recapitulate that of statin treatment, though in a more severe form. Specifically, the hmgr-1(tm4368) mutant has defects in growth, reproduction and protein prenylation, is rescued by exogenous mevalonate, exhibits constitutive activation of the UPRer and requires less mevalonate to be healthy when the UPRmt is activated by a constitutively active form of ATFS-1. We also show that different amounts of mevalonate are required for different physiological processes, with reproduction requiring the highest levels. Finally, we provide evidence that the mevalonate pathway is required for the activation of the UPRmt. PMID:24918786

Structure-activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase

PubMed Central

Bourne, Christina R.; Wakeham, Nancy; Nammalwar, Baskar; Tseitin, Vladimir; Bourne, Philip C.; Barrow, Esther W.; Mylvaganam, Shankari; Ramnarayan, Kal; Bunce, Richard A.; Berlin, K. Darrell; Barrow, William W.

2012-01-01

Background Bacterial resistance to antibiotic therapies is increasing and new treatment options are badly needed. There is an overlap between these resistant bacteria and organisms classified as likely bioterror weapons. For example, Bacillus anthracis is innately resistant to the anti-folate trimethoprim due to sequence changes found in the dihydrofolate reductase enzyme. Development of new inhibitors provides an opportunity to enhance the current arsenal of anti-folate antibiotics while also expanding the coverage of the anti-folate class. Methods We have characterized inhibitors of Bacillus anthracis dihydrofolate reductase by measuring the Ki and MIC values and calculating the energetics of binding. This series contains a core diaminopyrimidine ring, a central dimethoxybenzyl ring, and a dihydrophthalazine moiety. We have altered the chemical groups extended from a chiral center on the dihydropyridazine ring of the phthalazine moiety. The interactions for the most potent compounds were visualized by X-ray structure determination. Results We find that the potency of individual enantiomers is divergent with clear preference for the S-enantiomer, while maintaining a high conservation of contacts within the binding site. The preference for enantiomers seems to be predicated largely by differential interactions with protein residues Leu29, Gln30 and Arg53. Conclusions These studies have clarified the activity of modifications and of individual enantiomers, and highlighted the role of the less-active R-enantiomer in effectively diluting the more active S-enantiomer in racemic solutions. This directly contributes to the development of new antimicrobials, combating trimethoprim resistance, and treatment options for potential bioterrorism agents. PMID:22999981

Fragment Discovery for the Design of Nitrogen Heterocycles as Mycobacterium tuberculosis Dihydrofolate Reductase Inhibitors.

PubMed

Shelke, Rupesh U; Degani, Mariam S; Raju, Archana; Ray, Mukti Kanta; Rajan, Mysore G R

2016-08-01

Fragment-based drug design was used to identify Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitors. Screening of ligands against the Mtb DHFR enzyme resulted in the identification of multiple fragment hits with IC50 values in the range of 38-90 μM versus Mtb DHFR and minimum inhibitory concentration (MIC) values in the range of 31.5-125 μg/mL. These fragment scaffolds would be useful for anti-tubercular drug design. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The stats are in: an update on statin use in COPD.

PubMed

Carlson, Alexa A; Smith, Ethan A; Reid, Debra J

2015-01-01

COPD is a chronic inflammatory disease of the lungs associated with an abnormal inflammatory response to noxious particles, the most prevalent of which is cigarette smoke. Studies have demonstrated that cigarette smoking is associated with activation of the bone marrow, and chronic smoking can lead to the inflammatory changes seen in COPD. Due to the inflammatory nature of the disease, medications affecting the inflammatory pathway may have clinical benefit and are being evaluated. One such class of medications, HMG-CoA reductase inhibitors, have been evaluated in the COPD population. Early studies have suggested that HMG-CoA reductase inhibitors have a variety of benefits in COPD including improvements in inflammatory markers, exacerbation rates, and mortality rates. However, the majority of this data comes from retrospective cohort studies, suggesting the need for randomized controlled trials. Recently, two randomized controlled trials, STATCOPE and RODEO, evaluated the benefit of HMG-CoA reductase inhibitors in the COPD population and found no benefit in exacerbation rates and vascular or pulmonary function, respectively. These results are reflected in practice guidelines, which do not support the use of HMG-CoA reductase inhibitors for the purpose of reducing COPD exacerbations.

Quantitative evaluation of glandular and stromal compartments in hyperplastic dog prostates: effect of 5-alpha reductase inhibitors.

PubMed

Laroque, P A; Prahalada, S; Molon-Noblot, S; Cohen, S M; Soper, K; Duprat, P; Peter, C P; van Zwieten, M J

1995-09-01

The objective of this study was to determine the effects of 2 different 5-alpha reductase inhibitors (finasteride and MK-0434) on the glandular and stromal compartments of hyperplastic canine prostates. In this study, dogs received 1 of the 2 compounds orally, at a dose of 1 mg/kg/day for 16 weeks; control dogs received a placebo. The morphological changes in the glandular and stromal compartments in the prostate were quantitated by a point-counting method on Masson's trichrome-stained sections. Treatment with 5-alpha reductase inhibitors resulted in significant (P < or = 0.05) decreases in mean prostatic volumes, microscopic evidence of prostatic atrophy, and significant (P < or = 0.05) decreases in the absolute volumes of the prostatic glandular and stromal compartments compared to controls. In finasteride-treated dogs, the mean percent change from baseline was: epithelium, -52; lumens, -58; fibrovascular stroma, -41; and smooth muscle, -29. In MK-0434-treated dogs, the mean percent change from baseline was: epithelium, -77; lumens, -58; fibrovascular stroma, -38; and smooth muscle, -42. The effect on the glandular compartment in dogs treated with MK-0434 was slightly greater than in dogs treated with finasteride; however, the effect on the stroma was similar. These results clearly demonstrate that inhibition of 5-alpha reductase enzyme activity affects growth and maintenance of both glandular and stromal compartments of dog hyperplastic prostates. It is likely that the decrease in size of the prostate in finasteride-treated (Proscar) men is due to shrinkage of both glandular and stromal compartments.

Brevetoxin-2, is a unique inhibitor of the C-terminal redox center of mammalian thioredoxin reductase-1.

PubMed

Chen, Wei; Tuladhar, Anupama; Rolle, Shantelle; Lai, Yanhao; Rodriguez Del Rey, Freddy; Zavala, Cristian E; Liu, Yuan; Rein, Kathleen S

2017-08-15

Karenia brevis, the Florida red tide dinoflagellate produces a suite of neurotoxins known as the brevetoxins. The most abundant of the brevetoxins PbTx-2, was found to inhibit the thioredoxin-thioredoxin reductase system, whereas the PbTx-3 has no effect on this system. On the other hand, PbTx-2 activates the reduction of small disulfides such as 5,5'-dithio-bis-(2-nitrobenzoic acid) by thioredoxin reductase. PbTx-2 has an α, β-unsaturated aldehyde moiety which functions as an efficient electrophile and selenocysteine conjugates are readily formed. PbTx-2 blocks the inhibition of TrxR by the inhibitor curcumin, whereas curcumin blocks PbTx-2 activation of TrxR. It is proposed that the mechanism of inhibition of thioredoxin reduction is via the formation of a Michael adduct between selenocysteine and the α, β-unsaturated aldehyde moiety of PbTx-2. PbTx-2 had no effect on the rates of reactions catalyzed by related enzymes such as glutathione reductase, glutathione peroxidase or glutaredoxin. Copyright © 2017 Elsevier Inc. All rights reserved.

Structure-Based Approach to the Development of Potent and Selective Inhibitors of Dihydrofolate Reductase from Cryptosporidium

PubMed Central

Bolstad, David B.; Bolstad, Erin S. D.; Frey, Kathleen M.; Wright, Dennis L.; Anderson, Amy C.

2008-01-01

Cryptosporidiosis is an emerging infectious disease that can be life-threatening in an immune-compromised individual and causes gastrointestinal distress lasting up to 2 weeks in an immune-competent individual. There are few therapeutics available for effectively treating this disease. We have been exploring dihydrofolate reductase (DHFR) as a potential target in Cryptosporidium. On the basis of the structure of the DHFR enzyme from C. hominis, we have developed a novel scaffold that led to the discovery of potent (38 nM) and efficient inhibitors of this enzyme. Recently, we have advanced these inhibitors to the next stage of development. Using the structures of both the protozoal and human enzymes, we have developed inhibitors with nanomolar potency (1.1 nM) against the pathogenic enzyme and high levels (1273-fold) of selectivity over the human enzyme. PMID:18834108

Subatomic and atomic crystallographic studies of aldose reductase: implications for inhibitor binding.

PubMed

Podjarny, A; Cachau, R E; Schneider, T; Van Zandt, M; Joachimiak, A

2004-04-01

The determination of several of aldose reductase-inhibitor complexes at subatomic resolution has revealed new structural details, including the specific interatomic contacts involved in inhibitor binding. In this article, we review the structures of the complexes of ALR2 with IDD 594 (resolution: 0.66 angstrom, IC50 (concentration of the inhibitor that produced half-maximal effect): 30 nM, space group: P2(1)), IDD 393 (resolution: 0.90 angstrom, IC50: 6 nM, space group: P1), fidarestat (resolution: 0.92 angstrom, IC50: 9 nM, space group: P2(1)) and minalrestat (resolution: 1.10 angstrom, IC50: 73 nM, space group: P1). The structures are compared and found to be highly reproductible within the same space group (root mean square (RMS) deviations: 0.15 approximately 0.3 angstrom). The mode of binding of the carboxylate inhibitors IDD 594 and IDD 393 is analysed. The binding of the carboxylate head can be accurately determined by the subatomic resolution structures, since both the protonation states and the positions of the atoms are very precisely known. The differences appear in the binding in the specificity pocket. The high-resolution structures explain the differences in IC50, which are confirmed both experimentally by mass spectrometry measures of VC50 and theoretically by free energy perturbation calculations. The binding of the cyclic imide inhibitors fidarestat and minalrestat is also described, focusing on the observation of a Cl(-) ion which binds simultaneously with fidarestat. The presence of this anion, binding also to the active site residue His110, leads to a mechanism in which the inhibitor can bind in a neutral state and then become charged inside the active site pocket. This mechanism can explain the excellent in vivo properties of cyclic imide inhibitors. In summary, the complete and detailed information supplied by the subatomic resolution structures can explain the differences in binding energy of the different inhibitors.

Probing the Active Site of Candida Glabrata Dihydrofolate Reductase with High Resolution Crystal Structures and the Synthesis of New Inhibitors

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

Liu, J.; Bolstad, D; Smith, A

2009-01-01

Candida glabrata, a fungal strain resistant to many commonly administered antifungal agents, has become an emerging threat to human health. In previous work, we validated that the essential enzyme, dihydrofolate reductase, is a drug target in C. glabrata. Using a crystal structure of dihydrofolate reductase from C. glabrata bound to an initial lead compound, we designed a class of biphenyl antifolates that potently and selectively inhibit both the enzyme and the growth of the fungal culture. In this work, we explore the structure-activity relationships of this class of antifolates with four new high resolution crystal structures of enzyme:inhibitor complexes andmore » the synthesis of four new inhibitors. The designed inhibitors are intended to probe key hydrophobic pockets visible in the crystal structure. The crystal structures and an evaluation of the new compounds reveal that methyl groups at the meta and para positions of the distal phenyl ring achieve the greatest number of interactions with the pathogenic enzyme and the greatest degree of selectivity over the human enzyme. Additionally, antifungal activity can be tuned with substitution patterns at the propargyl and para-phenyl positions.« less

Pleiotropic effects of statins: new therapeutic targets in drug design.

PubMed

Bedi, Onkar; Dhawan, Veena; Sharma, P L; Kumar, Puneet

2016-07-01

The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins.

Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement.

PubMed

Banach, Maciej; Stulc, Tomas; Dent, Ricardo; Toth, Peter P

2016-12-15

Although statin therapy has proven to be the cornerstone for prevention and treatment of cardiovascular disease (CVD), there are many patients for whom long-term therapy remains suboptimal. The aims of this article are to review the current complex issues associated with statin use and to explore when novel treatment approaches should be considered. Statin discontinuation as well as adherence to statin therapy remain two of the greatest challenges for lipidologists. Evidence suggests that between 40 and 75% of patients discontinue their statin therapy within one year after initiation. Furthermore, whilst the reasons for persistence with statin therapy are complex, evidence shows that low-adherence to statins negatively impacts clinical outcomes and residual CV risk remains a major concern. Non-adherence or lack of persistence with long-term statin therapy in real-life may be the main cause of inadequate low density lipoprotein cholesterol lowering with statins. There is a large need for the improvement of the use of statins, which have good safety profiles and are inexpensive. On the other hand, in a non-cost-constrained environment, proprotein convertase subtilisin/kexin type 9 inhibitors should arguably be used more often in those patients in whom treatment with statins remains unsatisfactory. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases

PubMed Central

Friesen, Jon A; Rodwell, Victor W

2004-01-01

The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the conversion of HMG-CoA to mevalonate, a four-electron oxidoreduction that is the rate-limiting step in the synthesis of cholesterol and other isoprenoids. The enzyme is found in eukaryotes and prokaryotes; and phylogenetic analysis has revealed two classes of HMG-CoA reductase, the Class I enzymes of eukaryotes and some archaea and the Class II enzymes of eubacteria and certain other archaea. Three-dimensional structures of the catalytic domain of HMG-CoA reductases from humans and from the bacterium Pseudomonas mevalonii, in conjunction with site-directed mutagenesis studies, have revealed details of the mechanism of catalysis. The reaction catalyzed by human HMG-CoA reductase is a target for anti-hypercholesterolemic drugs (statins), which are intended to lower cholesterol levels in serum. Eukaryotic forms of the enzyme are anchored to the endoplasmic reticulum, whereas the prokaryotic enzymes are soluble. Probably because of its critical role in cellular cholesterol homeostasis, mammalian HMG-CoA reductase is extensively regulated at the transcriptional, translational, and post-translational levels. PMID:15535874

Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor.

PubMed

Clark, Richard V; Hermann, David J; Cunningham, Glenn R; Wilson, Timothy H; Morrill, Betsy B; Hobbs, Stuart

2004-05-01

Dihydrotestosterone (DHT) is the primary metabolite of testosterone in the prostate and skin. Testosterone is converted to DHT by 5alpha-reductase, which exists in two isoenzyme forms (types 1 and 2). DHT is associated with development of benign prostatic hyperplasia (BPH), and reduction in its level with 5alpha-reductase inhibitors improves the symptoms associated with BPH and reduces the risk of acute urinary retention and prostate surgery. A selective inhibitor of the type 2 isoenzyme (finasteride) has been shown to decrease serum DHT by about 70%. We hypothesized that inhibition of both isoenzymes with the dual inhibitor dutasteride would more effectively suppress serum DHT levels than selective inhibition of only the type 2 isoenzyme. A total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 +/- 1.2% with 5.0 mg dutasteride and 94.7 +/- 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 +/- 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo.

Modeled structure of trypanothione reductase of Leishmania infantum.

PubMed

Singh, Bishal K; Sarkar, Nandini; Jagannadham, M V; Dubey, Vikash K

2008-06-30

Trypanothione reductase is an important target enzyme for structure-based drug design against Leishmania. We used homology modeling to construct a three-dimensional structure of the trypanothione reductase (TR) of Leishmania infantum. The structure shows acceptable Ramachandran statistics and a remarkably different active site from glutathione reductase(GR). Thus, a specific inhibitor against TR can be designed without interfering with host (human) GR activity.

Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy.

PubMed

Akdim, Fatima; Stroes, Erik S G; Sijbrands, Eric J G; Tribble, Diane L; Trip, Mieke D; Jukema, J Wouter; Flaim, Joann D; Su, John; Yu, Rosie; Baker, Brenda F; Wedel, Mark K; Kastelein, John J P

2010-04-13

The aim of this study was to evaluate the efficacy and safety of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Mipomersen is an apolipoprotein (apo) B synthesis inhibitor that has demonstrated significant reductions in apo B and low-density lipoprotein (LDL) cholesterol in Phase 1 clinical trials in healthy volunteers. A randomized, placebo-controlled, dose-escalation Phase 2 study was designed to evaluate the effects of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Seventy-four subjects were enrolled sequentially into 1 of 6 dose cohorts at a 4:1 (active/placebo) ratio. Subjects received 7 doses of 30 to 400 mg over 5 weeks in the first 5 cohorts and 15 doses of 200 mg over 13 weeks in the sixth cohort. Pre-specified end points included percentage change from baseline in apo B and LDL cholesterol. Safety was assessed with laboratory test results and by the incidence and severity of adverse events. The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week mipomersen and higher in the 5-week treatment cohorts. Efficacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema [90%]) and hepatic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 subjects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations >or=3x the upper limit of normal, 4 of which persisted on 2 consecutive occasions. Mipomersen might hold promise for treatment of patients not reaching target LDL cholesterol levels on stable statin therapy. Further studies are needed to address the mechanisms and clinical relevance of transaminase changes after mipomersen administration. (Dose-Escalating Safety Study in Subjects on Stable Statin Therapy; NCT00231569). Copyright (c) 2010 American College of Cardiology Foundation. Published by

Squalene synthase inhibitors: An update on the search for new antihyperlipidemic and antiatherosclerotic agents.

PubMed

Kourounakis, A P; Katselou, M G; Matralis, A N; Ladopoulou, E M; Bavavea, E

2011-01-01

Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.

Aldose reductase inhibitors from the leaves of Myrciaria dubia (H. B. & K.) McVaugh.

PubMed

Ueda, H; Kuroiwa, E; Tachibana, Y; Kawanishi, K; Ayala, F; Moriyasu, M

2004-11-01

Ellagic acid (1) and its two derivatives, 4-O-methylellagic acid (2) and 4-(alpha-rhamnopyranosyl)ellagic acid (3) were isolated as inhibitors of aldose reductase (AR) from Myrciaria dubia (H. B. & K.) McVaugh. Compound 2 was the first isolated from the nature. Compound 3 showed the strongest inhibition against human recombinant AR (HRAR) and rat lens AR (RLAR). Inhibitory activity of compound 3 against HRAR (IC50 value = 4.1 x 10(-8) M) was 60 times more than that of quercetin (2.5 x 10(-6) M). The type of inhibition against HRAR was uncompetitive.

Potential Molecular Targets of Statins in the Prevention of Hepatocarcinogenesis.

PubMed

Ridruejo, Ezequiel; Romero-Caími, Giselle; Obregón, María J; Kleiman de Pisarev, Diana; Alvarez, Laura

2018-04-09

Hepatocellular carcinoma (HCC) represents 90% of liver tumors. Statins, may reduce the incidence of various tumors, including HCC. Antitumoral activities may be mediated by changes in transforming growth factor-beta (TGF-β1) and thyroid hormones (TH) regulation. The aim of our study is to establish the statins mechanism of action and the potential key molecules involved in an in vivo and in vitro HCC model. We used two models: in vivo (in rats) using diethylnitrosamine (DEN) and hexachlorobenzene (HCB) to develop HCC, we analyzed cell proliferation parameters (proliferating cell nuclear antigen, PCNA) and cholesterol metabolism (hydroxy-methylglutaryl-CoA reductase, HMGCoAR). In vitro (Hep-G2 cells) we evaluated the effects of different doses of Atorvastatin (AT) and Simvastatin (SM) on HCB induced proliferation and analyzed proliferative parameters, colesterol metabolism, TGF-β1 mRNA, c-Src and TH levels. In vivo, we observed that cell proliferation significantly increased as well as cholesterol serum levels in rats treated with HCB. In vitro, we observed the same results on PCNA as in vivo. The statins prevented the increase in HMG-CoAR mRNA levels induced by HCB, reaching levels similar to controls at máximum doses: AT (30 μM), and SM (20 μM). Increases in PCNA, TGF-β1, and pc-Src, and decreases in deiodinase I mRNA levels induced by HCB were not observed when cells were pre-treated with AT and SM at maximum doses. Statins can prevent the proliferative HCB effects on Hep-G2 cells. TGF-β1, c-Src and TH may be the statins molecular targets in hepatocarcinogenesis.

The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: a proposal as a therapeutic target and as a study model.

PubMed

Andrade-Pavón, Dulce; Sánchez-Sandoval, Eugenia; Rosales-Acosta, Blanca; Ibarra, José Antonio; Tamariz, Joaquín; Hernández-Rodríguez, César; Villa-Tanaca, Lourdes

2014-01-01

The enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzes the conversion of HMG-Co-A into mevalonate. This step is the limiting point for the synthesis of cholesterol in mammals and ergosterol in fungi. We describe in this article the genome organization of HMGR coding genes and those deduced from different fungi, recount the evidence showing statins as HMGR inhibitors for ergosterol synthesis and its effect in yeast viability, and propose fungal HMGR (HMGRf) as a model to study the use of pharmaceutical compounds to inhibit cholesterol and ergosterol synthesis. Bibliographical search and bioinformatic analyses were performed and discussed. HMGRfs belong to the class I with a high homology in the catalytic region. The sterol biosynthetic pathway in humans and fungi share many enzymes in the initial steps (such as the HMGR enzyme), but in the last steps enzymes are different rendering the two final products: cholesterol in mammals and ergosterol in fungi. With regards to inhibitors such as statins and other compounds, these affect also fungal viability. Since HMGR from Schizosaccharomyces pombe and Ustilago maydis are very similar to the human HMGR in the catalytic regions, we propose that fungal enzymes can be used to test inhibitors for a potential use in humans. We consider that HMGRf is a good therapeutic target to design and test new antifungal compounds. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012). Copyright © 2013 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Successful reintroduction of statin therapy after statin-associated rhabdomyolysis.

PubMed

Simons, Janet E; Holbrook, Anne M; Don-Wauchope, Andrew C

2015-01-01

The case report demonstrates the successful use of an alternative statin after a statin-related episode of rhabdomyolysis. Statin-associated rhabdomyolysis is a serious adverse event with a very low incidence and is considered the most severe of the muscle-related side effects of the statins. Rechallenge with statins is not a recommended practice after rhabdomyolysis. The patient experienced a myocardial infarct 1 y after the episode of rhabdomyolysis. He used alternative lipid-lowering therapy for 2 y. His low-density lipoprotein cholesterol was not meeting typical secondary prevention targets. An alternative statin was introduced and the patient has been followed for 4 years without recurrence of the rhabdomyolysis. This case suggests it may be time to reconsider the accepted practice of permanently avoiding statin therapy after rhabdomyolysis. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Alirocumab Injection

MedlinePlus

... injection is used along with diet and certain cholesterol-lowering medications (HMG-CoA reductase inhibitors [statins]) in ... familial heterozygous hypercholesterolemia (an inherited condition in which cholesterol cannot be removed from the body normally) or ...

Effects of HMG-CoA reductase inhibitors on learning and memory in the guinea pig.

PubMed

Maggo, Simran; Ashton, John C

2014-01-15

Statins reduce the risk of death from cardiovascular disease in millions of people worldwide. Recent pharmacovigilance data has suggested that people taking statins have an increased risk of psychiatric adverse events such as amnesia and anxiety. This study aimed to investigate the possibility of statin-induced amnesia through animal models of memory and learning. We conducted extracellular field recordings of synaptic transmission in area CA1 of hippocampal slices to examine the effects of acute cholesterol lowering with lipid lowering drugs. We also assessed the effect of six weeks of simvastatin (2mg/kg/d) and atorvastatin (1mg/kg/d) treatment using the Morris water maze. Long Term Potentiation (LTP) was significantly diminished in the presence of 3µM atorvastatin or simvastatin and by the cholesterol sequestering agent methyl-β-cyclodextrin (MBCD). The effects were reversed in the MBCD but not the statin treated slices by the addition of cholesterol. In the water maze, statin treatment did not cause any deficits in the first five days of reference memory testing, but statin treated guinea pigs preformed significantly worse than control animals in a working memory test. The deficits observed in our experiments in water maze performance and hippocampal LTP are suggestive of statin induced changes in hippocampal plasticity. The effects on LTP are independent of cholesterol regulation, and occur at concentrations that may be relevant to clinical use. Our results may help to explain some of the behavioural changes reported in some people after beginning statin treatment. © 2013 Published by Elsevier B.V.

Heme inhibition of ferrisiderophore reductase in Bacillus subtilis.

PubMed

Lodge, J S; Gaines, C G; Arceneaux, J E; Byers, B R

1982-11-01

Heme was a noncompetitive inhibitor (apparent K(i) and K'(i) = 0.043 mM) of a ferrisiderophore reductase purified from Bacillus subtilis; protoporphyrin IX had no effect. The cellular level of heme may partly regulate the function of this reductase to yield a controlled flow of iron into metabolism.

Statins: Do they have potential in the treatment of polycystic ovary syndrome?

PubMed Central

Kodaman, Pinar H.; Duleba, Antoni J.

2010-01-01

Many women of reproductive age are affected by polycystic ovary syndrome (PCOS), a heterogeneous endocrinopathy characterized by androgen excess, chronic oligo-anovulation and/or polycystic ovarian morphology. In addition, PCOS is often associated with insulin resistance, systemic inflammation and oxidative stress which, on one hand, lead to endothelial dysfunction and dyslipidemia with subsequent cardiovascular sequelae and, on the other hand, to hyperplasia of the ovarian theca compartment with resultant hyperandrogenism and anovulation. While traditionally statins have been used to treat dyslipidemia by blocking HMG-CoA reductase, the rate limiting step in cholesterol biosynthesis; in fact, they possess pleiotropic actions, resulting in antioxidant, anti-inflammatory and anti-proliferative effects. Statins offer a novel therapeutic approach to PCOS in that they address the dyslipidemia associated with the syndrome, as well as hyperandrogenism/hyperandrogenemia. These actions may be due to an inhibition of the effects of systemic inflammation and insulin resistance/hyperinsulinemia. Evidence to date, both in vitro and in vivo, suggests that statins have potential in the treatment of PCOS; however, further clinical trials are needed before they can be considered a standard of care in the medical management of this common endocrinopathy. PMID:18181091

Characterization of 5α-reductase activity and isoenzymes in human abdominal adipose tissues.

PubMed

Fouad Mansour, Mohamed; Pelletier, Mélissa; Tchernof, André

2016-07-01

The substrate for the generation of 5α-dihydrotestosterone (DHT) is either androstenedione (4-dione) which is first converted to androstanedione and then to DHT through 17-oxoreductase activity, or testosterone, which is directly converted to DHT. Three 5α-reductase isoenzymes have been characterized and designated as types 1, 2 and 3 (SRD5A1, 2 and 3). To define the predominant source of local DHT production in human adipose tissues, identify 5α-reductase isoenzymes and test their impact on preadipocyte differentiation. Cultures of omental (OM) and subcutaneous (SC) preadipocytes were treated for 0, 6 or 24h with 30nM (14)C-4-dione or (14)C-testosterone, with and without 500nM 5α-reductase inhibitors 17-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androstan-3-one (4-MA) or finasteride. Protein level and mRNA abundance of 5α-reductase isoenzymes/transcripts were examined in whole SC and OM adipose tissue. HEK-293 cells stably transfected with 5α-reductase type 1, 2 or 3 were used to test 5α-reductase inhibitors. We also assessed the impact of 5α-reductase inhibitors on preadipocyte differentiation. Over 24h, DHT formation from 4-dione increased gradually (p<0.05) and was significantly higher compared to that generated from testosterone (p<0.001). DHT formation from both 4-dione and testosterone was blocked by both 5α-reductase inhibitors. In whole adipose tissue from both fat compartments, SRD5A3 was the most highly expressed isoenzyme followed by SRD5A1 (p<0.001). SRD5A2 was not expressed. In HEK-293 cells, 4-MA and finasteride inhibited activity of 5α-reductases types 2 and 3 but not type 1. In preadipocyte cultures where differentiation was inhibited by 4-dione (p<0.05, n=7) or testosterone (p<0.05, n=5), the inhibitors 4-MA and finasteride abolished these effects. Although 4-dione is the main source of DHT in human preadipocytes, production of this steroid by 5α-reductase isoenzymes mediates the inhibitory effect of both 4-dione and testosterone on

Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study.

PubMed

Musset, Lucile; Allenbach, Yves; Benveniste, Olivier; Boyer, Olivier; Bossuyt, Xavier; Bentow, Chelsea; Phillips, Joe; Mammen, Andrew; Van Damme, Philip; Westhovens, René; Ghirardello, Anna; Doria, Andrea; Choi, May Y; Fritzler, Marvin J; Schmeling, Heinrike; Muro, Yoshinao; García-De La Torre, Ignacio; Ortiz-Villalvazo, Miguel A; Bizzaro, Nicola; Infantino, Maria; Imbastaro, Tiziana; Peng, Qinglin; Wang, Guochun; Vencovský, Jiří; Klein, Martin; Krystufkova, Olga; Franceschini, Franco; Fredi, Micaela; Hue, Sophie; Belmondo, Thibaut; Danko, Katalin; Mahler, Michael

2016-10-01

In an effort to find naturally occurring substances that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experienced muscle pain and weakness during treatment. In a smaller proportion of patients, the myopathy progressed to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients that develop an immune-mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies but, until today, a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls has not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria. Copyright © 2016. Published by Elsevier B.V.

Molecular structure, spectroscopic and docking analysis of 1,3-diphenylpyrazole-4-propionic acid: A good prostaglandin reductase inhibitor

NASA Astrophysics Data System (ADS)

Kavitha, T.; Velraj, G.

2018-03-01

The molecule 1,3-diphenylpyrazole-4-propionic acid (DPPA) was optimized to its minimum energy level using density functional theory (DFT) calculations. The vibrational frequencies of DPPA were calculated along with their potential energy distribution (PED) and the obtained values are validated with the help of experimental calculations. The reactivity nature of the molecule was investigated with the aid of various DFT methods such as global reactivity descriptors, local reactivity descriptors, molecular electrostatic potential (MEP), natural bond orbitals (NBOs), etc. The prediction of activity spectra for substances (PASS) result forecast that, DPPA can be more active as a prostaglandin (PG) reductase inhibitor. The PGs are biologically synthesized by the cyclooxygenase (COX) enzyme which exists in COX1 and COX2 forms. The PGs produced by COX2 enzyme induces inflammation and fungal infections and hence the inhibition of COX2 enzyme is indispensable in anti-inflammation and anti-fungal activities. The docking analysis of DPPA with COX enzymes (both COX1 and COX2) were carried out and eventually, it was found that DPPA can selectively inhibit COX2 enzyme and can serve as a PG reductase inhibitor thereby acting as a lead compound for the treatment of inflammation and fungal diseases.

[Do opioids, sedatives and proton-pump inhibitors increase the risk of fractures?

PubMed

Thorsdottir, Gudlaug; Benedikz, Elisabet; Thorgeirsdottir, Sigridur A; Johannsson, Magnus

2017-01-01

A pharmacoepidemiological study was conducted to analyse the relationship between bone fracture and the use of certain drugs. The study includes patients 40 years and older, diagnosed with bone fractures in the Emergency Department of Landspitali University Hospital in Reykjavik, Iceland, during a 10-year period (2002-2011). Also were included those who picked up from a pharmacy 90 DDD or more per year of the drugs included in the study in the capital region of Iceland during same period. Opiates, benzodiazepines/hypnotics (sedatives) were compared with HMG-CoA reductase inhibitors (statins), non-steroid anti-inflammatory drugs (NSAID) and beta blockers. Proton-pump inhibitors (PPI) and histamine H2-antagonists were also examined. To examine the association between above drugs and fractures the data from electronic hospital database were matched to the prescription database run by the Directorate of Health. A total of 29,056 fractures in 22,891 individuals were identified. The females with fractures were significantly older and twice as many, compared to males. The odds ratio (OR) for fractures was not significantly different between the NSAID, statins and beta blockers. OR for opiates showed almost double increased risk of fractures, 40% increased risk for sedatives and 30% increased risk for PPIs compared to beta blockers. No increased fracture-risk was noted in patients taking H2 antagonists. This study shows a relationship between the use of opiates, sedatives and bone fractures. The incidence of fractures was also increased in patients taking PPIs which is interesting in the light of the wide-spread use of PPIs in the community. Key words: Opiates, sedatives, proton- pump inhibitors, fractures. Correspondence: Magnus Johannsson, magjoh@hi.is.

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

PubMed Central

Trapani, Laura; Segatto, Marco; Pallottini, Valentina

2013-01-01

Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of

Genetically Guided Statin Therapy

DTIC Science & Technology

2017-03-01

prevent cardiovascular disease . Long-term adherence is a challenge, due, in part, to statin intolerance due to musculoskeletal side effects. In objective...Statins, cholesterol, LDL, cardiovascular disease , genetic-informed strategy, statin prescription, statin adherence 16. SECURITY CLASSIFICATION OF: 17...28 Mar 2017. 1.0 SUMMARY Statins are well established for lowering cholesterol and preventing cardiovascular disease . High rates of statin

Methyl-branched fatty acids, inhibitors of enoyl-ACP reductase with antibacterial activity from Streptomyces sp. A251.

PubMed

Zheng, Chang-Ji; Sohn, Mi-Jin; Chi, Seung-Wook; Kim, Won-Gon

2010-05-01

Bacterial enoyl-ACP reductase (FabI) has been demonstrated to be a novel antibacterial target. In the course of our screening for FabI inhibitors we isolated two methyl-branched fatty acids from Streptomyces sp. A251. They were identified as 14-methyl-9(Z)-pentadecenoic acid and 15-methyl-9(Z)-hexadecenoic acid by MS and NMR spectral data. These compounds inhibited Staphylococcus aureus FabI with IC50 of 16.0 and 16.3mu M, respectively, while didn't affect FabK, an enoyl-ACP reductase of Streptococcus pneumonia, at 100muM. Consistent with their selective inhibition for FabI, they blocked intracellular fatty acid synthesis as well as the growth of S. aureus, while didn't inhibit the growth of S. pneumonia. Additionally, these compounds showed reduced antibacterial activity against fabI-overexpressing S. aureus compared to the wild-type strain. These results demonstrate that the methyl-branched fatty acids showed antibacterial activity by inhibiting FabI in vivo.

Anti-neuroinflammatory efficacy of the aldose reductase inhibitor FMHM via phospholipase C/protein kinase C-dependent NF-κB and MAPK pathways

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

Zeng, Ke-Wu; Li, Jun; Dong, Xin

2013-11-15

Aldose reductase (AR) has a key role in several inflammatory diseases: diabetes, cancer and cardiovascular diseases. Therefore, AR inhibition seems to be a useful strategy for anti-inflammation therapy. In the central nervous system (CNS), microglial over-activation is considered to be a central event in neuroinflammation. However, the effects of AR inhibition in CNS inflammation and its underlying mechanism of action remain unknown. In the present study, we found that FMHM (a naturally derived AR inhibitor from the roots of Polygala tricornis Gagnep.) showed potent anti-neuroinflammatory effects in vivo and in vitro by inhibiting microglial activation and expression of inflammatory mediators.more » Mechanistic studies showed that FMHM suppressed the activity of AR-dependent phospholipase C/protein kinase C signaling, which further resulted in downstream inactivation of the IκB kinase/IκB/nuclear factor-kappa B (NF-κB) inflammatory pathway. Therefore, AR inhibition-dependent NF-κB inactivation negatively regulated the transcription and expression of various inflammatory genes. AR inhibition by FMHM exerted neuroprotective effects in lipopolysaccharide-induced neuron–microglia co-cultures. These findings suggested that AR is a potential target for neuroinflammation inhibition and that FMHM could be an effective agent for treating or preventing neuroinflammatory diseases. - Highlights: • FMHM is a natural-derived aldose reductase (AR) inhibitor. • FMHM inhibits various neuroinflammatory mediator productions in vitro and in vivo. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent NF-κB pathway. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent MAPK pathway. • FMHM protects neurons against inflammatory injury in microglia-neuron co-cultures.« less

Inhibition of CHK1 sensitizes Ewing sarcoma cells to the ribonucleotide reductase inhibitor gemcitabine

PubMed Central

Goss, Kelli L; Koppenhafer, Stacia L; Harmoney, Kathryn M; Terry, William W; Gordon, David J

2017-01-01

Ewing sarcoma is a bone and soft tissue sarcoma that occurs in children and young adults. The EWS-FLI1 gene fusion is the driver mutation in most Ewing sarcoma tumors and functions, in part, as an aberrant transcription factor. We recently identified that Ewing sarcoma cells are sensitive to inhibition of ribonucleotide reductase (RNR), which catalyzes the formation of deoxyribonucleotides from ribonucleotides. In this report, we show that Ewing sarcoma cells are sensitive to treatment with clofarabine, which is a nucleoside analogue and allosteric inhibitor of RNR. However, clofarabine is a reversible inhibitor of RNR and we found that the effect of clofarabine is limited when using a short (6-hour) drug treatment. Gemcitabine, on the other hand, is an irreversible inhibitor of the RRM1 subunit of RNR and this drug induces apoptosis in Ewing sarcoma cells when used in both 6-hour and longer drug treatments. Treatment of Ewing sarcoma cells with gemcitabine also results in activation of checkpoint kinase 1 (CHK1), which is a critical mediator of cell survival in the setting of impaired DNA replication. Notably, inhibition of CHK1 function in Ewing sarcoma cells using a small-molecule CHK1 inhibitor, or siRNA knockdown, in combination with gemcitabine results in increased toxicity both in vitro and in vivo in a mouse xenograft experiment. Overall, our results provide insight into Ewing sarcoma biology and identify a candidate therapeutic target, and drug combination, in Ewing sarcoma. PMID:29152060

A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site.

PubMed

Hardwicke, Mary Ann; Rendina, Alan R; Williams, Shawn P; Moore, Michael L; Wang, Liping; Krueger, Julie A; Plant, Ramona N; Totoritis, Rachel D; Zhang, Guofeng; Briand, Jacques; Burkhart, William A; Brown, Kristin K; Parrish, Cynthia A

2014-09-01

Human fatty acid synthase (hFAS) is a complex, multifunctional enzyme that is solely responsible for the de novo synthesis of long chain fatty acids. hFAS is highly expressed in a number of cancers, with low expression observed in most normal tissues. Although normal tissues tend to obtain fatty acids from the diet, tumor tissues rely on de novo fatty acid synthesis, making hFAS an attractive metabolic target for the treatment of cancer. We describe here the identification of GSK2194069, a potent and specific inhibitor of the β-ketoacyl reductase (KR) activity of hFAS; the characterization of its enzymatic and cellular mechanism of action; and its inhibition of human tumor cell growth. We also present the design of a new protein construct suitable for crystallography, which resulted in what is to our knowledge the first co-crystal structure of the human KR domain and includes a bound inhibitor.

Discovery of Fungal Denitrification Inhibitors by Targeting Copper Nitrite Reductase from Fusarium oxysporum.

PubMed

Matsuoka, Masaki; Kumar, Ashutosh; Muddassar, Muhammad; Matsuyama, Akihisa; Yoshida, Minoru; Zhang, Kam Y J

2017-02-27

The efficient application of nitrogenous fertilizers is urgently required, as their excessive and inefficient use is causing substantial economic loss and environmental pollution. A significant amount of applied nitrogen in agricultural soils is lost as nitrous oxide (N 2 O) in the environment due to the microbial denitrification process. The widely distributed fungus Fusarium oxysporum is a major denitrifier in agricultural soils and its denitrification activity could be targeted to reduce nitrogen loss in the form of N 2 O from agricultural soils. Here, we report the discovery of first small molecule inhibitors of copper nitrite reductase (NirK) from F. oxysporum, which is a key enzyme in the fungal denitrification process. The inhibitors were discovered by a hierarchical in silico screening approach consisting of pharmacophore modeling and molecular docking. In vitro evaluation of F. oxysporum NirK activity revealed several pyrimidone and triazinone based compounds with potency in the low micromolar range. Some of these compounds suppressed the fungal denitrification in vivo as well. The compounds reported here could be used as starting points for the development of nitrogenous fertilizer supplements and coatings as a means to prevent nitrogen loss by targeting fungal denitrification.

Evaluation of potent inhibitors of dihydrofolate reductase in a culture model for growth of Pneumocystis carinii.

PubMed

Bartlett, M S; Shaw, M; Navaran, P; Smith, J W; Queener, S F

1995-11-01

Many antifolates are known to inhibit dihydrofolate reductase from murine Pneumocystis carinii, with 50% inhibitory concentrations (IC50s) ranging from 10(-4) to 10(-11) M. The relationship of the potency against isolated enzyme to the potency against intact murine P. carinii cells was explored with 17 compounds that had proven selectivity for or potency against P. carinii dihydrofolate reductase. Pyrimethamine and one analog were inhibitory to P. carinii in culture at concentrations two to seven times the IC50s for the enzyme, suggesting that the compounds may enter P. carinii cells in culture. Methotrexate was a potent inhibitor of P. carinii dihydrofolate reductase, but the concentrations effective in culture were more than 1,000-fold higher than IC50s for the enzyme, since P. carinii lacks an uptake system for methotrexate. Analogs of methotrexate in which chlorine, bromine, or iodine was added to the phenyl ring had improved potency against the isolated enzyme but were markedly less effective in culture; polyglutamation also lowered the activity in culture but improved activity against the enzyme. Substitution of a naphthyl group for the phenyl group of methotrexate produced a compound with improved activity against the enzyme (IC50, 0.00019 microM) and excellent activity in culture (IC50, 0.1 microM). One trimetrexate analog in which an aspartate or a chlorine replaced two of the methoxy groups of trimetrexate was much more potent and was much more selective toward P. carinii dihydrofolate reductase than trimetrexate; this analog was also as active as trimetrexate in culture. These studies suggest that modifications of antifolate structures can be made that facilitate activity against intact organisms while maintaining the high degrees of potency and the selectivities of the agents can be made.

Statin-related myotoxicity.

PubMed

Fernandes, Vera; Santos, Maria Joana; Pérez, Antonio

2016-05-01

Statin therapy has a very important role in decreasing cardiovascular risk, and treatment non-compliance may therefore be a concern in high cardiovascular risk patients. Myotoxicity is a frequent side effect of statin therapy and one of the main causes of statin discontinuation, which limits effective treatment of patients at risk of or with cardiovascular disease. Because of the high proportion of patients on statin treatment and the frequency of statin-related myotoxicity, this is a subject of concern in clinical practice. However, statin-related myotoxicity is probably underestimated because there is not a gold standard definition, and its diagnosis is challenging. Moreover, information about pathophysiology and optimal therapeutic options is scarce. Therefore, this paper reviews the knowledge about the definition, pathophysiology and predisposing conditions, diagnosis and management of statin-related myotoxicity, and provides a practical scheme for its management in clinical practice. Copyright © 2016 SEEN. Published by Elsevier España, S.L.U. 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.

Drosophila as a Screening Platform for Novel Lung Cancer Therapeutics

DTIC Science & Technology

2016-09-01

CoA reductase, an activity that has proven useful clinically for lowering cholesterol (Figure 5A). Two additional statins, atorvastatin and simvastatin...prenylation, are inhibited by GGTI and FTI. Inhibitors are listed in red. (B) Two additional statins, atorvastatin (p % 0.05) and simvastatin (p% 0.05...H., Hou, J., Zhang, X., Zhang, C., Yue, L., Wen, X., Liu, D., Shi, H., Yuan, J., et al. (2013). Atorvastatin overcomes gefitinib resistance in KRAS

Statins attenuate the development of atherosclerosis and endothelial dysfunction induced by exposure to urban particulate matter (PM{sub 10})

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

Miyata, Ryohei; Hiraiwa, Kunihiko; Cheng, Jui Chih

Exposure to ambient air particulate matter (particles less than 10 μm or PM{sub 10}) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM{sub 10}. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM{sub 10}/saline exposure for 4 weeks ± lovastatin (5 mg/kg/day) treatment. PM{submore » 10} exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM{sub 10} impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM{sub 10} increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM{sub 10}. Taken together, statins protect against PM{sub 10}-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties. - Highlights: • Coarse particulate matter (PM{sub 10}) accelerated balloon injury-induced plaque formation. • Lovastatin decreased

Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?

PubMed

Brennan, Emily T; Joy, Tisha R

2017-05-01

Statin-associated muscle symptoms (SAMS) are common. Rechallenge with the same statin (same-statin rechallenge) has recently been included as part of a proposed scoring index for diagnosing SAMS, but data regarding tolerability and efficacy of same-statin rechallenge, compared with other strategies, is minimal. In this study we evaluated the tolerability, percent change in low-density lipoprotein cholesterol (LDL-C), and proportion of patients achieving their LDL-C targets among 3 common management strategies-same-statin rechallenge, switching to a different statin (statin switch), and use of nonstatin medications only. We performed a retrospective analysis of 118 patients referred to our tertiary care centre for management of SAMS, defined as development of muscle-related symptoms with 2 or more statins. Baseline and last follow-up lipid parameters were documented. Patients were classified as tolerant of a strategy if, at their last follow-up, they remained on that strategy. After a median follow-up of 17 months, most (n = 79; 67%) patients were able to tolerate a statin. Tolerability was similar among the 3 treatment strategies (71% same-statin rechallenge vs 53% statin switch vs 57% for nonstatin therapy only; P = 0.11). Those in the same-statin rechallenge and statin switch groups achieved greater LDL-C reductions compared with those who only tolerated nonstatins (-38.8 ± 3.4% vs -36.4 ± 2.9% vs -17.3 ± 4.5%; P = 0.0007). A greater proportion of patients in the same-statin rechallenge group achieved their target LDL-C compared with those in the nonstatin therapy only group (50% vs 15%; odds ratio, 6.8; 95% confidence interval, 1.5-40.7; P = 0.04). Among individuals with a history of SAMS, most will tolerate statin therapy. Same-statin rechallenge was highly tolerable and efficacious. Thus, same-statin rechallenge might warrant increased utilization. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Design, synthesis, and evaluation of inhibitors of trypanosomal and leishmanial dihydrofolate reductase.

PubMed

Chowdhury, S F; Villamor, V B; Guerrero, R H; Leal, I; Brun, R; Croft, S L; Goodman, J M; Maes, L; Ruiz-Perez, L M; Pacanowska, D G; Gilbert, I H

1999-10-21

This paper concerns the design, synthesis, and evaluation of inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Initially study was made of the structures of the leishmanial and human enzyme active sites to see if there were significant differences which could be exploited for selective drug design. Then a series of compounds were synthesized based on 5-benzyl-2, 4-diaminopyrimidines. These compounds were assayed against the protozoan and human enzymes and showed selectivity for the protozoan enzymes. The structural data was then used to rationalize the enzyme assay data. Compounds were also tested against the clinically relevant forms of the intact parasite. Activity was seen against the trypanosomes for a number of compounds. The compounds were in general less active against Leishmania. This latter result may be due to uptake problems. Two of the compounds also showed some in vivo activity in a model of African trypanosomiasis.

Short-term changes of serum potassium concentration induced by physical exercise in patient with arterial hypertension treated with angiotensin-converting enzyme inhibitor alone or in combination with statin.

PubMed

Deska, P; Nowicki, M

2017-02-01

Intensive physical exercise may facilitate potassium release from skeletal muscles that may result in hyperkalemia. Commonly used drugs including angiotensin converting enzyme inhibitors (ACEI) and statins increase a risk of hyperkalemia. It is not known whether the effect of these drugs on serum potassium during physical exercise is additive. The study compared the effect of physical exercise on the changes of serum potassium in hypertensive patients receiving ACEI alone or in combination with statin. Eighteen patients with arterial hypertension with normal renal function were included in a prospective placebo-controlled cross-over study. The patients underwent 3 exercise tests on a bicycle ergometer with 55 - 60% of maximum oxygen consumption each lasting 30 minutes, i.e. after being treated with ACEI alone for six months, and then in a random order after the administration of ACEI with statin or ACEI with placebo each time for eight weeks separated by 2-week wash-out. Serum potassium was measured with atomic emission flame spectrometry before and after 15 and 30 minutes exercise and after 30-minute recovery. During the exercise serum potassium concentration increased moderately but significantly during all exercise tests. Mean serum potassium during exercise remained within the normal range. There were no differences in the exercise-induced changes of serum potassium during the exercise tests performed after ACEI combined with statin or with placebo. Addition of statin to ACEI does not increase the risk of hyperkalemia in hypertensive patients with preserved renal function during physical exercise with intensity typical for routine daily activities.

Guideline concordance of new statin prescriptions: who got a statin?

PubMed

Cascino, Thomas; Vali, Marzieh; Redberg, Rita; Bravata, Dawn M; Boscardin, John; Eilkhani, Elnaz; Keyhani, Salomeh

2017-09-01

Statins are recommended to reduce serum cholesterol in patients at risk for atherosclerotic cardiovascular disease. Despite the prevalence of statin use, little is known about the indications for new prescriptions. We assessed the concordance of new statin prescriptions in the Veterans Health Administration (VHA) compared with the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) guidelines (the guidelines in force in 2012) and the American College of Cardiology (ACC)-American Heart Association (AHA) 2013 guidelines. Cross-sectional study. We identified every patient who received a new prescription (no statin use in the prior year) in the VHA in 2012. Patients were excluded if they had incomplete data, triglycerides greater than 400 mg/dL, or fewer than 2 primary care visits to ensure adequate baseline data to calculate Framingham and ACC-AHA 2013 risk scores. We identified 250,243 new statin prescriptions in 2012 in the VHA, with 121,081 meeting inclusion criteria. Among new prescriptions, 68% were prescribed for primary prevention and 32% were prescribed for secondary prevention. Among patients receiving new statins for primary prevention, 48% did not have an indication supported by the ATP III guideline and 20% did not have an indication supported by the ACC/AHA guideline. Overall, approximately 19% of patients may have received a statin for an indication not supported by either guideline. Veterans are commonly prescribed statins for indications not supported by professional society guidelines. The finding of common use of statins outside established guidelines represents an opportunity to improve the quality and value of the healthcare delivery.

Statin Intolerance: the Clinician's Perspective.

PubMed

Stulc, Tomáš; Ceška, Richard; Gotto, Antonio M

2015-12-01

Muscle problems and other adverse symptoms associated with statin use are frequent reasons for non-adherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. However, most patients who experience adverse symptoms during statin use are able to tolerate at least some degree of statin therapy. Given the profound cardiovascular benefits derived from statins, an adequate practical approach to statin intolerance is, therefore, of great clinical importance. Statin intolerance can be defined as the occurrence of myalgia or other adverse symptoms that are attributed to statin therapy and that lead to its discontinuation. In reality, these symptoms are actually unrelated to statin use in many patients, especially in those with atypical presentations following long periods of treatment. Thus, the first step in approaching patients with adverse symptoms during the course of statin therapy is identification of those patients for whom true statin intolerance is unlikely, since most of these patients would probably be capable of tolerating adequate statin therapy. In patients with statin intolerance, an altered dosing regimen of very low doses of statins should be attempted and, if tolerated, should gradually be increased to achieve the highest tolerable doses. In addition, other lipid-lowering drugs may be needed, either in combination with statins, or alone, if statins are not tolerated at all. Stringent control of other risk factors can aid in reducing cardiovascular risk if attaining lipid treatment goals proves difficult.

Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial.

PubMed

Visser, Maartje E; Wagener, Gilbert; Baker, Brenda F; Geary, Richard S; Donovan, Joanne M; Beuers, Ulrich H W; Nederveen, Aart J; Verheij, Joanne; Trip, Mieke D; Basart, Dick C G; Kastelein, John J P; Stroes, Erik S G

2012-05-01

A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD). Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of mipomersen administration, LDL-c was reduced by 47 ± 18% (P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively (P < 0.001 vs. placebo). Four mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases ≥ 3× the upper limit of normal were observed in seven (33%) subjects assigned to mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis. The present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required. ClinicalTrials.gov identifier: NCT00707746.

Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia.

PubMed

Seiki, Stephanie; Frishman, William H

2009-01-01

Hypercholesterolemia is a major risk factor for the development of atherosclerotic vascular diseases. The most popular agents for cholesterol reduction are the statin drugs, which are competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the primary rate-limiting enzyme in the hepatic biosynthesis of cholesterol. Although relatively safe and effective, the available statins can cause elevations in liver enzymes and myopathy. Squalene synthase is another enzyme that is downstream to HMG-CoA reductase in the cholesterol synthesis pathway and modulates the first committed step of hepatic cholesterol biosynthesis at the final branch point of the cholesterol biosynthetic pathway. Squalene epoxidase and oxidosqualene cyclase are other enzymes that act distally to squalene synthase. Pharmacologic inhibitors of these downstream enzymes have been developed, which may reduce low-density lipoprotein cholesterol and reduce the myopathy side effect seen with upstream inhibition of HMG-CoA. At this juncture, one squalene synthase inhibitor, lapaquistat (TAK-475) is in active clinical trials as a monotherapy, but there have been suggestions of increased hepatotoxicity with the drug.

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway

PubMed Central

Rauthan, Manish; Ranji, Parmida; Aguilera Pradenas, Nataly; Pitot, Christophe; Pilon, Marc

2013-01-01

Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction. PMID:23530189

The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway.

PubMed

Rauthan, Manish; Ranji, Parmida; Aguilera Pradenas, Nataly; Pitot, Christophe; Pilon, Marc

2013-04-09

Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction.

CYP2D6*4 polymorphism is associated with statin-induced muscle effects.

PubMed

Frudakis, Tony N; Thomas, Matthew J; Ginjupalli, Siva N; Handelin, Barbara; Gabriel, Richard; Gomez, Hector J

2007-09-01

Statin use is associated with a variety of overtly related muscle symptoms including muscle pain, myalgia, creatine kinase elevations without pain with myolysis and myositis (rhabdomyolysis), a potentially fatal side effect that led to the withdrawal of cerivastatin in 2001. Unintended drug response phenotypes have an impact on patient compliance and sometimes patient health and the assessment of risk on an individual basis could enhance therapeutic benefit. We therefore investigated whether common single nucleotide polymorphisms were associated with the expression of broadly grouped atorvastatin-induced muscle events in a case-control study (n=263 samples, n=388 SNPs). Of a number of associations identified in a discovery sample (51 atorvastatin-induced muscle and 55 normal) only those corresponding to the CYP2D6*4 allele were significantly associated in the sample (24 atorvastatin-induced muscle and 133 normal) (Discovery P=0.004, odds ratio=3.6; Validation P=0.036, odds ratio=2.7; total P=0.001, odds ratio=2.5). The frequency of the CYP2D6*4 allele was about 50% in atorvastatin-induced muscle patients but only 28% in controls, similar to that of other patient types (28.5%). The association was independent of various demographic variables and not explained by gross demographic, clinical or population-structure differences among cases and controls. Surprisingly, the CYP2D6*4 allele appeared similarly distributed among controls and patients expressing simvastatin-induced muscle events (n=169, frequency in case participants=49.2%, P=0.067, odds ratio=1.7). Our results suggest that the CYP2D6*4 allele is associated with broadly related muscle events caused by at least two structurally dissimilar HMG-CoA reductase inhibitors, and as such, may have implications for a better understanding of this statin-wide phenomena.

Synthesis of organic nitrates of luteolin as a novel class of potent aldose reductase inhibitors.

PubMed

Wang, Qi-Qin; Cheng, Ning; Zheng, Xiao-Wei; Peng, Sheng-Ming; Zou, Xiao-Qing

2013-07-15

Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) μM to (2.833±0.102) μM. O(7)-Nitrooxyethyl-O(3'),O(4')-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50=(0.099±0.008) μM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure-activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications. Copyright © 2013 Elsevier Ltd. All rights reserved.

Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study.

PubMed

Antony, Priya; Vijayan, Ranjit

2015-01-01

Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors.

Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study

PubMed Central

Antony, Priya; Vijayan, Ranjit

2015-01-01

Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors. PMID:26384019

Advance in dietary polyphenols as aldose reductases inhibitors: structure-activity relationship aspect.

PubMed

Xiao, Jianbo; Ni, Xiaoling; Kai, Guoyin; Chen, Xiaoqing

2015-01-01

The dietary polyphenols as aldose reductases inhibitors (ARIs) have attracted great interest among researchers. The aim of this review is to give an overview of the research reports on the structure-activity relationship of dietary polyphenols inhibiting aldose reductases (AR). The molecular structures influence the inhibition of the following: (1) The methylation and methoxylation of the hydroxyl group at C3, C3', and C4' of flavonoids decreased or little affected the inhibitory potency. However, the methylation and methoxylation of the hydroxyl group at C5, C6, and C8 significantly enhanced the inhibition. Moreover, the methylation and methoxylation of C7-OH influence the inhibitory activity depending on the substitutes on rings A and B of flavonoids. (2) The glycosylation on 3-OH of flavonoids significantly increased or little affected the inhibition. However, the glycosylation on 7-OH and 4'-OH of flavonoids significantly decreased the inhibition. (3) The hydroxylation on A-ring of flavones and isoflavones, especially at positions 5 and 7, significantly improved the inhibition and the hydroxylation on C3' and C4' of B-ring of flavonoids remarkably enhanced the inhibition; however, the hydroxylation on the ring C of flavones significantly weakened the inhibition. (4) The hydrogenation of the C2=C3 double bond of flavones reduced the inhibition. (5) The hydrogenation of α=β double bond of stilbenes hardly affected the inhibition and the hydroxylation on C3' of stilbenes decreased the inhibition. Moreover, the methylation of the hydroxyl group of stilbenes obviously reduced the activity. (6) The hydroxylation on C4 of chalcone significantly increased the inhibition and the methylation on C4 of chalcone remarkably weakened the inhibition.

Effect of Statin Use on Outcomes of Adults with Candidemia

PubMed Central

Cuervo, Guillermo; Garcia-Vidal, Carolina; Nucci, Marcio; Puchades, Francesc; Fernández-Ruiz, Mario; Mykietiuk, Analía; Manzur, Adriana; Gudiol, Carlota; Pemán, Javier; Viasus, Diego; Ayats, Josefina; Carratalà, Jordi

2013-01-01

Background Statins have immunomodulatory properties and hinder Candida growth. However, it is unknown whether they may improve prognosis in patients with candidemia. We sought to determine the effect of prior statin use on the clinical outcomes of patients suffering candidemia. Methods and Findings Multicenter cohort study of hospitalized adults with candidemia between 2005 and 2011 in six hospitals in Spain, Brazil and Argentina. Of 326 candidemias, 44 (13.5%) occurred in statin users and 282 (86.5%) in statin non-users. The median value of APACHE II at candidemia diagnosis was similar between groups (18 vs. 16; p=.36). Candida albicans was the most commonly isolated species, followed by C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei. There were no differences regarding appropriate empirical antifungal treatment. Statin users had a lower early (5 d) case-fatality rate than non-users (4.5 vs. 17%; p=.031). This effect was not observed with other cardiovascular drugs (aspirin, beta blockers and ACE inhibitors). Independent factor related to early case-fatality rate was APACHE II score (AOR, 1.08; 95% CI, 1.03–1.14; p=.002). An appropriate empirical antifungal therapy (AOR, 0.11; 95% CI, 0.04–0.26; p=<.001) and prior statin use were independently associated with lower early case-fatality (AOR, 0.17; 95% CI, 0.03–0.93; p=.041). Fourteen days (14d) and overall (30d) case-fatality rates were similar between groups (27% vs. 29%; p=0.77 and 40% vs. 44%; p=.66). Conclusions The use of statins might have a beneficial effect on outcomes of patients with candidemia. This hypothesis deserves further evaluation in randomized trials. PMID:24155941

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

Ezetimibe-Statin Combination Therapy.

PubMed

Nußbaumer, Barbara; Glechner, Anna; Kaminski-Hartenthaler, Angela; Mahlknecht, Peter; Gartlehner, Gerald

2016-07-01

To date, most clinical comparisons of ezetimibe-statin combination therapy versus statin monotherapy have relied entirely on surrogate variables. In this systematic review, we study the efficacy and safety of ezetimibe-statin combination therapy in comparison to statin monotherapy in terms of the prevention of cardiovascular events in hyperlipidemic patients with atherosclerosis and/or diabetes mellitus. This review is based on a systematic literature search (1995 to July 2015) in PubMed, the Excerpta Medica Database (EMBASE), the Cochrane Library, and the ClinicalTrials.gov registry. Nine randomized, controlled trials with data from a total of 19 461 patients were included. Ezetimibe-statin combination therapy was associated with a lower risk of cardiovascular events than statin monotherapy: 33% of the patients treated with ezetimibe and a statin, and 35% of those treated with a statin alone, had a cardiovascular event within seven years (number needed to treat [NNT]: 50 over 7 years). Combination therapy was also significantly more effective in preventing a composite endpoint consisting of death due to cardiovascular disease, nonfatal myocardial infarction, unstable angina pectoris, coronary revascularization, and nonfatal stroke (hazard ratio [HR] 0.94, 95% confidence interval [0,89; 0,99]; p = 0.016). Diabetic patients benefited from combination therapy rather than monotherapy with respect to cardiovascular morbidity (HR 0.87 [0.78; 0.94]). On the other hand, the addition of ezetimibe to statin therapy did not lessen either cardiovascular or overall mortality. Serious undesired events occurred in 38% of the patients taking ezetimibe and a statin nd in 39% of the patients taking a statin alone (relative risk 1.09 [0.77; 1.55]). In high-risk patients with an acute coronary syndrome, combination therapy with ezetimibe and a statin lowered the risk of cardiovascular events in comparison to statin monotherapy. The risk of dying or suffering an adverse drug effect

Safety of statins.

PubMed

Brown, William Virgil

2008-12-01

To examine the evidence for the adverse effects that have been reported during the use of statins. We now have over twenty years of prescription use and many large well controlled trials with statin therapy for hypercholesterolemia. There is only one significant and well documented adverse effect with this group of drugs, rhabdomyolysis. Significant muscle damage is very rare when statin therapy is used in patients carefully screened for concomitant use of other drugs which may interfere with statin catabolism and excretion. Patients with severely impaired liver function are also at risk due to the importance of hepatic excretion of all statins. Chronic myalgias or other pain syndromes have not been confirmed by blinded placebo controlled trials. A significant and reproducible rise in liver enzymes (alanine and aspartate aminotransferases) is observed in 1 to 3% of patients but actual liver damage may not occur at all. Benign and transient proteinuria occurs without evidence of altered renal function. Creatinine clearance is usually increased by statins. Peripheral neuropathy may be a rare adverse effect and this needs further study. Statins are very effective at reducing the incidence of myocardial infarction, stroke and other manifestations of vascular disease. The adverse event rates are very uncommon and the benefit risk ratio is extremely high.

Statin Prescriptions and Breast Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort Study

PubMed Central

Pedersen, Lars; Tarp, Maja; Cronin-Fenton, Deirdre P.; Garne, Jens Peter; Silliman, Rebecca A.; Sørensen, Henrik Toft; Lash, Timothy L.

2011-01-01

Background Accumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied. Methods We conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I–III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18 769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. All statistical tests were two-sided. Results Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference = −0.10, 95% confidence interval = −0.11 to −0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = −0.01 to 0

ESR studies on reactivity of protein-derived tyrosyl radicals formed by prostaglandin H synthase and ribonucleotide reductase.

PubMed

Lassmann, G; Curtis, J; Liermann, B; Mason, R P; Eling, T E

1993-01-01

Using ESR spectroscopy, the ability of enzyme inhibitors to quench protein-derived tyrosyl radicals was studied in two different enzymes, prostaglandin H synthase and ribonucleotide reductase. The prostaglandin H synthase inhibitors indomethacin, eugenol, and MK-410 effectively prevent the formation of tyrosyl radicals during the oxidation of arachidonic acid by prostaglandin H synthase from ram seminal vesicles. A direct reaction with preformed tyrosyl radicals was observed only with eugenol. The other prostaglandin H synthase inhibitors were ineffective. The ribonucleotide reductase inhibitors hydroxyurea and 4-hydroxyanisole, which effectively inactivate the tyrosyl radical in the active site of ribonucleotide reductase present in tumor cells, exhibit a different reactivity with tyrosyl radicals formed by prostaglandin H synthase. Hydroxyurea quenches preformed tyrosyl radicals in prostaglandin H synthase weakly, whereas 4-hydroxyanisole does not quench tyrosyl radicals in prostaglandin H synthase at all. Eugenol, which quenches preformed prostaglandin H synthase-derived tyrosyl radicals, also quenches the tyrosyl radical in ribonucleotide reductase. The results suggest that the reactivity of protein-linked tyrosyl radicals in ribonucleotide reductase and those formed during prostaglandin H synthase catalysis are very different and have unrelated roles in enzyme catalysis.

Emerging lipid-lowering drugs: squalene synthase inhibitors.

PubMed

Elsayed, Raghda K; Evans, Jeffery D

2008-06-01

Lapaquistat was the only squalene synthase inhibitor in Phase III clinical trials in Europe and the United States, but was recently discontinued from clinical development. Unlike statins, the inhibition of de novo cholesterol biosynthesis by lapaquistat does not deplete mevalonate, a precursor of isoprenoids. Isoprenoids are critical in cell growth and metabolism. The present review will focus on the chemistry, pharmacology, and lipid-lowering effects of novel squalene synthase inhibitors. A search of Pubmed, IPA, and GoogleScholar for studies (animal and human) and review articles published in English between 1990 and April 2008, using the search terms "squalene synthase inhibitors" or "lapaquistat". All clinical trials identified were then cross-referenced for their citations. All literature identified was then complied for this analysis. Lapaquistat mainly targets LDL-C, but may have some effect on HDL-C and TG. Preliminary reports on Phase II and Phase III associated lapaquistat 100 mg with elevated hepatic enzymes. Hepatotoxicity, possible drug-drug interaction with statins, and the investigation of a statin/coenzyme Q10 combination are among the few challenges that impeded lapaquistat's clinical development.

Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect

PubMed Central

Cao, Peirang; Hanai, Jun-ichi; Tanksale, Preeti; Imamura, Shintaro; Sukhatme, Vikas P.; Lecker, Stewart H.

2009-01-01

Statins are widely used to treat hypercholesterolemia but can lead to a number of side effects in muscle, including rhabdomyolysis. Our recent findings implicated the induction of atrogin-1, a gene required for the development of muscle atrophy, in statin-induced muscle damage. Since statins inhibit many biochemical reactions besides cholesterol synthesis, we sought to define the statin-inhibited pathways responsible for atrogin-1 expression and muscle damage. We report here that lovastatin-induced atrogin-1 expression and muscle damage in cultured mouse myotubes and zebrafish can be prevented in the presence of geranylgeranol but not farnesol. Further, inhibitors of the transfer of geranylgeranyl isoprene units to protein targets cause statin muscle damage and atrogin-1 induction in cultured cells and in fish. These findings support the concept that dysfunction of small GTP-binding proteins lead to statin-induced muscle damage since these molecules require modification by geranylgeranyl moieties for their cellular localization and activity. Collectively, our animal and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be regulated by novel signaling pathways.—Cao, P., Hanai, J., Tanksale, P., Imamura, S., Sukhatme, V. P., Lecker, S. H. Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect. PMID:19406843

Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial

PubMed Central

Visser, Maartje E.; Wagener, Gilbert; Baker, Brenda F.; Geary, Richard S.; Donovan, Joanne M.; Beuers, Ulrich H.W.; Nederveen, Aart J.; Verheij, Joanne; Trip, Mieke D.; Basart, Dick C.G.; Kastelein, John J.P.; Stroes, Erik S.G.

2012-01-01

Aims A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD). Methods and results Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of mipomersen administration, LDL-c was reduced by 47 ± 18% (P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively (P < 0.001 vs. placebo). Four mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases ≥3× the upper limit of normal were observed in seven (33%) subjects assigned to mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis. Conclusion The present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00707746 PMID:22507979

Ketopantoyl-lactone reductase from Candida parapsilosis: purification and characterization as a conjugated polyketone reductase.

PubMed

Hata, H; Shimizu, S; Hattori, S; Yamada, H

1989-02-24

Ketopantoyl-lactone reductase (2-dehydropantoyl-lactone reductase, EC 1.1.1.168) was purified and crystallized from cells of Candida parapsilosis IFO 0708. The enzyme was found to be homogeneous on ultracentrifugation, high-performance gel-permeation liquid chromatography and SDS-polyacrylamide gel electrophoresis. The relative molecular mass of the native and SDS-treated enzyme is approximately 40,000. The isoelectric point of the enzyme is 6.3. The enzyme was found to catalyze specifically the reduction of a variety of natural and unnatural polyketones and quinones other than ketopantoyl lactone in the presence of NADPH. Isatin and 5-methylisatin are rapidly reduced by the enzyme, the Km and Vmax values for isatin being 14 microM and 306 mumol/min per mg protein, respectively. Ketopantoyl lactone is also a good substrate (Km = 333 microM and Vmax = 481 mumol/min per mg protein). Reverse reaction was not detected with pantoyl lactone and NADP+. The enzyme is inhibited by quercetin, several polyketones and SH-reagents. 3,4-Dihydroxy-3-cyclobutene-1,2-dione, cyclohexenediol-1,2,3,4-tetraone and parabanic acid are uncompetitive inhibitors for the enzyme, the Ki values being 1.4, 0.2 and 3140 microM, respectively, with isatin as substrate. Comparison of the enzyme with the conjugated polyketone reductase of Mucor ambiguus (S. Shimizu, H. Hattori, H. Hata and H. Yamada (1988) Eur. J. Biochem. 174, 37-44) and ketopantoyl-lactone reductase of Saccharomyces cerevisiae suggested that ketopantoyl-lactone reductase is a kind of conjugated polyketone reductase.

Statin-induced inhibition of breast cancer proliferation and invasion involves attenuation of iron transport: intermediacy of nitric oxide and antioxidant defence mechanisms.

PubMed

Kanugula, Anantha Koteswararao; Gollavilli, Paradesi Naidu; Vasamsetti, Sathish Babu; Karnewar, Santosh; Gopoju, Raja; Ummanni, Ramesh; Kotamraju, Srigiridhar

2014-08-01

Accumulating evidence from in vitro, in vivo, clinical and epidemiological studies shows promising results for the use of statins against many cancers including breast carcinoma. However, the molecular mechanisms responsible for the anti-proliferative and anti-invasive properties of statins still remain elusive. In this study, we investigated the involvement of nitric oxide, iron homeostasis and antioxidant defence mechanisms in mediating the anti-proliferative and anti-invasive properties of hydrophobic statins in MDA-MB-231, MDA-MB-453 and BT-549 metastatic triple negative breast cancer cells. Fluvastatin and simvastatin significantly increased cytotoxicity which was reversed with mevalonate. Interestingly, fluvastatin downregulated transferrin receptor (TfR1), with a concomitant depletion of intracellular iron levels in these cells. Statin-induced effects were mimicked by geranylgeranyl transferase inhibitor (GGTI-298) but not farnesyl transferase inhibitor (FTI-277). Further, it was observed that TfR1 downregulation is mediated by increased nitric oxide levels via inducible nitric oxide synthase (iNOS) expression. NOS inhibitors (asymmetric dimethylarginine and 1400W) counteracted and sepiapterin, a precursor of tetrahydrobiopterin, exacerbated statin-induced depletion of intracellular iron levels. Notably, fluvastatin increased manganese superoxide dismutase (by repressing the transcription factor DNA damage-binding protein 2), catalase and glutathione which, in turn, diminished H2 O2 levels. Fluvastatin-induced downregulation of TfR1, matrix metalloproteinase-2, -9 and inhibition of invasion were reversed in the presence of aminotriazole, a specific inhibitor of catalase. Finally, we conclude that fluvastatin, by altering iron homeostasis, nitric oxide generation and antioxidant defence mechanisms, induces triple negative breast cancer cell death. © 2014 FEBS.

Comparative evaluation of HMG CoA reductase inhibitors in experimentally-induced myocardial necrosis: Biochemical, morphological and histological studies.

PubMed

Variya, Bhavesh C; Patel, Snehal S; Trivedi, Jinal I; Gandhi, Hardik P; Rathod, S P

2015-10-05

The present study was carried out to evaluate the protective effect of different statins on isoproterenol (ISO) induced myocardial necrosis. Atorvastatin, rosuvastatin, fluvastatin, simvastatin and pravastatin (10 mg/kg/day) were administered for 12 weeks. After pretreatment of 12 weeks myocardial necrosis was induced by subsequent injection of ISO (85 mg/kg/day, s.c.) to wistar rats. Serum biochemical parameters like glucose, lipid profile, cardiac markers and transaminases were evaluated. Animals were killed and heart was excised for histopathology and antioxidant study. Statins pretreated rats showed significant protection against ISO induced elevation in serum biochemical parameters and serum level of cardiac marker enzymes and transaminase level as compared to ISO control group. Mild to moderate protection was observed in different statins treated heart in histopathology and TTC stained sections. Result from our study also revealed that statins could efficiently protect against ISO intoxicated myocardial necrosis by impairing membrane bound enzyme integrity and endogenous antioxidant enzyme levels. Amongst all statins used, rosuvastatin and pravastatin were found to have maximum cardio-protective activity against ISO induced myocardial necrosis as compared to other statins. Copyright © 2015 Elsevier B.V. All rights reserved.

Identification and Development of Novel Inhibitors of Toxoplasma gondii Enoyl Reductase

PubMed Central

Tipparaju, Suresh K.; Muench, Stephen P.; Mui, Ernest J.; Ruzheinikov, Sergey N.; Lu, Jeffrey Z.; Hutson, Samuel L.; Kirisits, Michael J.; Prigge, Sean T.; Roberts, Craig W.; Henriquez, Fiona L.; Kozikowski, Alan P.; Rice, David W.; McLeod, Rima L.

2010-01-01

Toxoplasmosis causes significant morbidity and mortality and yet available medicines are limited by toxicities and hypersensitivity. Since improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have anti-parasite MIC90s ≤6μM without toxicity to host cells, three compounds have IC90s <45nM against recombinant TgENR and two protect mice. To further understand the mode of inhibition, the co-crystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7Å. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii. PMID:20698542

Ribonucleotide Reductase Inhibitors Reduce Atherosclerosis in a Double-Injury Rabbit Model

PubMed Central

Gallaugher, Laura D; Henry, Jon C; Kearns, Patrick N; Elford, Howard L; Bergdall, Valerie K; Cardounel, Arturo J

2009-01-01

Atheroproliferative disorders such as atherosclerosis are an important health problem and one of the leading causes of morbidity and mortality in the United States. Minimally invasive therapeutic procedures, including angioplasty with stent deployment, are used frequently for obstructive coronary artery disease. However, restenosis, a proliferative vascular response, is a common sequela to this procedure. The current study investigated the effect of inhibiting ribonucleotide reductase (RR), an enzyme necessary for cellular proliferation, in an attempt to ameliorate the proliferative response. Two RR inhibitors, didox and hydroxyurea, were chosen for their potent antiproliferative properties. Studies were carried out by using a double-injury rabbit model, in which endothelial denudation was followed by the administration of a high-fat diet. At 4 wk after initial endothelial denudation, the developing atherosclerotic lesion was subjected to transluminal balloon dilation to simulate clinical intervention with percutaneous transluminal angioplasty. The degree of restenosis and atheroproliferation was assessed at 8 wk. Histologic evaluation of the lesion demonstrated that treatment with didox and hydroxyurea significantly decreased lesion area and lumen loss. These results suggest that RR inhibition may be an effective new tool for the treatment of atheroproliferative disorders. PMID:20034432

Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death.

PubMed

Sierra, Saleta; Ramos, Maria C; Molina, Pilar; Esteo, Cynthia; Vázquez, Jose Antonio; Burgos, Javier S

2011-01-01

There is growing evidence to support the hypothesis that statins may act as neuroprotectants in several neuropathological conditions, including Alzheimer's disease. The mechanisms for neuroprotection are only partially understood, however, and pleiotropic phenomena could be involved. We have made a comparative study of 9 statins (lovastatin, mevastatin, pravastatin, simvastatin, cerivastatin, atorvastatin, fluvastatin, pitavastatin, and rosuvastatin), analyzing several parameters that could be related to neuroprotection, such as chemical structure, lipophilicity, potential blood-brain-barrier penetration (BBB), 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibition, cholesterol modulation in neurons, glia, and human hepatocyte cell lines, and protection against neurodegeneration caused by tau hyperphosphorylation induced by okadaic acid. Our results indicate that monacolin J derivatives (natural and semi-synthetic statins) are the best candidates for the prevention of neurodegenerative conditions due to their higher potential BBB penetration capacity, cholesterol lowering effect on neurons with a satisfactory safety profile, and in vitro protection against cell death caused by okadaic acid in culture. Among the nine statins studied, simvastatin presented the best characteristics for preventing neurodegenerative conditions.

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

Management of statin-intolerant patient.

PubMed

Arca, M; Pigna, G; Favoccia, C

2012-06-01

Large scale clinical trials have undoubtedly demonstrated that statins are effective in reducing cardiovascular events and all-cause mortality in almost all patient populations. Also the short and long-term safety of statin therapy has been well established in the majority of treated patients. Nevertheless, intolerance to statins must be frequently faced in the clinical practice. The most commonly observed adverse effects of statins are muscle symptoms and elevation of hepatic aminotransferase and creatinine kinase (CK) levels. Overall, myalgia (muscle pain with or without plasma CK elevations) and a single abnormally elevated liver function test constitute approximately two-thirds of reported adverse events during statin therapy. These side effects raise concerns in the patients and are likely to reduce patient's adherence and, consequently, the cardiovascular benefit. Therefore, it is mandatory that clinicians improve knowledge on the clinical aspects of side effects of statins and the ability to manage patients with intolerance to statins. Numerous different approaches to statin-intolerant patients have been suggested, but an evidence-based consensus is difficult to be reached due to the lack of controlled trials. Therefore, it might be useful to review protocols and procedures to control statin intolerance. The first step in managing intolerant patients is to determine whether the adverse events are indeed related to statin therapy. Then, the switching to another statin or lower dosage, the alternate dosing options and the use of non-statin compounds may be practical strategies. However, the cardiovascular benefit of these approaches has not been established, so that their use has to be employed after a careful clinical assessment of each patient.

Statins induce apoptosis through inhibition of Ras signaling pathways and enhancement of Bim and p27 expression in human hematopoietic tumor cells.

PubMed

Fujiwara, Daichiro; Tsubaki, Masanobu; Takeda, Tomoya; Tomonari, Yoshika; Koumoto, Yu-Ichi; Sakaguchi, Katsuhiko; Nishida, Shozo

2017-10-01

Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal-regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.

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.

Statins and biomineralization: data from the past and stratagies for the future

NASA Astrophysics Data System (ADS)

Kearney, S.

The background to this paper is based on research conducted by Dr. Gregory Mundy, at the University of Texas Health Science Center, and published in Science, 3rd December 1999. In it, he identified two types of statins (a highly prescribed class of pharmacological compounds, otherwise known as HMG Coa Reductase Inhibitors, that are currently used to lower high cholesterol and treat heart disease) that may have the potential to treat osteoporosis. This research is significant, given that his research found that the two types of statins in question (lovostatin and simvastatin) both decreased osteoclast (i.e. bone decomposing cells) activity while also, and importantly, increasing osteoblast (i.e. bone forming cells) activity. The advantages of such a drug, if found to be truly effective, are many when compared to the current pharmacological treatments of osteoporosis. This is for two primary reasons, namely greater effectiveness and lesser side effects. For example, the widely prescribed class of drugs known as bisphosphonates only block resorption (i.e. stop osteoclast activity) while another drug, calcitonin, causes nausea, vomiting and diarrhea. Hence, this research may have important implications for human spaceflight, in particular as a countermeasure against the bone wastage suffered by astronauts during long duration spaceflight. However, since Mundy's paper was first published, a number of epidemiological (i.e. observational) studies on the relationship between statin use and increased bone mass have been published. While some of these papers supported Mundy's results, a number have thrown doubt on the supposed benefits of statin use to treat osteoporosis. Hence the need to further investigate the actual effectiveness of this drug. It is proposed to utilize the facilities available onboard the international space station (ISS) to supplement ground-based research into this drug. This may encompass utilization of ESA's Biolab and NASA's Human Research Facility

Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: discovery, synthesis, and characterization of their binding mode by protein crystallography.

PubMed

Patterson, Stephen; Alphey, Magnus S; Jones, Deuan C; Shanks, Emma J; Street, Ian P; Frearson, Julie A; Wyatt, Paul G; Gilbert, Ian H; Fairlamb, Alan H

2011-10-13

Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.

Immune-mediated statin myopathy.

PubMed

Loganathan, Priyadarshini; Oddis, Chester V; Aggarwal, Rohit

2016-01-01

Statin-induced necrotizing autoimmune myopathy (SINAM) is associated with a unique clinical 5 phenotype of severe proximal muscle weakness during or after exposure to statins in patients with high creatine kinase (CK) levels. Electromyography (EMG) and muscle biopsy reveal features of a necrotizing myopathy and the anti-HMGCR autoantibody is frequently detected. Treatment requires a combination of statin discontinuation as well as immunomodulatory or immunosuppressive therapy. HLA typing (HLADRB1*1101) is strongly associated with anti-10 HMGCR autoantibody positivity in statin-exposed patients. It is well documented that statin triggers autoimmune disease in those with a genetic susceptibility. With the commercial availability of an accurate ELISA test, the natural history of the disease and its phenotypic features are becoming increasingly understood.

Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease.

PubMed

Kazi, Dhruv S; Moran, Andrew E; Coxson, Pamela G; Penko, Joanne; Ollendorf, Daniel A; Pearson, Steven D; Tice, Jeffrey A; Guzman, David; Bibbins-Domingo, Kirsten

2016-08-16

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recently approved for lowering low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease (ASCVD) and have potential for broad ASCVD prevention. Their long-term cost-effectiveness and effect on total health care spending are uncertain. To estimate the cost-effectiveness of PCSK9 inhibitors and their potential effect on US health care spending. The Cardiovascular Disease Policy Model, a simulation model of US adults aged 35 to 94 years, was used to evaluate cost-effectiveness of PCSK9 inhibitors or ezetimibe in heterozygous FH or ASCVD. The model incorporated 2015 annual PCSK9 inhibitor costs of $14,350 (based on mean wholesale acquisition costs of evolocumab and alirocumab); adopted a health-system perspective, lifetime horizon; and included probabilistic sensitivity analyses to explore uncertainty. Statin therapy compared with addition of ezetimibe or PCSK9 inhibitors. Lifetime major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke), incremental cost per quality-adjusted life-year (QALY), and total effect on US health care spending over 5 years. Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316,300 MACE at a cost of $503,000 per QALY gained compared with adding ezetimibe to statins (80% uncertainty interval [UI], $493,000-$1,737,000). In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $414,000 per QALY (80% UI, $277,000-$1,539,000). Reducing annual drug costs to $4536 per patient or less would be needed for PCSK9 inhibitors to be cost-effective at less than $100,000 per QALY. At 2015 prices, PCSK9 inhibitor use in all eligible patients was estimated to reduce cardiovascular care costs by $29 billion over 5 years, but drug costs increased by an estimated $592 billion (a 38

Efficacy of Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers in Coronary Artery Disease without Heart Failure in the Modern Statin Era: a Meta-Analysis of Randomized-Controlled Trials.

PubMed

Hoang, Vu; Alam, Mahboob; Addison, Daniel; Macedo, Francisco; Virani, Salim; Birnbaum, Yochai

2016-04-01

Current practice guidelines support the use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) in patients with coronary artery disease (CAD) without heart failure (HF). However, a number of cited trials were performed prior to the era of prevalent statin use. Our objective was to evaluate the effectiveness of ACEi and ARBs in reducing cardiovascular events as well as the impact of statin therapy. We searched the MEDLINE and EMBASE databases for randomized-controlled trials (1/1/1980 - 8/31/2015) with ACEi or ARBs as the single intervention for patients with CAD without HF. We assessed the outcomes of non-fatal myocardial infarction (MI), stroke, cardiovascular mortality and all-cause mortality. The relationship between these outcomes and the percentages of patients on statin therapy was evaluated using meta-regression analysis. A total of ten ACEi trials and five ARB trials were included for analysis, with 78,761 patients followed for a mean of 36 months. Treatment with ACEi was associated with decreased non-fatal MI (RR 0.83; 95 % CI 0.75-0.91), stroke (RR 0.76; 95 % CI 0.68-0.86), cardiovascular mortality (RR 0.83; 95 % CI 0.72-0.95), and all-cause mortality (RR 0.86; 95 % CI 0.80-0.93). Treatment with ARBs was associated only with a decreased incidence of stroke (RR 0.92; 95 % CI 0.87-0.98). When adjusted for statin use, there was a trend towards an attenuated effect of ACEi in reducing cardiovascular mortality with increased use of statins (p-value = 0.063). In CAD patients without HF, ACEi, but not ARBs decreases the risk of non-fatal MI, cardiovascular mortality and all-cause mortality, while both ACEi and ARBs decrease the risk of stroke.

Resolution and partial characterization of two aldehyde reductases of mammalian liver.

PubMed

Tulsiani, D R; Touster

1977-04-25

Investigation of NADP-dependent aldehyde reductase activity in mouse liver led to the finding that two distinct reductases are separable by DE52 ion exchange chromatography. Aldehyde reductase I (AR I) appears in the effluent, while aldehyde reductase II (AR II) is eluted with a salt gradient. By several procedures AR II was purified over 1100-fold from liver supernatant fraction, but AR I could be pruified only 107-fold because of its instability. The two enzymes are different in regard to pH optimum, substrate specificity, response to inhibitors, and reactivity with antibody to AR II. While both enzymes utilize aromatic aldehydes well, only AR II ACTS ON D-glucuronate, indicating that it is the aldyhyde reductase recently reported to be identical to NADP-L-gulonate dehydrogenase. The presence of two NADP-linked aldehyde reductases in liver has apparently not heretofore been reported.

Statins, fibrates, nicotinic acid, cholesterol absorption inhibitors, anion-exchange resins, omega-3 fatty acids: which drugs for which patients?

PubMed

Drexel, Heinz

2009-12-01

Classes of lipid lowering drugs differ strongly with respect to the types of lipids or lipoproteins they predominantly affect. Statins inhibit the de-novo synthesis of cholesterol. Consequently, the liver produces less VLDL, and the serum concentration primarily of LDL cholesterol (but, to a lesser extent, also of triglycerides) is lowered. Further, statins somewhat increase HDL cholesterol. There is abundant evidence that statins lower the rate of cardiovascular events. Cardiovascular risk reduction is the better, the lower the LDL cholesterol values achieved with statin therapy are. Some evidence is available that anion exchange resins which also decrease LDL cholesterol decrease vascular risk, too. This is not the case for the ezetimibe, which strongly lowers LDL cholesterol: its potential to decrease vascular risk remains to be proven. In contrast evidence for cardiovascular risk reduction through the mainly triglyceride lowering fibrates as well as for niacin is available. Niacin is the most potent HDL increasing drug currently available and besides increasing HDL cholesterol efficaciously lowers triglycerides and LDL cholesterol. Large ongoing trials address the decisive question whether treatment with fibrates and niacin provides additional cardiovascular risk reduction when given in addition to statin treatment.

[Severe hypercholesterolaemia--when to use the proprotein convertase subtilisin-kexin type 9 protease inhibitors (PCSK9 inhibitors)? Polish Society of Cardiology experts' group statement].

PubMed

Cybulska, Barbara; Gaciong, Zbigniew; Hoffman, Piotr; Jankowski, Piotr; Kłosiewicz-Latoszek, Longina; Kaźmierczak, Jarosław; Mitręga, Katarzyna; Opolski, Grzegorz; Pająk, Andrzej; Ponikowski, Piotr; Rynkiewicz, Andrzej; Stępińska, Janina; Średniawa, Beata; Kalarus, Zbigniew

2016-01-01

The severe hypercholesterolaemia can be recognised when low density lipoprotein cholesterol (LDL-C) serum levels are equal to or above 5 mmol/L (≥ 190 mg/dL). The prevalence of LDL-C ≥ 5 mmol/L is 3.8% in Polish population aged 18-79 years. Among these adults there are patients with familial hypercholesterolaemia (FH). According to meta-analysis of 6 Polish population surveys prevalence of heterozygous FH (HeFH) diagnosed using Dutch Lipid Clinic criteria is 0.4% (95% Cl 0.28-0.53%) in men and women aged 20-74 years, i.e. one in every 250 people. As HeFH is a wellknown cause of premature coronary heart disease the rigorous treatment targets for LDL-C have been established in clinical guidelines. Their achievements, even with a high dose of high efficacy statin therapy is difficult or even impossible. New strong hypolipidaemic drugs i.e. PCSK9 inhibitors have been initiated against this chalange. Both drugs, evolocumab and alirocumab, have been extensively studied in numerous phase 2 and phase 3 trials. Fewer studies with bococizumab are available until now. The PCSK9 inhibitors, as monotherapy as well in combination with statins were associated with mean LDL-C reduction about 60%. It means that the majority of patients (70-90%) with severe hypercholesterolaemia (including HeFH), treated with statins, after addition of PCSK9 inhibitors were able to achieve an LDL-C < 2.5 mmol/L (< 100 mg/dL) or < 1.8 mmol/L (< 70 mg/dL) level. Another group of patients who may benefit from PCSK9 inhibitors include those who need lipid lowering therapy, but who are statin intolerant, especially because of statin-associated muscle symptoms (SAMS). In our statement we have accepted the diagnosis of SAMS proposed recently by European Atherosclerosis Society. Today the longest clinical trial with evolocumab (11 months) was the open OSLER study, and with alirocumab ODYSSEY LONG TERM (78 weeks). In the first one the reduction of cardiovascular events by 53% (95% Cl 22-72%) was observed

Organic Ion Transporters and Statin Drug Interactions.

PubMed

Kellick, Kenneth

2017-11-25

Statin drug-drug interactions (DDIs) are both troublesome to patients as well as costly to medical resources. The ability to predict and avoid these events could lead to improved outcomes as well as patient satisfaction. This review will explore efforts to better understand and predict these interactions specifically related to one drug transport system, the organic anion-transporting polypeptides (OATPs) specifically OATP1B1 and OATP1B3. Since the publication of the discovery of OATPs, there have been various pharmacokinetic models that have been proposed to explain the variation in pharmacokinetic and clinical effects related to the OATPs. The effects in transport activity appear to be partially related to the individual polymorphisms studied. Drug-drug interactions can occur when other drugs compete for the metabolic site on the OATPs. Various medications are identified as substrates and/or inhibitors of the OATPs, thereby complicating the ability to fully predict the impact on levels and effects. All of the models reviewed claim successes but show limited clinical utility. There are specific populations that have been identified, predominately various Asian descendants that require lower doses of statins to avoid adverse events. The concept of attributing these actions to the OATPs has been explored, but current models cannot accurately predict statin blood levels or elimination constants. The current research only points to the differences in the human genome and the single-nucleotide polymorphisms that exist between us. Based upon the currently available studies, there is beginning to be a glimmer in the understanding how different populations respond to statin transport and elimination. Additionally and unfortunately, there are other enzymes to be studied to better predict patient differences. Clearly, there has been much work completed, yet many more questions require answering to better understand these transport proteins.

Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol.

PubMed

Smeriglio, Antonella; Giofrè, Salvatore V; Galati, Enza M; Monforte, Maria T; Cicero, Nicola; D'Angelo, Valeria; Grassi, Gianpaolo; Circosta, Clara

2018-02-07

Aldose reductase (ALR2) is a key enzyme involved in diabetic complications and the search for new aldose reductase inhibitors (ARIs) is currently very important. The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications. Non-psychotropic phytocannabinoids exert multiple pharmacological effects with therapeutic potential in many diseases such as inflammation, cancer, diabetes. Here, we have investigated the inhibitory effects of extracts and their fractions from two Cannabis sativa L. chemotypes with high content of cannabidiol (CBD)/cannabidiolic acid (CBDA) and cannabigerol (CBG)/cannabigerolic acid (CBGA), respectively, on human recombinant and pig kidney aldose reductase activity in vitro. A molecular docking study was performed to evaluate the interaction of these cannabinoids with the active site of ALR2 compared to known ARIs. The extracts showed significant dose-dependent aldose reductase inhibitory activity (>70%) and higher than fractions. The inhibitory activity of the fractions was greater for acidic cannabinoid-rich fractions. Comparative molecular docking results have shown a higher stability of the ALR2-cannabinoid acids complex than the other inhibitors. The extracts of Cannabis with high content of non-psychotropic cannabinoids CBD/CBDA or CBG/CBGA significantly inhibit aldose reductase activity. These results may have some relevance for the possible use of C. sativa chemotypes based preparations as aldose reductase inhibitors. Copyright © 2018 Elsevier B.V. All rights reserved.

Radiolabelling and positron emission tomography of PT70, a time-dependent inhibitor of InhA, the Mycobacterium tuberculosis enoyl-ACP reductase

DOE PAGES

Wang, Hui; Liu, Li; Lu, Yang; ...

2015-07-14

PT70 is a diaryl ether inhibitor of InhA, the enoyl-ACP reductase in the Mycobacterium tuberculosis fatty acid biosynthesis pathway. It has a residence time of 24 min on the target, and also shows antibacterial activity in a mouse model of tuberculosis infection. Due to the interest in studying target tissue pharmacokinetics of PT70, we developed a method to radiolabel PT70 with carbon-11 and have studied its pharmacokinetics in mice and baboons using positron emission tomography.

Radiolabelling and positron emission tomography of PT70, a time-dependent inhibitor of InhA, the Mycobacterium tuberculosis enoyl-ACP reductase

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

Wang, Hui; Liu, Li; Lu, Yang

PT70 is a diaryl ether inhibitor of InhA, the enoyl-ACP reductase in the Mycobacterium tuberculosis fatty acid biosynthesis pathway. It has a residence time of 24 min on the target, and also shows antibacterial activity in a mouse model of tuberculosis infection. Due to the interest in studying target tissue pharmacokinetics of PT70, we developed a method to radiolabel PT70 with carbon-11 and have studied its pharmacokinetics in mice and baboons using positron emission tomography.

The effect of statins on erectile dysfunction: a meta-analysis of randomized trials.

PubMed

Kostis, John B; Dobrzynski, Jeanne M

2014-07-01

Erectile dysfunction (ED) is common in older men, especially those with comorbidities such as diabetes and atherosclerotic disease, conditions where statins are frequently prescribed. To examine the effect of statin therapy on ED using the five-item version of the International Inventory of Erectile Function (IIEF). We performed a random-effects meta-analysis of studies identified by a systematic search of MEDLINE, Web of Knowledge, the Cochrane Database, and ClinicalTrials.gov. Examination of the 186 retrieved citations resulted in the selection of 11 randomized trials for inclusion in the meta-analysis. Change in the IIEF score. IIEF increased by 3.4 points (95% CI 1.7-5.0, P = 0.0001) with statins compared to control. This effect remained statistically significant after multiple sensitivity analyses, including analysis for publication bias, a cumulative meta-analysis, and 11 repeated analyses with each study omitted sequentially. The increase in IIEF with statins was approximately one-third to one-half of that previously reported with phosphodiesterase-5 inhibitors and larger than the effect of lifestyle modification. Metaregression showed an increase in benefit with decreasing lipophilicity. The average age of participants and the degree of LDL cholesterol lowering did not alter the effect on IIEF. Statins cause a clinically relevant improvement of erectile function as measured by the five-item version of the IIEF. © 2014 International Society for Sexual Medicine.

Severe Rhabdomyolysis Associated with the Cerivastatin-Gemfibrozil Combination Therapy

PubMed Central

Lau, Theodore K.; Leachman, D. Richard; Lufschanowski, Roberto

2001-01-01

Cerivastatin is the new 3rd-generation of the synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, the 1st drugs of choice for treating hypercholesterolemia. A potent inhibitor of HMG-CoA reductase, it possesses a high affinity for liver tissue and decreases plasma low-density lipoprotein cholesterol at microgram doses. Cerivastatin produces reductions in low-density lipoprotein cholesterol of 31.3% and 36.1% at doses of 0.3 and 0.4 mg/day, respectively. It is an uncomplicated agent with regard to its pharmacokinetic profile, low potential for interaction with other drugs, and suitability for use in those with impaired renal function. Most other statins have been implicated in causing rhabdomyolysis, either as mono-therapy or in combination with other agents. We report what to our knowledge is the most profound case yet in the literature of rhabdomyolysis in association with ceriva-statin-gemfibrozil combination therapy, in regard both to the extreme elevation in serum creatinine kinase and to the patient's near-paralytic weakness. PMID:11453128

Rational design of nitrofuran derivatives: Synthesis and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase.

PubMed

Arias, D G; Herrera, F E; Garay, A S; Rodrigues, D; Forastieri, P S; Luna, L E; Bürgi, M D L M; Prieto, C; Iglesias, A A; Cravero, R M; Guerrero, S A

2017-01-05

The rational design and synthesis of a series of 5-nitro-2-furoic acid analogues are presented. The trypanocidal activity against epimastigote forms of Trypanosoma cruzi and the toxic effects on human HeLa cells were tested. Between all synthetic compounds, three of thirteen had an IC 50 value in the range of Nfx, but compound 13 exhibited an improved effect with an IC 50 of 1.0 ± 0.1 μM and a selective index of 70 in its toxicity against HeLa cells. We analyzed the activity of compounds 8, 12 and 13 to interfere in the central redox metabolic pathway in trypanosomatids, which is dependent of reduced trypanothione as the major pivotal thiol. The three compounds behaved as better inhibitors of trypanothione reductase than Nfx (Ki values of 118 μM, 61 μM and 68 μM for 8, 12 and 13, respectively, compared with 245 μM for Nfx), all following an uncompetitive enzyme inhibition pattern. Docking analysis predicted a binding of inhibitors to the enzyme-substrate complex with binding energy calculated in-silico that supports such molecular interaction. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Statin intolerance - a question of definition.

PubMed

Algharably, Engi Abdel-Hady; Filler, Iris; Rosenfeld, Stephanie; Grabowski, Katja; Kreutz, Reinhold

2017-01-01

Statin therapy is the backbone of pharmacologic therapy for low-density lipoproteins cholesterol lowering and plays a pivotal role in cardiovascular disease prevention. Statin intolerance is understood as the inability to continue using a statin to reduce individual cardiovascular risk sufficiently, due to the development of symptoms or laboratory abnormalities attributable to the initiation or dose escalation of a statin. Muscle symptoms are the most common side effects observed. Areas covered: The main aim of this article is to present a review on published definitions of statin intolerance. In addition, a brief review on clinical aspects and risk factors of statin intolerance is provided and features for a common definition for statin intolerance are suggested. Expert opinion: A definition of statin intolerance by major drug regulatory agencies is not available. In clinical studies, different definitions are chosen and results are not comparable; different medical associations do not agree on one common definition. There is an unmet need to establish a common definition of statin intolerance to ensure an appropriate clinical use of this important drug class. Further work is required to develop a consensus definition on statin intolerance that could have significant positive impact on both research and clinical management.

Manumycin A Is a Potent Inhibitor of Mammalian Thioredoxin Reductase-1 (TrxR-1).

PubMed

Tuladhar, Anupama; Rein, Kathleen S

2018-04-12

The anticancer effect of manumycin A (Man A) has been attributed to the inhibition of farnesyl transferase (FTase), an enzyme that is responsible for post-translational modification of Ras proteins. However, we have discovered that Man A inhibits mammalian cytosolic thioredoxin reductase 1 (TrxR-1) in a time-dependent manner, with an IC 50 of 272 nM with preincubation and 1586 nM without preincubation. The inhibition of TrxR-1 by Man A is irreversible and is the result of a covalent interaction between Man A and TrxR-1. Evidence presented herein demonstrates that Man A forms a Michael adduct with the selenocysteine residue, which is located in the C-terminal redox center of TrxR-1. Inhibitors of TrxR-1, which act through this mechanism, convert TrxR-1 into a SecTRAP, which utilizes NADPH to reduce oxygen to superoxide radical anion (O 2 -• ).

Does Googling lead to statin intolerance?

PubMed

Khan, Sarah; Holbrook, Anne; Shah, Baiju R

2018-07-01

The nocebo effect, where patients with expectations of adverse effects are more likely to experience them, may contribute to the high rate of statin intolerance found in observational studies. Information that patients read on the internet may be a precipitant of this effect. The objective of the study was to establish whether the number of websites about statin side effects found using Google is associated with the prevalence of statin intolerance. The prevalence of statin intolerance in 13 countries across 5 continents was established in a recent study via a web-based survey of primary care physicians and specialists. Using the Google search engine for each country, the number of websites about statin side effects was determined, and standardized to the number of websites about statins overall. Searches were restricted to pages in the native language, and were conducted after connecting to each country using a virtual private network (VPN). English-speaking countries (Australia, Canada, UK, USA) had the highest prevalence of statin intolerance and also had the largest standardized number of websites about statin side effects. The sample Pearson correlation coefficient between these two variables was 0.868. Countries where patients using Google are more likely to find websites about statin side effects have greater levels of statin intolerance. The nocebo effect driven by online information may be contributing to statin intolerance. Copyright © 2018 Elsevier B.V. All rights reserved.

Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants.

PubMed

Srinivasan, Bharath; Rodrigues, João V; Tonddast-Navaei, Sam; Shakhnovich, Eugene; Skolnick, Jeffrey

2017-07-21

In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems. Dihydrofolate reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds discovered by a combination of pocket-based virtual ligand screening and systematic scaffold hopping. These inhibitors show a unique uncompetitive or noncompetitive inhibition mechanism, distinct from those reported for all known inhibitors of DHFR, indicative of binding to a unique pocket distinct from either substrate or cofactor-binding pockets. Furthermore, we demonstrate that rescue mutants of EcDHFR, with reduced affinity to all known classes of DHFR inhibitors, are inhibited at the same concentration as the wild-type. These compounds also exhibit antibacterial activity against E. coli harboring the drug-resistant variant of DHFR. This discovery is the first report on a novel class of inhibitors targeting a unique pocket on EcDHFR.

Risk of Colchicine-Associated Myopathy in Gout: Influence of Concomitant Use of Statin.

PubMed

Kwon, Oh Chan; Hong, Seokchan; Ghang, Byeongzu; Kim, Yong-Gil; Lee, Chang-Keun; Yoo, Bin

2017-05-01

The purpose of this study was to investigate the risk of myopathy when statins are coadministered with colchicine in patients with gout. In gout patients who received colchicine with or without statin, clinical data collected included medications and history of hypertension, chronic kidney disease, and liver cirrhosis. Myopathy was defined as the presence of muscle symptoms with elevated creatine kinase or myoglobin. Multivariate analysis was performed to identify risk factors for myopathy. Inverse probability of treatment weighting (IPTW)-adjusted analysis was used to evaluate the influence of concomitant colchicine and statin use on myopathy. Of 674 patients, 486 received colchicine alone and 188 also received statin. The incidence of myopathy was not significantly higher in those on both drugs than in those on colchicine alone (2.7% vs 1.4%, P = .330). On multivariate analysis, chronic kidney disease (hazard ratio [HR] 29.056; 95% confidence interval [CI], 4.387-192.450; P <.001), liver cirrhosis (HR 10.676; 95% CI, 1.279-89.126; P = .029), higher colchicine dose (HR 20.960; 95% CI, 1.835-239.481; P = .014), and concomitant CYP3A4 inhibitor (HR 12.027; 95% CI, 2.743-52.725; P = .001) were associated with increased risk of myopathy. Concomitant use of statins, however, was not, even after adjusting for confounders (HR 1.123; 95% CI, 0.262-4.814; P = .875; IPTW-adjusted HR 0.321; 95% CI, 0.077-1.345; P = .120). Concomitant use of statin and colchicine was not associated with increased risk of myopathy. Thus, concomitant use of statin with colchicine seems to be safe from myotoxicity in gout patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Individualized Statin Benefit for Determining Statin Eligibility in the Primary Prevention of Cardiovascular Disease.

PubMed

Thanassoulis, George; Williams, Ken; Altobelli, Kathleen Kimler; Pencina, Michael J; Cannon, Christopher P; Sniderman, Allan D

2016-04-19

Current guidelines recommend statins in the primary prevention of cardiovascular disease on the basis of predicted cardiovascular risk without directly considering the expected benefits of statin therapy based on the available randomized, controlled trial evidence. We included 2134 participants representing 71.8 million American residents potentially eligible for statins in primary prevention from the National Health and Nutrition Examination Survey for the years 2005 to 2010. We compared statin eligibilities using 2 separate approaches: a 10-year risk-based approach (≥7.5% 10-year risk) and an individualized benefit approach (ie, based on predicted absolute risk reduction over 10 years [ARR10] ≥2.3% from randomized, controlled trial data). A risk-based approach led to the eligibility of 15.0 million (95% confidence interval, 12.7-17.3 million) Americans, whereas a benefit-based approach identified 24.6 million (95% confidence interval, 21.0-28.1 million). The corresponding numbers needed to treat over 10 years were 21 (range, 9-44) and 25 (range, 9-44). The benefit-based approach identified 9.5 million lower-risk (<7.5% 10-year risk) Americans not currently eligible for statin treatment who had the same or greater expected benefit from statins (≥2.3% ARR10) compared with higher-risk individuals. This lower-risk/acceptable-benefit group includes younger individuals (mean age, 55.2 versus 62.5 years; P<0.001 for benefit based versus risk based) with higher low-density lipoprotein cholesterol (140 versus133 mg/dL; P=0.01). Statin treatment in this group would be expected to prevent an additional 266 508 cardiovascular events over 10 years. An individualized statin benefit approach can identify lower-risk individuals who have equal or greater expected benefit from statins in primary prevention compared with higher-risk individuals. This approach may help develop guideline recommendations that better identify individuals who meaningfully benefit from statin

A [32P]-NAD+-based method to identify and quantitate long residence time enoyl-ACP reductase inhibitors

PubMed Central

Yu, Weixuan; Neckles, Carla; Chang, Andrew; Bommineni, Gopal Reddy; Spagnuolo, Lauren; Zhang, Zhuo; Liu, Nina; Lai, Christina; Truglio, James; Tonge, Peter J.

2015-01-01

The classical methods for quantifying drug-target residence time (tR) use loss or regain of enzyme activity in progress curve kinetic assays. However, such methods become imprecise at very long residence times, mitigating the use of alternative strategies. Using the NAD(P)H-dependent FabI enoyl-ACP reductase as a model system, we developed a Penefsky column-based method for direct measurement of tR, where the off-rate of the drug was determined with radiolabeled [adenylate-32P] NAD(P+) cofactor. Twenty-three FabI inhibitors were analyzed and a mathematical model was used to estimate limits to the tR values of each inhibitor based on percent drug-target complex recovery following gel filtration. In general, this method showed good agreement with the classical steady state kinetic methods for compounds with tR values of 10-100 min. In addition, we were able to identify seven long tR inhibitors (100-1500 min) and to accurately determine their tR values. The method was then used to measure tR as a function of temperature, an analysis not previously possible using the standard kinetic approach due to decreased NAD(P)H stability at elevated temperatures. In general, a 4-fold difference in tR was observed when the temperature was increased from 25 °C to 37 °C . PMID:25684450

Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)

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

Mehboob, Shahila; Song, Jinhua; Hevener, Kirk E.

Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. In the bacterial FASII pathway we found it a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here, we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. Furthermore, these compounds display an improved low nanomolar enzymatic activity as well as promisingmore » low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). Finally, the improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity.« less

Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI)

DOE PAGES

Mehboob, Shahila; Song, Jinhua; Hevener, Kirk E.; ...

2015-01-29

Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. In the bacterial FASII pathway we found it a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here, we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. Furthermore, these compounds display an improved low nanomolar enzymatic activity as well as promisingmore » low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). Finally, the improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity.« less

Impact of statin guidelines on statin utilization and costs in an employer-based primary care clinic.

PubMed

Gurgle, Holly E; Schauerhamer, Marisa B; Rodriguez, Simón A; McAdam-Marx, Carrie

2017-12-01

The purpose of this study was to describe statin utilization and costs in an employer-based patient cohort by comparing actual practice and assumed adoption of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) or 2016 US Preventive Services Task Force (USPSTF) statin recommendations versus the guidelines described in 2001 (and supplemented in 2004) in the Third Report of the National Cholesterol Education Program's Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATPIII). Descriptive cohort analysis included patients treated in an employer-based primary care clinic between January 2012 and April 2014. ATPIII, ACC/AHA, and USPSTF recommendations were retrospectively applied at the patient level based on lipid levels and statin prescribing data collected from a health risk assessment and electronic health record. Actual statin prescribing was compared with prescribing predicted by guideline recommendations. Costs for each strategy were estimated using employer pharmacy claims data. The study included 555 patients, of whom 112 (20.2%) were treated with a statin at baseline. ATPIII and ACC/AHA recommended statin use in 284 (51.2%) and 279 (50.3%) patients, respectively. Within the subgroup of 479 primary prevention patients, ACC/AHA recommended statin use in 203 (42.4%) versus USPSTF, which recommended statin use in 91 (19.0%). The 90-day cost per patient was similar to baseline with implementation of ATPIII or ACC/AHA recommendations, excluding use of brand name-only high-intensity statins, and costs could be reduced slightly with implementation of USPSTF guidelines. Despite differences in ATPIII, ACC/AHA, and USPSTF guidelines, application of any of these statin recommendations would result in optimized statin utilization and fairly neutral effects on cost in this real-world employer-based population.

A novel class of α-glucosidase and HMG-CoA reductase inhibitors from Ganoderma leucocontextum and the anti-diabetic properties of ganomycin I in KK-Ay mice.

PubMed

Wang, Kai; Bao, Li; Ma, Ke; Zhang, Jinjin; Chen, Baosong; Han, Junjie; Ren, Jinwei; Luo, Huajun; Liu, Hongwei

2017-02-15

Three new meroterpenoids, ganoleucin A-C (1-3), together with five known meroterpenoids (4-8), were isolated from the fruiting bodies of Ganoderma leucocontextum. The structures of the new compounds were elucidated by extensive spectroscopic analysis, circular dichroism (CD) spectroscopy, and chemical transformation. The inhibitory effects of 1-8 on HMG-CoA reductase and α-glucosidase were tested in vitro. Ganomycin I (4), 5, and 8 showed stronger inhibitory activity against HMG-CoA reductase than the positive control atorvastatin. Compounds 1, and 3-8 presented potent noncompetitive inhibitory activity against α-glucosidase from both yeast and rat small intestinal mucosa. Ganomycin I (4), the most potent inhibitor against both α-glucosidase and HMG-CoA reductase, was synthesized and evaluated for its in vivo bioactivity. Pharmacological results showed that ganomycin I (4) exerted potent and efficacious hypoglycemic, hypolipidemic, and insulin-sensitizing effects in KK-A y mice. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Early Statin Use and the Progression of Alzheimer Disease: A Total Population-Based Case-Control Study.

PubMed

Lin, Feng-Cheng; Chuang, Yun-Shiuan; Hsieh, Hui-Min; Lee, Tzu-Chi; Chiu, Kuei-Fen; Liu, Ching-Kuan; Wu, Ming-Tsang

2015-11-01

The protective effect of statin on Alzheimer disease (AD) is still controversial, probably due to the debate about when to start the use of statin and the lack of any large-scale randomized evidence that actually supports the hypothesis. The purpose of this study was to examine the protective effect of early statin use on mild-to-moderate AD in the total Taiwanese population.This was a total population-based case-control study, using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The study patients were those with newly diagnosed dementia (ICD-9 290.x) and prescribed any acetylcholinesterase inhibitors (AChEI) from the Taiwan National Health Insurance dataset in 1997 to 2008. The newly diagnosed eligible mild-to-moderate AD patients were traced from the dates of their index dates, which was defined as the first day to receive any AChEI treatment, back to 1 year (exposure period) to categorize them into AD with early statin use and without early statin use. Early statin use was defined as patients using statin before AChEI treatment. Alzheimer disease patients with early statin use were those receiving any statin treatment during the exposure period. Then, we used propensity-score-matched strategy to match these 2 groups as 1:1. The matched study patients were followed-up from their index dates. The primary outcome was the discontinuation of AChEI treatment, indicating AD progression.There were 719 mild-to-moderate AD-paired patients with early statin use and without early statin use for analyses. Alzheimer disease progression was statistically lower in AD patients with early statin use than those without (P = 0.00054). After adjusting for other covariates, mild-to-moderate AD patients with early stain use exhibited a 0.85-risk (95% CI = 0.76-0.95, P = 0.0066) to have AD progression than those without.Early statin use was significantly associated with a reduction in AD

The inhibitor protein of phosphorylated nitrate reductase from spinach (Spinacia oleracea) leaves is a 14-3-3 protein.

PubMed

Bachmann, M; Huber, J L; Liao, P C; Gage, D A; Huber, S C

1996-06-03

The inhibitor protein (IP) that inactivates spinach leaf NADH:nitrate reductase (NR) has been identified for the first time as a member of the eukaryotic 14-3-3 protein family based on three lines of evidence. First, the sequence of an eight amino acid tryptic peptide, obtained from immunopurified IP, matched that of a highly conserved region of the 14-3-3 proteins. Second, an authentic member of the 14-3-3 family, recombinant Arabidopsis GF14omega, caused inactivation of phospho-NR in a magnesium-dependent manner identical to IP. Third, an anti-GF14 monoclonal antibody cross-reacted with IP and anti-IP monoclonal antibodies cross-reacted with GF14omega.

Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management

PubMed Central

Stroes, Erik S.; Thompson, Paul D.; Corsini, Alberto; Vladutiu, Georgirene D.; Raal, Frederick J.; Ray, Kausik K.; Roden, Michael; Stein, Evan; Tokgözoğlu, Lale; Nordestgaard, Børge G.; Bruckert, Eric; De Backer, Guy; Krauss, Ronald M.; Laufs, Ulrich; Santos, Raul D.; Hegele, Robert A.; Hovingh, G. Kees; Leiter, Lawrence A.; Mach, Francois; März, Winfried; Newman, Connie B.; Wiklund, Olov; Jacobson, Terry A.; Catapano, Alberico L.; Chapman, M. John; Ginsberg, Henry N.; Stroes, Erik; Thompson, Paul D.; Corsini, Alberto; Vladutiu, Georgirene D.; Raal, Frederick J.; Ray, Kausik K.; Roden, Michael; Stein, Evan; Tokgözoğlu, Lale; Nordestgaard, Børge G.; Bruckert, Eric; Krauss, Ronald M.; Laufs, Ulrich; Santos, Raul D.; März, Winfried; Newman, Connie B.; John Chapman, M.; Ginsberg, Henry N.; John Chapman, M.; Ginsberg, Henry N.; de Backer, Guy; Catapano, Alberico L.; Hegele, Robert A.; Kees Hovingh, G.; Jacobson, Terry A.; Leiter, Lawrence; Mach, Francois; Wiklund, Olov

2015-01-01

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential. PMID:25694464

Risk of Late-Onset Alzheimer's Disease by Plasma Cholesterol: Rational In Silico Drug Investigation of Pyrrole-Based HMG-CoA Reductase Inhibitors.

PubMed

Shahbazi, Sajad; Kaur, Jagdeep; Kuanar, Ananya; Kar, Dattatreya; Singh, Shikha; Sobti, Ranbir Chander

Alzheimer's disease (AD), a worldwide renowned progressive neurodegenerative disorder, is the most common cause of dementia. There are several studies on the important role of cholesterol metabolism in AD pathogenesis, which indicated that the high concentrations of serum cholesterol increase the risk of AD. Biosynthesis of the plasma cholesterol and other isoprenoids is catalyzed by 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) through the conversion of HMG-CoA to mevalonic acid in mevalonate pathway. Normally, the high level of plasma cholesterol is downregulated by HGMCR inhibition as the result of degradation of LDL, but in abnormal conditions, for example, high blood glucose, the HMGCR over activated resulting in uncontrolled blood cholesterol. Selective HMGCR inhibitor drugs such as statins, which increase the catabolism of plasma LDL and reduce the plasma concentration of cholesterol, have been investigated as a possible treatment for AD. In the present study, we have identified the binding modes of 22 various derivatives of 3-sulfamoylpyrroles 16, prepared via a [3 + 2] cycloaddition of a münchnone with a sulfonamide-substituted alkyne, by using efficient biocomputational tools. Out of 22, 5 ligands, with code numbers 5b, 5c, 5d, 5i, and 5j, possessed most absorption, distribution, metabolism, and excretion (ADME) and toxicity profiles in acceptable ranges. Among ligands, 5j (sodium (3R,5R)-7-(3-(N,N-dimethylsulfamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate) could inhibit HMGCR enzyme in inhibitory binding site with affinity value -12.17 kcal/mol and binding energy -94.10 kcal/mol through 5 hydrogen bonds. It showed the best ADME and toxicity profiling and higher affinity values than other potent candidate and market drugs such as atorvastatin and rosuvastatin. Therefore, it is suggested for further in vivo investigation, the druggability of 5j and its cholesterol regulatory impact on AD.

Statins and hip fracture risk in men: a population-based case-control study.

PubMed

Adams, Annette L; Shi, Jiaxiao M; Reynolds, Kristi; Haque, Reina; Cheetham, T Craig; Kawatkar, Aniket A; Fithian, Donald C; Jacobsen, Steven J

2015-11-01

To estimate the association between hydroxymethylglutaryl-CoA inhibitor (statin) use and hip fracture. We conducted a population-based case-control study. Cases were 6774 male enrollees in a large managed care organization, aged 45 or more years, with an incident hip fracture from 1997 to 2006. Controls without fracture (n = 6774) were matched to cases on age, race, and medical center. Electronic information on pharmaceutical use was used to identify the dispensing of statins from 1991 forward. Overall, 1884 (27.8%) cases and 2150 controls (31.7%) used a statin before index date (matched odds ratio [mOR] = 0.81, 95% confidence interval [CI] = 0.74-0.87). Adjustment for comorbidity burden strengthened the magnitude of the overall association (mOR = 0.68, CI = 0.62-0.74). The adjusted association was similar across age groups but was strongest among men aged 80 years or more (mOR = 0.62, CI = 0.54-0.71) and was most pronounced in African Americans (mOR = 0.43, CI = 0.28-0.64). Greater duration of statin use did not alter the odds ratios. These data add to the growing evidence of a potential protective effect of statin use on bone health. However, these results need to be replicated in a prospective study that can account for confounding by indication which may explain these findings. Copyright © 2015 Elsevier Inc. All rights reserved.

Inhibition of human anthracycline reductases by emodin — A possible remedy for anthracycline resistance

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

Hintzpeter, Jan, E-mail: hintzpeter@toxi.uni-kiel.de; Seliger, Jan Moritz; Hofman, Jakub

2016-02-15

The clinical application of anthracyclines, like daunorubicin and doxorubicin, is limited by two factors: dose-related cardiotoxicity and drug resistance. Both have been linked to reductive metabolism of the parent drug to their metabolites daunorubicinol and doxorubicinol, respectively. These metabolites show significantly less anti-neoplastic properties as their parent drugs and accumulate in cardiac tissue leading to chronic cardiotoxicity. Therefore, we aimed to identify novel and potent natural inhibitors for anthracycline reductases, which enhance the anticancer effect of anthracyclines by preventing the development of anthracycline resistance. Human enzymes responsible for the reductive metabolism of daunorubicin were tested for their sensitivity towards anthrachinones,more » in particular emodin and anthraflavic acid. Intense inhibition kinetic data for the most effective daunorubicin reductases, including IC{sub 50}- and K{sub i}-values, the mode of inhibition, as well as molecular docking, were compiled. Subsequently, a cytotoxicity profile and the ability of emodin to reverse daunorubicin resistance were determined using multiresistant A549 lung cancer and HepG2 liver cancer cells. Emodin potently inhibited the four main human daunorubicin reductases in vitro. Further, we could demonstrate that emodin is able to synergistically sensitize human cancer cells towards daunorubicin at clinically relevant concentrations. Therefore, emodin may yield the potential to enhance the therapeutic effectiveness of anthracyclines by preventing anthracycline resistance via inhibition of the anthracycline reductases. In symphony with its known pharmacological properties, emodin might be a compound of particular interest in the management of anthracycline chemotherapy efficacy and their adverse effects. - Highlights: • Natural and synthetic compounds were identified as inhibitors for human daunorubicin reductases. • Emodin is a potent inhibitor for human daunorubicin

Current status of 5α-reductase inhibitors in prostate disease management.

PubMed

Kang, Dong Il; Chung, Jae Il

2013-04-01

The key enzyme in the androgen synthesis and androgen receptor pathways is 5α-reductase (5-AR), which occurs as three isoenzymes. Types I and II 5-ARs the most important clinically, and two different 5-AR inhibitors (5-ARIs), finasteride and dutasteride, have been developed. Several urology associations have recommended and upgraded the use of 5-ARIs for an enlarged prostate with lower urinary tract symptoms. In the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events Trial, 5-ARIs reduced the incidence of low-grade prostate cancer. However, despite the documented reductions in the overall incidence of prostate cancer, 5-ARIs are at the center of a dispute. The American Society of Clinical Oncology (ASCO) and the American Urology Association (AUA) presented clinical guidelines for the use of 5-ARIs for chemoprevention of prostate cancer in 2008. However, ASCO/AUA has eliminated these from the main "Clinical Guidelines" in 2012, because the U.S. Food and Drug Administration denied a supplemental New Drug Application for the use of dutasteride for prostate cancer chemoprevention. The 5-ARIs can also be used to manage hemospermia and prostatic hematuria, and to prevent intraoperative bleeding, although there is insufficient evidence for a standard strategy. This review summarizes the current use of 5-ARIs for prostate disease, including benign prostate hyperplasia, prostate cancer, prostate-related bleeding, and hemospermia.

Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.

PubMed

Stroes, Erik S; Thompson, Paul D; Corsini, Alberto; Vladutiu, Georgirene D; Raal, Frederick J; Ray, Kausik K; Roden, Michael; Stein, Evan; Tokgözoğlu, Lale; Nordestgaard, Børge G; Bruckert, Eric; De Backer, Guy; Krauss, Ronald M; Laufs, Ulrich; Santos, Raul D; Hegele, Robert A; Hovingh, G Kees; Leiter, Lawrence A; Mach, Francois; März, Winfried; Newman, Connie B; Wiklund, Olov; Jacobson, Terry A; Catapano, Alberico L; Chapman, M John; Ginsberg, Henry N

2015-05-01

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Quinone Reductase 2 Is a Catechol Quinone Reductase

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

Fu, Yue; Buryanovskyy, Leonid; Zhang, Zhongtao

2008-09-05

The functions of quinone reductase 2 have eluded researchers for decades even though a genetic polymorphism is associated with various neurological disorders. Employing enzymatic studies using adrenochrome as a substrate, we show that quinone reductase 2 is specific for the reduction of adrenochrome, whereas quinone reductase 1 shows no activity. We also solved the crystal structure of quinone reductase 2 in complexes with dopamine and adrenochrome, two compounds that are structurally related to catecholamine quinones. Detailed structural analyses delineate the mechanism of quinone reductase 2 specificity toward catechol quinones in comparison with quinone reductase 1; a side-chain rotational difference betweenmore » quinone reductase 1 and quinone reductase 2 of a single residue, phenylalanine 106, determines the specificity of enzymatic activities. These results infer functional differences between two homologous enzymes and indicate that quinone reductase 2 could play important roles in the regulation of catecholamine oxidation processes that may be involved in the etiology of Parkinson disease.« less

Steroidal 5α-reductase and 17α-hydroxylase/17,20-lyase (CYP17) inhibitors useful in the treatment of prostatic diseases.

PubMed

Salvador, Jorge A R; Pinto, Rui M A; Silvestre, Samuel M

2013-09-01

The role of steroidal inhibitors of androgen biosynthesis as potential weapons in the treatment of prostatic diseases, such as benign prostatic hyperplasia and prostatic cancer will be reviewed. Two enzymes have been targeted in the development of inhibitors that potentially could be useful in the management of such conditions. 5α-Reductase is primarily of interest in benign prostatic disease, though some role in the chemoprevention of prostatic carcinoma have been considered, whereas the 17α-hydroxylase/17,20-lyase (CYP17) enzyme is of interest in the treatment of malignant disease. An overview of the main achievements obtained during the past years will be presented, however special focus will be made on steroidal molecules that reached clinical trials or have been commercially launched. Relevant examples of such drugs are finasteride, dutasteride, abiraterone acetate and galeterone (TOK-001, formerly known as VN/124-1). This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors". Copyright © 2013 Elsevier Ltd. All rights reserved.

NADPH-dependent coenzyme Q reductase is the main enzyme responsible for the reduction of non-mitochondrial CoQ in cells.

PubMed

Takahashi, Takayuki; Okuno, Masaaki; Okamoto, Tadashi; Kishi, Takeo

2008-01-01

We purified an NADPH-dependent coenzyme Q reductase (NADPH-CoQ reductase) in rat liver cytosol and compared its enzymatic properties with those of the other CoQ10 reductases such as NADPH: quinone acceptor oxidoreductase 1 (NQO1), lipoamide dehydrogenase, thioredoxine reductase and glutathione reductase. NADPH-CoQ reductase was the only enzyme that preferred NADPH to NADH as an electron donor and was also different from the other CoQ10 reductases in the sensitivities to its inhibitors and stimulators. Especially, Zn2+ was the most powerful inhibitor for NADPH-CoQ reductase, but CoQ10 reduction by the other CoQ10 reductases could not be inhibited by Zn2+. Furthermore, the reduction of the CoQ9 incorporated into HeLa cells was also inhibited by Zn2+ in the presence of pyrithione, a zinc ionophore. Moreover, NQO1 gene silencing in HeLa cells by transfection of a small interfering RNA resulted in lowering of both the NQO1 protein level and the NQO1 activity by about 75%. However, this transfection did not affect the NADPH-CoQ reductase activity and the reduction of CoQ9 incorporated into the cells. These results suggest that the NADPH-CoQ reductase located in cytosol may be the main enzyme responsible for the reduction of non-mitochondrial CoQ in cells.

Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A.

PubMed

Howard, E I; Sanishvili, R; Cachau, R E; Mitschler, A; Chevrier, B; Barth, P; Lamour, V; Van Zandt, M; Sibley, E; Bon, C; Moras, D; Schneider, T R; Joachimiak, A; Podjarny, A

2004-06-01

The first subatomic resolution structure of a 36 kDa protein [aldose reductase (AR)] is presented. AR was cocrystallized at pH 5.0 with its cofactor NADP+ and inhibitor IDD 594, a therapeutic candidate for the treatment of diabetic complications. X-ray diffraction data were collected up to 0.62 A resolution and treated up to 0.66 A resolution. Anisotropic refinement followed by a blocked matrix inversion produced low standard deviations (<0.005 A). The model was very well ordered overall (CA atoms' mean B factor is 5.5 A2). The model and the electron-density maps revealed fine features, such as H-atoms, bond densities, and significant deviations from standard stereochemistry. Other features, such as networks of hydrogen bonds (H bonds), a large number of multiple conformations, and solvent structure were also better defined. Most of the atoms in the active site region were extremely well ordered (mean B approximately 3 A2), leading to the identification of the protonation states of the residues involved in catalysis. The electrostatic interactions of the inhibitor's charged carboxylate head with the catalytic residues and the charged coenzyme NADP+ explained the inhibitor's noncompetitive character. Furthermore, a short contact involving the IDD 594 bromine atom explained the selectivity profile of the inhibitor, important feature to avoid toxic effects. The presented structure and the details revealed are instrumental for better understanding of the inhibition mechanism of AR by IDD 594, and hence, for the rational drug design of future inhibitors. This work demonstrates the capabilities of subatomic resolution experiments and stimulates further developments of methods allowing the use of the full potential of these experiments. Copyright 2004 Wiley-Liss, Inc.

How to take statins

MedlinePlus

... tablets are also available. They include a statin plus medicine to manage another condition, such as high ... 24514899 . Lee JW, Morris JK, Wald NJ. Grapefruit Juice and Statins. Am J Med . 2016;129(1): ...

Rhabdomyolysis from Statins: What's the Risk?

MedlinePlus

... do you know if you have rhabdomyolysis from statin use, and how likely is it? Answers from ... pain is a relatively common side effect of statins, some people who take statin medications to lower ...

[C-reactive protein changes with antihypertensive and statin treatment].

PubMed

Rodilla, Enrique; Gómez-Belda, Ana; Costa, José A; Aragó, Miriam; Miralles, Amparo; González, Carmen; Pascual, José M

2005-10-29

The aim of this study was to evaluate the modifications of high sensitivity C-reactive protein (CRP) with antihypertensive and statin treatment in a hypertensive population with a wide range of coronary risks (CR). Retrospective follow-up study in 665 hypertensive patients: 556 (52% male) without dyslipidemia and CR (Framingham at 10 years) of 8.3 (7.6) as a control group (C) and 109 (61% male) with dyslipidemia and CR of 13.1 (8.8) who were treated with statins (T). Statins treatment was established according to NCEP-ATP-III. In both groups, the antihypertensive treatment was optimized in order to achieve blood pressure (BP) control (< 140/90 mmHg). A lipid profile and high sensitivity CRP (analyzed by nephelometry) was performed at the beginning and at the end of follow up [14.3 (3.6) months]. CRP levels were reduced in the T group -0.17 (0.2) mg/L vs. 0.14 (0.09) mg/L (p = 0.003, Mann-Whitney) in C. The lessening of CRP was not related to the reduction of lipids levels: total cholesterol (r = 0.06; p = 0.49), LDL-C (r = 0.11; p = 0.24), triglycerides (r = -0.02; p = 0.81) (Spearman), or to the reduction of systolic BP (r = -0.07; p = 0.44) and diastolic BP (r = -0.121; p = 0.21). The T group was treated with more antihypertensive drugs than C (2.2 [2.3] vs. 2.5 [1.2]; p = 0.02). Patients treated with ECA inhibitors or angiotensin II antagonist showed a tendency to decreasing the CRP levels more (p = 0.08). In hypertensive populations, statins induce a reduction of CRP levels. The reduction is not related to the lowering of lipids levels or BP values. The effect of statins on the reduction of CRP in hypertensive patients is not related to the lowering of lipids or BP.

The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis.

PubMed

Liu, Binliang; Yi, Zongbi; Guan, Xiuwen; Zeng, Yi-Xin; Ma, Fei

2017-07-01

Breast cancer is the most common cancer in females and the leading cause of death worldwide. The effects of statins on breast cancer prognosis have long been controversial; thus, it is important to investigate the relationship between statin type, exposure time, and breast cancer prognosis. This study sought to explore the effect of statins, as well as the different effects of statin solubility and variable follow-up times, on breast cancer prognosis. We searched the MEDLINE (via PubMed), EMBASE (via OvidSP), Cochrane Library, and ISI Web of Knowledge databases using combinations of the terms "breast neoplasms[MeSH]," "statins" or "lipid-lowering drug," "prognosis" or "survival," or "mortality" or "outcome" with no limit on the publication date. We searched the databases between inception and October 15, 2016. Reference lists of the included studies and relevant reviews were also manually screened. The initial search identified 71 publications, and 7 of these studies, which included a total of 197,048 women, met the selection criteria. Two authors independently screened each study for inclusion and extracted the data. The data were analyzed using Stata/SE 11.0. Overall statin use was associated with lower cancer-specific mortality and all-cause mortality, although the benefit appeared to be constrained by statin type and follow-up time. Lipophilic statins were associated with decreased breast cancer-specific and all-cause mortality; however, hydrophilic statins were weakly protective against only all-cause mortality and not breast cancer-specific mortality. Of note, one group with more than 4 years of follow-up did not show a significant correlation between statin use and cancer-specific mortality or all-cause mortality, whereas groups with less than 4 years of follow-up still showed the protective effect of statins against cancer-specific mortality and all-cause mortality. Although statins can reduce breast cancer patient mortality, the benefit appears to be

Management of statin-intolerant high-risk patients.

PubMed

Tziomalos, Konstantinos; Athyros, Vasilios G; Karagiannis, Asterios; Mikhailidis, Dimitri P

2010-09-01

Statins are an essential part of the management of patients at high vascular risk and are generally well-tolerated. However, statin intolerance will be observed more frequently as more stringent low density lipoprotein cholesterol (LDL-C) targets are pursued in an ever increasing number of patients. We review the management options for high-risk patients intolerant to statin treatment. Potential strategies include switching to a different statin, reducing the frequency of statin administration, substituting statins with other LDL-C-lowering agents (e.g. ezetimibe, colesevelam or nicotinic acid) and combining low-dose statin treatment with other lipid-modifying drugs. A limited number of studies specifically assessed statin-intolerant patients and most were small and of short duration. It is therefore difficult to make evidence-based recommendations for the management of this population. In addition, all treatment options have limitations in terms of safety and/or efficacy.

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

Rational Design of Broad Spectrum Antibacterial Activity Based on a Clinically Relevant Enoyl-Acyl Carrier Protein (ACP) Reductase Inhibitor*

PubMed Central

Schiebel, Johannes; Chang, Andrew; Shah, Sonam; Lu, Yang; Liu, Li; Pan, Pan; Hirschbeck, Maria W.; Tareilus, Mona; Eltschkner, Sandra; Yu, Weixuan; Cummings, Jason E.; Knudson, Susan E.; Bommineni, Gopal R.; Walker, Stephen G.; Slayden, Richard A.; Sotriffer, Christoph A.; Tonge, Peter J.; Kisker, Caroline

2014-01-01

Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms. PMID:24739388

Rational design of broad spectrum antibacterial activity based on a clinically relevant enoyl-acyl carrier protein (ACP) reductase inhibitor.

PubMed

Schiebel, Johannes; Chang, Andrew; Shah, Sonam; Lu, Yang; Liu, Li; Pan, Pan; Hirschbeck, Maria W; Tareilus, Mona; Eltschkner, Sandra; Yu, Weixuan; Cummings, Jason E; Knudson, Susan E; Bommineni, Gopal R; Walker, Stephen G; Slayden, Richard A; Sotriffer, Christoph A; Tonge, Peter J; Kisker, Caroline

2014-06-06

Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors.

PubMed

Chacón-Vargas, Karla Fabiola; Nogueda-Torres, Benjamin; Sánchez-Torres, Luvia E; Suarez-Contreras, Erick; Villalobos-Rocha, Juan Carlos; Torres-Martinez, Yuridia; Lara-Ramirez, Edgar E; Fiorani, Giulia; Krauth-Siegel, R Luise; Bolognesi, Maria Laura; Monge, Antonio; Rivera, Gildardo

2017-02-01

Chagas disease or American trypanosomiasis is a worldwide public health problem. In this work, we evaluated 26 new propyl and isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as potential trypanocidal agents. Additionally, molecular docking and enzymatic assays on trypanothione reductase (TR) were performed to provide a basis for their potential mechanism of action. Seven compounds showed better trypanocidal activity on epimastigotes than the reference drugs, and only four displayed activity on trypomastigotes; T-085 was the lead compound with an IC50 = 59.9 and 73.02 µM on NINOA and INC-5 strain, respectively. An in silico analysis proposed compound T-085 as a potential TR inhibitor with better affinity than the natural substrate. Enzymatic analysis revealed that T-085 inhibits parasite TR non-competitively. Compound T-085 carries a carbonyl, a CF3, and an isopropyl carboxylate group at 2-, 3- and 7-position, respectively. These results suggest the chemical structure of this compound as a good starting point for the design and synthesis of novel trypanocidal derivatives with higher TR inhibitory potency and lower toxicity.

A new strategy for strain improvement of Aurantiochytrium sp. based on heavy-ions mutagenesis and synergistic effects of cold stress and inhibitors of enoyl-ACP reductase.

PubMed

Cheng, Yu-Rong; Sun, Zhi-Jie; Cui, Gu-Zhen; Song, Xiaojin; Cui, Qiu

2016-11-01

Developing a strain with high docosahexaenoic acid (DHA) yield and stable fermenting-performance is an imperative way to improve DHA production using Aurantiochytrium sp., a microorganism with two fatty acid synthesis pathways: polyketide synthase (PKS) pathway and Type I fatty acid synthase (FAS) pathway. This study investigated the growth and metabolism response of Aurantiochytrium sp. CGMCC 6208 to two inhibitors of enoyl-ACP reductase of Type II FAS pathway (isoniazid and triclosan), and proposed a method of screening high DHA yield Aurantiochytrium sp. strains with heavy ion mutagenesis and pre-selection by synergistic usage of cold stress (4°C) and FAS inhibitors (triclosan and isoniazid). Results showed that (1) isoniazid and triclosan have positive effects on improving DHA level of cells; (2) mutants from irradiation dosage of 120Gy yielded more DHA compared with cells from 40Gy, 80Gy treatment and wild type; (3) DHA contents of mutants pre-selected by inhibitors of enoyl-ACP reductase of Type II FAS pathway (isoniazid and triclosan)at 4°C, were significantly higher than that of wild type; (4) compared to the wild type, the DHA productivity and yield of a mutant (T-99) obtained from Aurantiochytrium sp. CGMCC 6208 by the proposed method increased by 50% from 0.18 to 0.27g/Lh and 30% from 21 to 27g/L, respectively. In conclusion, this study developed a feasible method to screen Aurantiochytrium sp. with high DHA yield by a combination of heavy-ion mutagenesis and mutant-preselection by FAS inhibitors and cold stress. Copyright © 2016 Elsevier Inc. All rights reserved.

Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial.

PubMed

Hotta, Nigishi; Akanuma, Yasuo; Kawamori, Ryuzo; Matsuoka, Kempei; Oka, Yoshitomo; Shichiri, Motoaki; Toyota, Takayoshi; Nakashima, Mitsuyoshi; Yoshimura, Isao; Sakamoto, Nobuo; Shigeta, Yukio

2006-07-01

We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) >or=40 m/s, and HbA(1c)

2'-Deoxy-2'-methylenecytidine and 2'-deoxy-2',2'-difluorocytidine 5'-diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase.

PubMed

Baker, C H; Banzon, J; Bollinger, J M; Stubbe, J; Samano, V; Robins, M J; Lippert, B; Jarvi, E; Resvick, R

1991-06-01

It has been found that 2'-deoxy-2'-methyleneuridine (MdUrd), 2'-deoxy-2'-methylenecytidine (MdCyd), and 2'-deoxy-2',2'-difluorocytidine (dFdCyd) 5'-diphosphates (MdUDP (1) MdCDP (2) and dFdCDP (3), respectively) function as irreversible inactivators of the Escherichia coli ribonucleoside diphosphate reductase (RDPR). 2 is a much more potent inhibitor than its uridine analogue 1. It is proposed that 2 undergoes abstraction of H3' to give an allylic radical that captures a hydrogen atom and decomposes to an active alkylating furanone species. RDPR also accepts 3 as an alternative substrate analogue and presumably executes an initial abstraction of H3' to initiate formation of a suicide species. Both 2 and 3 give inactivation results that differ from those of previously studied inhibitors. The potent anticancer activities of MdCyd and dFdCyd indicate a significant chemotherapeutic potential. The analogous RDPR of mammalian cells should be regarded as a likely target and/or activating enzyme for these novel mechanism-based inactivators.

Algorithms to Identify Statin Intolerance in Medicare Administrative Claim Data.

PubMed

Colantonio, Lisandro D; Kent, Shia T; Huang, Lei; Chen, Ligong; Monda, Keri L; Serban, Maria-Corina; Manthripragada, Angelika; Kilgore, Meredith L; Rosenson, Robert S; Muntner, Paul

2016-10-01

To compare characteristics of patients with possible statin intolerance identified using different claims-based algorithms versus patients with high adherence to statins. We analyzed 134,863 Medicare beneficiaries initiating statins between 2007 and 2011. Statin intolerance and discontinuation, and high adherence to statins, defined by proportion of days covered ≥80 %, were assessed during the 365 days following statin initiation. Definition 1 of statin intolerance included statin down-titration or discontinuation with ezetimibe initiation, having a claim for a rhabdomyolysis or antihyperlipidemic event followed by statin down-titration or discontinuation, or switching between ≥3 types of statins. Definition 2 included beneficiaries who met Definition 1 and those who down-titrated statin intensity. We also analyzed beneficiaries who met Definition 2 of statin intolerance or discontinued statins. The prevalence of statin intolerance was 1.0 % (n = 1320) and 5.2 % (n = 6985) using Definitions 1 and 2, respectively. Overall, 45,266 (33.6 %) beneficiaries had statin intolerance by Definition 2 or discontinued statins and 55,990 (41.5 %) beneficiaries had high adherence to statins. Compared with beneficiaries with high adherence to statins, those with statin intolerance and who had statin intolerance or discontinued statins were more likely to be female versus male, and black, Hispanic or Asian versus white. The multivariable adjusted odds ratio for statin intolerance by Definitions 1 and 2 comparing patients initiating high versus low/moderate intensity statins were 2.82 (95%CI: 2.42-3.29), and 8.58 (8.07-9.12), respectively, and for statin intolerance or statin discontinuation was 2.35 (2.25-2.45). Definitions of statin intolerance presented herein can be applied to analyses using administrative claims data.

Statins and musculoskeletal conditions, arthropathies, and injuries.

PubMed

Mansi, Ishak; Frei, Christopher R; Pugh, Mary Jo; Makris, Una; Mortensen, Eric M

2013-07-22

Statin use may be associated with increased musculoskeletal adverse events, especially in physically active individuals. To determine whether statin use is associated with musculoskeletal conditions, including arthropathy and injury, in a military health care system. A retrospective cohort study with propensity score matching. San Antonio Military Multi-Market. Tricare Prime/Plus beneficiaries evaluated from October 1, 2003, to March 1, 2010. Statin use during fiscal year 2005. On the basis of medication fills, patients were divided into 2 groups: statin users (received a statin for at least 90 days) and nonusers (never received a statin throughout the study period). Using patients' baseline characteristics, we generated a propensity score that was used to match statin users and nonusers; odds ratios (ORs) were determined for each outcome measure. Secondary analyses determined adjusted ORs for all patients who met study criteria and a subgroup of patients with no comorbidities identified using the Charlson Comorbidity Index. Sensitivity analysis further determined adjusted ORs for a subgroup of patients with no musculoskeletal diseases at baseline and a subgroup of patients who continued statin therapy for 2 years or more. The occurrence of musculoskeletal conditions was determined using prespecified groups of International Classification of Diseases, Ninth Revision, ClinicalModification codes: Msk1, all musculoskeletal diseases; Msk1a, arthropathies and related diseases; Msk1b, injury-related diseases (dislocation, sprain, strain); and Msk2, drug-associated musculoskeletal pain. A total of 46 249 individuals met study criteria (13 626 statin users and 32 623 nonusers). Of these, we propensity score-matched 6967 statin users with 6967 nonusers. Among matched pairs, statin users had a higher OR for Msk1 (OR, 1.19; 95% CI, 1.08-1.30), Msk1b (1.13; 1.05-1.21), and Msk2 (1.09; 1.02-1.18); the OR for Msk1a was 1.07 (0.99-1.16; P = .07). Secondary and sensitivity

Cardiovascular disease guideline adherence and self-reported statin use in longstanding type 1 diabetes: results from the Canadian study of longevity in diabetes cohort.

PubMed

Bai, Johnny W; Boulet, Geneviève; Halpern, Elise M; Lovblom, Leif E; Eldelekli, Devrim; Keenan, Hillary A; Brent, Michael; Paul, Narinder; Bril, Vera; Cherney, David Z I; Weisman, Alanna; Perkins, Bruce A

2016-01-25

Older patients with longstanding type 1 diabetes have high cardiovascular disease (CVD) risk such that statin therapy is recommended independent of prior CVD events. We aimed to determine self-reported CVD prevention guideline adherence in patients with longstanding diabetes. 309 Canadians with over 50 years of type 1 diabetes completed a medical questionnaire for presence of lifestyle and pharmacological interventions, stratified into primary or secondary CVD prevention subgroups based on absence or presence of self-reported CVD events, respectively. Associations with statin use were analyzed using multivariable logistic regression. The 309 participants had mean ± SD age 65.7 ± 8.5 years, median diabetes duration 54.0 [IQR 51.0, 59.0] years, and HbA1c of 7.5 ± 1.1 % (58 mmol/mol). 159 (52.7 %) participants reported diet adherence, 296 (95.8 %) smoking avoidance, 217 (70.5 %) physical activity, 218 (71.5 %) renin-angiotensin-system inhibitor use, and 220 (72.1 %) statin use. Physical activity was reported as less common in the secondary prevention subgroup, and current statin use was significantly lower in the primary prevention subgroup (65.5 % vs. 84.8 %, p = 0.0004). In multivariable logistic regression, the odds of statin use was 0.38 [95 % CI 0.15-0.95] in members of the primary compared to the secondary prevention subgroup, adjusting for age, sex, hypertension history, body mass, HbA1c, cholesterol, microvascular complications, acetylsalicylic acid use, and renin-angiotensin system inhibitor use. Despite good self-reported adherence to general CVD prevention guidelines, against the principles of these guidelines we found that statin use was substantially lower in those without CVD history. Interventions are needed to improve statin use in older type 1 diabetes patients without a history of CVD.

Statin therapy in patients with community-acquired pneumonia.

PubMed

Grudzinska, Frances S; Dosanjh, Davinder Ps; Parekh, Dhruv; Dancer, Rachel Ca; Patel, Jaimin; Nightingale, Peter; Walton, Georgia M; Sapey, Elizabeth; Thickett, David R

2017-10-01

Community-acquired pneumonia (CAP) is the leading cause of death from infection in developed countries. There is evidence of an association between improved survival from infection and statin use. The possible beneficial effects of statins are complicated by the common use of macrolide antibiotics for pneumonia, with current guidance suggesting that concurrent macrolide and statin use is contraindicated.We conducted an observational study of statin use in patients with CAP. Of 2,067 patients with CAP, 30.4% were on statin therapy at admission. Statin users were more likely to survive the admission (p<0.001). In addition, we conducted a survey of doctors and found that knowledge regarding concurrent macrolide and statin use was lacking.These data suggest a potential role of statins in the management of CAP. Further research using high-dose statins is required to assess their safe use in subjects with mild to moderate infections. © Royal College of Physicians 2017. All rights reserved.

Statins for acute coronary syndrome.

PubMed

Vale, Noah; Nordmann, Alain J; Schwartz, Gregory G; de Lemos, James; Colivicchi, Furio; den Hartog, Frank; Ostadal, Petr; Macin, Stella M; Liem, Anho H; Mills, Edward; Bhatnagar, Neera; Bucher, Heiner C; Briel, Matthias

2011-06-15

The early period following the onset of acute coronary syndromes (ACS) represents a critical stage of coronary heart disease with a high risk for recurrent events and deaths. The short-term effects of early treatment with statins in patients suffering from ACS on patient-relevant outcomes are unclear. To assess the benefits and harms of early administered statins in patients with ACS from randomized controlled trials (RCTs). We searched CENTRAL, MEDLINE, EMBASE, and CINAHL (to 1 February 2010). No language restrictions were applied. We supplemented the search by contacting experts in the field, by reviewing reference lists of reviews and editorials on the topic, and by searching trial registries. RCTs comparing statins with placebo or usual care, initiation of statin therapy within 14 days following the onset of ACS, and follow-up of at least 30 days reporting at least one clinical outcome. Two authors independently assessed study quality and extracted data. We pooled treatment effects and calculated risk ratios (RRs) for all outcomes in the treatment and control groups using a random effects model. Eighteen studies (14,303 patients) compared early statin treatment versus placebo or usual care in patients with ACS. Compared to placebo or usual care, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction (MI), and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) and four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up. There were no statistically significant risk reductions from statins for total death, total MI, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month and at four months, although there were favorable trends related to statin use for each of these endpoints. The incidence of episodes of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine

Potency of a novel saw palmetto ethanol extract, SPET-085, for inhibition of 5alpha-reductase II.

PubMed

Pais, Pilar

2010-08-01

The nicotinamide adenine dinucleotide phosphate (NADPH)-dependent membrane protein 5alpha-reductase irreversibly catalyses the conversion of testosterone to the most potent androgen, 5alpha-dihydrotestosterone (DHT). In humans, two 5alpha-reductase isoenyzmes are expressed: type I and type II. Type II is found primarily in prostate tissue. Saw palmetto extract (SPE) has been widely used for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH). The mechanisms of the pharmacological effects of SPE include the inhibition of 5alpha-reductase, among other actions. Clinical studies of SPE have been equivocal, with some showing significant results and others not. These inconsistent results may be due, in part, to varying bioactivities of the SPE used in the studies. The aim of the present study was to determine the in vitro potency of a novel saw palmetto ethanol extract (SPET-085), an inhibitor of the 5alpha-reductase isoenzyme type II, in a cell-free test system. On the basis of the enzymatic conversion of the substrate androstenedione to the 5alpha-reduced product 5alpha-androstanedione, the inhibitory potency was measured and compared to those of finasteride, an approved 5alpha-reductase inhibitor. SPET-085 concentration-dependently inhibited 5alpha-reductase type II in vitro (IC(50)=2.88+/-0.45 microg/mL). The approved 5alpha-reductase inhibitor, finasteride, tested as positive control, led to 61% inhibition of 5alpha-reductase type II. SPET-085 effectively inhibits the enzyme that has been linked to BPH, and the amount of extract required for activity is very low compared to data reported for other extracts. It can be concluded from data in the literature that SPET-085 is as effective as a hexane extract of saw palmetto that exhibited the highest levels of bioactivity, and is more effective than other SPEs tested. This study confirmed that SPET-085 has prostate health-promoting bioactivity that also corresponds favorably to

Statin and NSAID Use and Prostate Cancer Risk

PubMed Central

Coogan, Patricia F.; Kelly, Judith Parsells; Strom, Brian L.; Rosenberg, Lynn

2010-01-01

Purpose Some studies have reported reduced risks of advanced, but not early, prostate cancer among statin users, and one study found a reduced risk only among statin users who had also used nonsteroidal anti-inflammatory drugs (NSAIDs). We have previously reported no association between statin use and prostate cancer in our hospital-based Case Control Surveillance Study. The purpose of the present analyses was to update the findings by cancer stage and to evaluate the joint use of statins and NSAIDs. Methods Cases were 1367 men with prostate cancer and controls were 2007 men with diagnoses unrelated to statin or NSAID use. We used multivariable logistic regression analyses to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for statin use compared with no use, and joint use of statin and NSAIDs compared with use of neither. Results The odds ratio among regular statin users was 1.1 (95% CI 0.9–1.5), and odds ratios were similar among early and late stage cancers. The odds ratio among joint statin and NSAID users was 1.1 (95% CI 0.7–1.6). Conclusion The present results do not support a protective effect of statin use, or statin and NSAID use, on the risk of advanced prostate cancer. PMID:20582910

Practical aspects in the management of statin-associated muscle symptoms (SAMS).

PubMed

Laufs, Ulrich; Filipiak, Krysztof J; Gouni-Berthold, Ioanna; Catapano, Alberico L

2017-04-01

Statin-associated muscle symptoms (SAMS) frequently cause statin non-adherence, switching and discontinuation, contributing to adverse cardiovascular (CV) outcomes. Therefore, the management of SAMS is key in the effective treatment of patients with cardiovascular disease (CVD), through achievement of maximum-tolerated statin dosing and other practical aspects. The aim of this article is to provide practical, focused advice for healthcare professionals on the management of patients with SAMS. An expert working group combined current evidence, published guidelines and experiences surrounding a number of topics concerning SAMS to provide recommendations on how to best assess and manage this condition and reach the highest tolerated dose of statin for each individual patient. The group collaborated to provide guidance on definitions in the SAMS field, psychological issues, re-challenging and switching treatments, as well as interpretation of current guidelines and optimal treatment of SAMS in different patient populations. An algorithm was developed to guide the management of patients with SAMS. In addition, the expert working group considered some of the more complex scenarios in a series of frequently asked questions and suggested answers. The expert working group gave recommendations for healthcare professionals on the management of SAMS but highlighted the importance of tailoring the treatment approach to each individual patient. Evidence supporting the role of nutraceuticals and complementary therapies, such as vitamin D, was lacking, however the majority of the group favoured combination therapy with ezetimibe and the addition of PCSK9 inhibitors in high-risk patients. Copyright © 2017 Elsevier B.V. All rights reserved.

A facile synthesis of lanost-8-en-3 beta-ol-24-one (24-ketolanosterol). An inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.

PubMed

Parish, E J; Honda, H; Chitrakorn, S; Taylor, F R

1988-10-01

A facile chemical synthesis of lanost-8-en-3 beta-ol-24-one (24-ketolanosterol) is described. This compound was found to be a potent inhibitor of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity in cultured mouse L cells. The synthetic scheme developed in this study utilizes commercial lanosterol as a starting material and involves selective hydroboration of the C-24 double bond followed by oxidation of the carbon-boron bond at C-24 by pyridinium chlorochromate (PCC).

Prospecting for Novel Plant-Derived Molecules of Rauvolfia serpentina as Inhibitors of Aldose Reductase, a Potent Drug Target for Diabetes and Its Complications

PubMed Central

Pathania, Shivalika; Randhawa, Vinay; Bagler, Ganesh

2013-01-01

Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects. PMID:23613832

Prospecting for novel plant-derived molecules of Rauvolfia serpentina as inhibitors of Aldose Reductase, a potent drug target for diabetes and its complications.

PubMed

Pathania, Shivalika; Randhawa, Vinay; Bagler, Ganesh

2013-01-01

Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects.

Detection of Metastatic Potential in Breast Cancer by RhoC-GTPase and WISP3 Proteins

DTIC Science & Technology

2007-05-01

De A, Gambhir SV, Merajver SD, Kolodney MS. Atorvastatin Prevents RhoC Isoprenylation, Invasion and Metastasis in Human Melanoma Cells. Molecular...3-hydroxy-3- methylglutaryl-CoA) reductase inhibitors (statins). In particular, atorvastatin has been clearly shown to inhibit RhoC driven phenotypes...Gambhir SS, Merajver SD, Kolodney MS: Atorvastatin prevents RhoC isoprenylation, inva- sion, and metastasis in human melanoma cells Mol Cancer Ther 2: 941

Statins and risk of poststroke hemorrhagic complications

PubMed Central

MacIsaac, Rachael L.; Abdul-Rahim, Azmil H.; Siegerink, Bob; Bath, Philip M.; Endres, Matthias; Lees, Kennedy R.; Nolte, Christian H.

2016-01-01

Objective: To assess whether statin treatment before or after acute ischemic stroke (AIS) affects the risk of acute intracerebral hemorrhage (ICH), postacute ICH, and mortality within 90 days. Methods: Data were sought from the Virtual International Stroke Trials Archive, an international repository of clinical trials data. Using propensity score matching, we retrospectively compared patients with prior statin treatment and newly initiated statin within 3 days after AIS to patients without statin exposure. Outcomes of interest were acute symptomatic ICH (sICH), any acute ICH, postacute ICH, and mortality during follow-up of 3 months. Results: A total of 8,535 patients (mean age 70 years, 54% male, median baseline NIH Stroke Scale score 13) were analyzed. After propensity score matching, prior statin use was not strongly associated with sICH (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.83–2.14) or any ICH (adjusted OR 1.35, 95% CI 0.92–1.98). There was no evidence of an interaction between prior statin use and thrombolysis. New initiation of statins was not associated with postacute ICH (adjusted hazard ratio [HR] 1.60, 95% CI 0.70–3.65). There was a signal towards lower 90-day mortality in patients with prior statin use (adjusted HR 0.84, 95% CI 0.70–1.00) and especially early initiation of statins (adjusted HR 0.67, 95% CI 0.46–0.97). Conclusions: Statin use prior to AIS was not associated with early hemorrhagic complications, irrespective of treatment with thrombolysis. New initiation of statin treatment early after AIS did not affect risk of postacute ICH, but might be associated with reduced mortality. PMID:27016519

Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies.

PubMed

Fong, Clifford W

2014-10-06

The atomic electrostatic potentials calculated by the CHELPG method have been shown to be sensitive indicators of the gas phase and solution properties of the statins. Solvation free energies in water, n-octanol and n-octane have been determined using the SMD solvent model. The percentage hydrophilicity and hydrophobicity (or lipophilicity) of the statins in solution have been determined using (a) the differences in solvation free energies between n-octanol and n-octane as a measure of hydrophilicity, and the solvation energy in octane as a measure of hydrophobicity (b) the sum of the atomic electrostatic charges on the hydrogen bonding and polar bonding nuclei of the common pharmacophore combined with a solvent measure of hydrophobicity, and (c) using the buried surface areas after statin binding to HMGCR to calculate the hydrophobicity of the bound statins. The data suggests that clinical definitions of statins as either "hydrophilic" or "lipophilic" based on experimental partition coefficients are misleading. An estimate of the binding energy between rosuvastatin and HMGCR has been made using: (a) a coulombic electrostatic interaction model, (b) the calculated desolvation and resolvation of the statin in water, and (c) the first shell transfer solvation energy as a proxy for the restructuring of the water molecules immediately adjacent to the active binding site of HMGCR prior to binding. Desolvation and resolvation of the statins before and after binding to HMGCR are major determinants of the energetics of the binding process. An analysis of the amphiphilic nature of lovastatin anion, acid and lactone and fluvastatin anion and their abilities to cross the blood brain barrier has indicated that this process may be dominated by desolvation and resolvation effects, rather than the statin molecular size or statin-lipid interactions within the bilayer. The ionization energy and electron affinity of the statins are sensitive physical indicators of the ease that the

Characterization of a Novel Dithiocarbamate Glutathione Reductase Inhibitor and Its Use as a Tool to Modulate Intracellular Glutathione*

PubMed Central

Seefeldt, Teresa; Zhao, Yong; Chen, Wei; Raza, Ashraf S.; Carlson, Laura; Herman, Jocqueline; Stoebner, Adam; Hanson, Sarah; Foll, Ryan; Guan, Xiangming

2009-01-01

Thiol redox state (TRS) is an important parameter to reflect intracellular oxidative stress and is associated with various normal and abnormal biochemical processes. Agents that can be used to increase intracellular TRS will be valuable tools in TRS-related research. Glutathione reductase (GR) is a critical enzyme in the homeostasis of TRS. The enzyme catalyzes the reduction of GSSG to GSH to maintain a high GSH:GSSG ratio. Inhibition of the enzyme can be used to increase TRS. Despite the reports of various GR inhibitors, N,N-bis(2-chloroethyl)-N-nitrosourea, an anticancer drug with IC50 = 647 μm against yeast GR, remains the most commonly used GR inhibitor in the literature. However, the toxicity caused by nonspecific interactions, as well as inhibition of DNA synthesis, complicates the use of N,N-bis(2-chloroethyl)-N-nitrosourea as a GR inhibitor. We report 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2-AAPA) as a novel irreversible GR inhibitor. 2-AAPA was prepared by one-step synthesis from commercially available reagents. The Ki and kinact of 2-AAPA against yeast GR were determined to be 56 μm and 0.1 min–1, respectively. At the concentration that produced >80% yeast GR inhibition, 2-AAPA showed no inhibition against glutamylcysteine synthetase, glutathione synthetase, catalase, and superoxide dismutase, but minimal inhibition against glutathione S-transferase and glutathione peroxidase. In CV-1 cells, 2-AAPA (0.1 mm) produced 97% GR inhibition, 25% GSH reduction, and a 5-fold increase in GSSG in 20 min. The compound can be a useful tool in TRS-related research. PMID:19049979

Design, synthesis and biological evaluation of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives as dual 5α-reductase inhibitors and androgen receptor antagonists.

PubMed

Lao, Kejing; Sun, Jie; Wang, Chong; Wang, Ying; You, Qidong; Xiao, Hong; Xiang, Hua

2017-09-01

Prostate cancer (PCa) is the second leading cause of death in men. Recently, some researches have showed that 5α-reductase inhibitors were beneficial in PCa treatment as well. In this study, a series of novel 3-oxo-4-oxa-5α-androst-17β-amide derivatives have been designed and synthesized in a more simple and convenient method. Most of the synthesized compounds displayed good 5α-reductase inhibitory activities and androgen receptor binding affinities. Their anti-proliferation activities in PC-3 and LNCaP cell lines were also evaluated and the results indicated that most of the synthesized compounds exhibited potent anti-proliferative activities. It is obvious that the androgen-dependent cell line LNCaP was much more sensitive than the androgen-independent cell line PC-3. Among all the synthesized compounds, 11d and 11k displayed the best inhibition activity with 4-fold more sensitive toward LNCaP than PC-3, which was consistent with their high affinities observed in AR binding assay. Molecular modeling studies suggested that 11k could bind to AR in a manner similar to the binding of dihydrotestosterone to AR. Compared to the finasteride, 11k showed a longer plasma half-life (4h) and a better bioavailability. Overall, based on biological activities data, compound 11d and 11k can be identified as potential dual 5α-reductase inhibitors and AR antagonists which might be of therapeutic importance for prostate cancer treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial.

PubMed

Takase, Susumu; Matoba, Tetsuya; Nakashiro, Soichi; Mukai, Yasushi; Inoue, Shujiro; Oi, Keiji; Higo, Taiki; Katsuki, Shunsuke; Takemoto, Masao; Suematsu, Nobuhiro; Eshima, Kenichi; Miyata, Kenji; Yamamoto, Mitsutaka; Usui, Makoto; Sadamatsu, Kenji; Satoh, Shinji; Kadokami, Toshiaki; Hironaga, Kiyoshi; Ichi, Ikuyo; Todaka, Koji; Kishimoto, Junji; Egashira, Kensuke; Sunagawa, Kenji

2017-02-01

We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels. The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional

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

Consequences of succinylcholine administration to patients using statins.

PubMed

Turan, Alparslan; Mendoza, Maria L; Gupta, Shipra; You, Jing; Gottlieb, Alexandru; Chu, Weihan; Saager, Leif; Sessler, Daniel I

2011-07-01

Statins cause structural changes in myocytes and provoke myotoxicity, myopathy, and myalgias. Thus, patients taking statins may be especially susceptible to succinylcholine-induced muscle injury. The authors tested the hypothesis that succinylcholine increases plasma concentrations of myoglobin, potassium, and creatine kinase more in patients who take statins than in those who do not and that succinylcholine-induced postoperative muscle pain is aggravated in statin users. Patients who took statins for at least 3 months and those who had never used statins were enrolled. General anesthesia was induced and included 1.5 mg/kg succinylcholine for intubation. The incidence and degree of fasciculation after succinylcholine administration were recorded. Blood samples were obtained before induction and 5 and 20 min and 24 h after succinylcholine administration. Patients were interviewed 2 and 24 h after surgery to determine the degree of myalgia. The authors enrolled 38 patients who used statins and 32 who did not. At 20 min, myoglobin was higher in statin users versus nonusers (ratio of medians 1.34 [95% CI: 1.1, 1.7], P = 0.018). Fasciculations in statin users were more intense than in nonusers (P = 0.047). However, plasma potassium and creatine kinase concentrations were similar in statin users and nonusers, as was muscle pain. The plasma myoglobin concentration at 20 min was significantly greater in statin users than nonusers, although the difference seems unlikely to be clinically important. The study results suggest that the effect of succinylcholine given to patients taking statins is likely to be small and probably of limited clinical consequence.

Statins improve the resolution of established murine venous thrombosis: reductions in thrombus burden and vein wall scarring.

PubMed

Kessinger, Chase W; Kim, Jin Won; Henke, Peter K; Thompson, Brian; McCarthy, Jason R; Hara, Tetsuya; Sillesen, Martin; Margey, Ronan J P; Libby, Peter; Weissleder, Ralph; Lin, Charles P; Jaffer, Farouc A

2015-01-01

Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins--lipid-lowering agents with anti-thrombotic and anti-inflammatory properties--in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy.

Statins, the renin-angiotensin-aldosterone system and hypertension - a tale of another beneficial effect of statins.

PubMed

Drapala, Adrian; Sikora, Mariusz; Ufnal, Marcin

2014-09-01

Statins, a class of lipid lowering drugs, decrease mortality associated with cardiovascular events. As hypercholesterolemia is often accompanied by hypertension, a large number of patients receive therapy with statins and antihypertensive drugs which act via the renin-angiotensin-aldosterone system (RAAS). New guidelines published by the American Heart Association and American College of Cardiology on the treatment of dyslipidaemia and the reduction of atherosclerotic cardiovascular risk, which use a risk prediction algorithm based on risk factors such as hypertension but not low-density lipoprotein (LDL) level, may even further increase the number of patients receiving such concomitant therapy. In this paper we review studies on an interaction between statins, the RAAS and antihypertensive drugs acting via the RAAS. Accumulating evidence suggests that the combination of statins and drugs affecting the RAAS exerts a synergistic effect on the circulatory system. For example, statins may lower arterial blood pressure and augment the effect of antihypertensive drugs acting via the RAAS. Statins may interact with the RAAS in a number of ways i.e. to decrease the expression of receptors for angiotensin II (Ang II), inhibit the Ang II-dependent intracellular signalling, reduce the RAAS-dependent oxidative stress and inflammation as well as inhibit the synthesis of Ang II and aldosterone. Although statins given either alone or together with antihypertensive drugs acting via the RAAS may lower arterial blood pressure, further research is needed to evaluate the mechanisms and their therapeutic significance. © The Author(s) 2014.

Effects of 5-alpha reductase inhibitors on erectile function, sexual desire and ejaculation.

PubMed

Gur, Serap; Kadowitz, Philip J; Hellstrom, Wayne Jg

2013-01-01

Treatment with 5-alpha reductase inhibitors (5ARI) is commonly utilized for the treatment of benign prostatic hyperplasia (BPH). The true prevalence of sexual side effects with 5ARI treatment is currently unknown. The current article reviews the reported adverse effects of 5ARI in regard to erectile function, sexual desire and ejaculation. A PubMed search was performed of all articles from 1990 to present, which reported any sexual side effects with finasteride or dutasteride. Preference was given to more recent and human studies where available. Clinical trials with 5ARI report prevalence rates of de novo erectile dysfunction of 5 - 9%. Decreased circulating dihydrotestosterone (DHT) resulting from 5ARI use is associated with diminished sexual desire and/or orgasm. The presence of adverse sexual effects is associated with decreased self-esteem, quality of life and ability to maintain an intimate relationship. Inhibition of 5ARI additionally influences progesterone and deoxycorticosterone levels and may alter psychological functions, including increased depression, melancholy and loss of general well being. Ejaculatory dysfunction has not been well studied in patients using 5ARI. Patients receiving therapy with 5ARI should be counseled as to potential sexual and psychological adverse effects. Future clinical studies are needed to further investigate the sexual side effects associated with this class of drugs.

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

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

Camphene, a Plant-Derived Monoterpene, Reduces Plasma Cholesterol and Triglycerides in Hyperlipidemic Rats Independently of HMG-CoA Reductase Activity

PubMed Central

Vallianou, Ioanna; Peroulis, Nikolaos; Pantazis, Panayotis; Hadzopoulou-Cladaras, Margarita

2011-01-01

Background Central to the pathology of coronary heart disease is the accumulation of lipids, cholesterol and triglycerides, within the intima of arterial blood vessels. The search for drugs to treat dislipidemia, remains a major pharmaceutical focus. In this study, we evaluated the hypolipidemic properties of the essential oil from Chios mastic gum (MGO). Methodology/Principal Findings The hypolipidemic effect of MGO was investigated in naïve as well as in rats susceptible to detergent-induced hyperlipidemia. Serum cholesterol and triglycerides were determined using commercial kits. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase activity was measured in HepG2 cell extracts using a radioactive assay; cellular cholesterol and cholesterol esters were assessed using gas chromatography. MGO administration into naïve rats resulted in a dose-dependent reduction in the constitutive synthesis of serum cholesterol and triglycerides. In hyperlipidemic rats, MGO treatment had also a strong hypolipidemic effect. By testing various components of MGO, we show for the first time that the hypolipidemic action is associated with camphene. Administration of camphene at a dose of 30 µg/gr of body weight in hyperlipidemic rats resulted in a 54.5% reduction of total cholesterol (p<0.001), 54% of Low Density Lipoprotein (LDL)-cholesterol (p<0.001) and 34.5% of triglycerides (p<0.001). Treatment of HepG2 cells with camphene led to a decrease in cellular cholesterol content to the same extend as mevinolin, a known HMG-CoA reductase inhibitor. The hypolipidemic action of camphene is independent of HMG-CoA reductase activity, suggesting that its hypocholesterolemic and hypotriglyceridemic effects are associated with a mechanism of action different than that of statins. Conclusions Given the critical role that the control of hyperlipidemia plays in cardiovascular disease, the results of our study provide insights into the use of camphene as an alternative lipid lowering agent

Statins: Do They Cause ALS?

MedlinePlus

Statins: Do they cause ALS? Do statins cause amyotrophic lateral sclerosis (ALS)? Answers from Francisco Lopez-Jimenez, M.D. ... D. Ingre C, et al. Risk factors for amyotrophic lateral sclerosis. Clinical Epidemiology. 2015; 7:181. Riva N, et ...

An innovative strategy for dual inhibitor design and its application in dual inhibition of human thymidylate synthase and dihydrofolate reductase enzymes.

PubMed

Arooj, Mahreen; Sakkiah, Sugunadevi; Cao, Guang ping; Lee, Keun Woo

2013-01-01

Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases. Nevertheless, to design multitarget inhibitors is concurrently a great challenge for medicinal chemists. We have developed a novel computational approach by integrating the affinity predictions from structure-based virtual screening with dual ligand-based pharmacophore to discover potential dual inhibitors of human Thymidylate synthase (hTS) and human dihydrofolate reductase (hDHFR). These are the key enzymes in folate metabolic pathway that is necessary for the biosynthesis of RNA, DNA, and protein. Their inhibition has found clinical utility as antitumor, antimicrobial, and antiprotozoal agents. A druglike database was utilized to perform dual-target docking studies. Hits identified through docking experiments were mapped over a dual pharmacophore which was developed from experimentally known dual inhibitors of hTS and hDHFR. Pharmacophore mapping procedure helped us in eliminating the compounds which do not possess basic chemical features necessary for dual inhibition. Finally, three structurally diverse hit compounds that showed key interactions at both active sites, mapped well upon the dual pharmacophore, and exhibited lowest binding energies were regarded as possible dual inhibitors of hTS and hDHFR. Furthermore, optimization studies were performed for final dual hit compound and eight optimized dual hits demonstrating excellent binding features at target systems were also regarded as possible dual inhibitors of hTS and hDHFR. In general, the strategy used in the current study could be a promising computational approach and may be generally applicable to other dual target drug designs.

An Innovative Strategy for Dual Inhibitor Design and Its Application in Dual Inhibition of Human Thymidylate Synthase and Dihydrofolate Reductase Enzymes

PubMed Central

Arooj, Mahreen; Sakkiah, Sugunadevi; Cao, Guang ping; Lee, Keun Woo

2013-01-01

Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases. Nevertheless, to design multitarget inhibitors is concurrently a great challenge for medicinal chemists. We have developed a novel computational approach by integrating the affinity predictions from structure-based virtual screening with dual ligand-based pharmacophore to discover potential dual inhibitors of human Thymidylate synthase (hTS) and human dihydrofolate reductase (hDHFR). These are the key enzymes in folate metabolic pathway that is necessary for the biosynthesis of RNA, DNA, and protein. Their inhibition has found clinical utility as antitumor, antimicrobial, and antiprotozoal agents. A druglike database was utilized to perform dual-target docking studies. Hits identified through docking experiments were mapped over a dual pharmacophore which was developed from experimentally known dual inhibitors of hTS and hDHFR. Pharmacophore mapping procedure helped us in eliminating the compounds which do not possess basic chemical features necessary for dual inhibition. Finally, three structurally diverse hit compounds that showed key interactions at both active sites, mapped well upon the dual pharmacophore, and exhibited lowest binding energies were regarded as possible dual inhibitors of hTS and hDHFR. Furthermore, optimization studies were performed for final dual hit compound and eight optimized dual hits demonstrating excellent binding features at target systems were also regarded as possible dual inhibitors of hTS and hDHFR. In general, the strategy used in the current study could be a promising computational approach and may be generally applicable to other dual target drug designs. PMID:23577115

Efficacy and safety of statins and exercise combination therapy compared to statin monotherapy in patients with dyslipidaemia: A systematic review and meta-analysis.

PubMed

Gui, Ya-Jun; Liao, Cai-Xiu; Liu, Qiong; Guo, Yuan; Yang, Tao; Chen, Jing-Yuan; Wang, Ya-Ting; Hu, Jia-Hui; Xu, Dan-Yan

2017-06-01

Background Statin treatment in association with physical exercise can substantially reduce mortality in dyslipidaemic individuals. However, the available data to compare the efficacy and safety of statins and exercise combination therapy with statin monotherapy are limited. Design Systematic review and meta-analysis. Methods We systematically searched PubMed, Embase and the Cochrane Library from database inception until December 2016. We included randomised and non-randomised studies that compared the efficacy and safety of statins and exercise combination therapy with statin monotherapy in patients with dyslipidaemia. Standardised mean differences were calculated and pooled by means of fixed effects models. The risk of bias and heterogeneity among trials was also assessed. Seven articles were assessed in terms of the efficacy of therapy and 13 from the viewpoint of therapeutic safety. Results In terms of efficacy, statins and exercise combination decreased the incidence of diabetes mellitus, improved insulin sensitivity and inflammation, but caused no change in lipid profile compared to statins alone. In terms of safety, statins and exercise combination increased peak oxygen uptake (standardised mean difference 1.01, 95% confidence interval 0.46 to 1.57) compared to statins alone. In contrast to statin-induced myopathy, chronic exercise training prior to statin treatment could counteract statin-induced adverse effects in skeletal muscle. Conclusion Statins and exercise combination therapy is more effective than statin monotherapy in terms of insulin sensitivity, inflammation and exercise capacity. The small number of studies warrants the need for more randomised controlled trials evaluating the efficacy and safety of combination therapy.

Purification and properties of a dissimilatory nitrate reductase from Haloferax denitrificans

NASA Technical Reports Server (NTRS)

Hochstein, L. I.; Lang, F.

1991-01-01

A membrane-bound nitrate reductase (nitrite:(acceptor) oxidoreductase, EC 1.7.99.4) from the extremely halophilic bacterium Haloferax denitrificans was solubilized by incubating membranes in buffer lacking NaCl and purified by DEAE, hydroxylapatite, and Sepharose 6B gel filtration chromatography. The purified nitrate reductase reduced chlorate and was inhibited by azide and cyanide. Preincubating the enzyme with cyanide increased the extent of inhibition which in turn was intensified when dithionite was present. Although cyanide was a noncompetitive inhibitor with respect to nitrate, nitrate protected against inhibition. The enzyme, as isolated, was composed of two subunits (Mr 116,000 and 60,000) and behaved as a dimer during gel filtration (Mr 380,000). Unlike other halobacterial enzymes, this nitrate reductase was most active, as well as stable, in the absence of salt.

PCSK9 Inhibitors: Novel Therapeutic Strategies for Lowering LDL-Cholesterol.

PubMed

Liu, Zhao-Peng; Wang, Yan

2018-04-22

Statins are currently the major therapeutic strategies to lower low-density lipoprotein cholesterol (LDL-C) levels. However, a number of hypercholesterolemia patients still have a residual cardiovascular disease (CVD) risk despite taking the maximum-tolerated dose of statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein receptor (LDLR), inducing its degradation in the lysosome and inhibiting LDLR recirculating to the cell membranes. The gain-of-function mutations in PCSK9 elevate the LDL-C levels in plasma. Therefore, PCSK9 inhibitors become novel therapeutic approaches in the treatment of hypercholesterolemia. Several PCSK9 inhibitors have been under investigation, and much progress has been made in clinical trials, especially for monoclonal antibodies (MoAbs). Two MoAbs, evolocumab and alirocumab, are now in clinical use. In this review, we summarize the development of PCSK9 inhibitors, including antisense oligonucleotides (ASOs), small interfering RNA (siRNA), small molecule inhibitor, MoAbs, mimetic peptides and adnectins, and the related safety issues. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

The safety of statins in clinical practice.

PubMed

Armitage, Jane

2007-11-24

Statins are effective cholesterol-lowering drugs that reduce the risk of cardiovascular disease events (heart attacks, strokes, and the need for arterial revascularisation). Adverse effects from some statins on muscle, such as myopathy and rhabdomyolysis, are rare at standard doses, and on the liver, in increasing levels of transaminases, are unusual. Myopathy--muscle pain or weakness with blood creatine kinase levels more than ten times the upper limit of the normal range--typically occurs in fewer than one in 10,000 patients on standard statin doses. However, this risk varies between statins, and increases with use of higher doses and interacting drugs. Rhabdomyolysis is a rarer and more severe form of myopathy, with myoglobin release into the circulation and risk of renal failure. Stopping statin use reverses these side-effects, usually leading to a full recovery. Asymptomatic increases in concentrations of liver transaminases are recorded with all statins, but are not clearly associated with an increased risk of liver disease. For most people, statins are safe and well-tolerated, and their widespread use has the potential to have a major effect on the global burden of cardiovascular disease.

1H and 13C NMR Chemical Shift Assignments and Conformational Analysis for the Two Diastereomers of the Vitamin K Epoxide Reductase Inhibitor Brodifacoum

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

Cort, John R.; Cho, Herman M.

2009-10-01

Proton and 13C NMR chemical shift assignments and 1H-1H scalar couplings for the two diastereomers of the vitamin K epoxide reductase (VKOR) inhibitor brodifacoum have been determined from acetone solutions containing both diastereomers. Data were obtained from homo- and heteronuclear correlation spectra acquired at 1H frequencies of 750 and 900 MHz over a 268-303 K temperature range. Conformations inferred from scalar coupling and 1-D NOE measurements exhibit large differences between the diastereomers. Pacific Northwest National Laboratory is operated by Battelle for the US Department of Energy.

Different time trends of caloric and fat intake between statin users and nonusers among US adults: gluttony in the time of statins?

PubMed

Sugiyama, Takehiro; Tsugawa, Yusuke; Tseng, Chi-Hong; Kobayashi, Yasuki; Shapiro, Martin F

2014-07-01

Both dietary modification and use of statins can lower blood cholesterol. The increase in caloric intake among the general population is reported to have plateaued in the last decade, but no study has examined the relationship between the time trends of caloric intake and statin use. To examine the difference in the temporal trends of caloric and fat intake between statin users and nonusers among US adults. A repeated cross-sectional study in a nationally representative sample of 27,886 US adults, 20 years or older, from the National Health and Nutrition Examination Survey, 1999 through 2010. Statin use. Caloric and fat intake measured through 24-hour dietary recall. Generalized linear models with interaction term between survey cycle and statin use were constructed to investigate the time trends of dietary intake for statin users and nonusers after adjustment for possible confounders. We calculated model-adjusted caloric and fat intake using these models and examined if the time trends differed by statin use. Body mass index (BMI) changes were also compared between statin users and nonusers. In the 1999-2000 period, the caloric intake was significantly less for statin users compared with nonusers (2000 vs 2179 kcal/d; P = .007). The difference between the groups became smaller as time went by, and there was no statistical difference after the 2005-2006 period. Among statin users, caloric intake in the 2009-2010 period was 9.6% higher (95% CI, 1.8-18.1; P = .02) than that in the 1999-2000 period. In contrast, no significant change was observed among nonusers during the same study period. Statin users also consumed significantly less fat in the 1999-2000 period (71.7 vs 81.2 g/d; P = .003). Fat intake increased 14.4% among statin users (95% CI, 3.8-26.1; P = .007) while not changing significantly among nonusers. Also, BMI increased more among statin users (+1.3) than among nonusers (+0.4) in the adjusted model (P = .02). Caloric and fat intake

Targeting the Mevalonate Pathway to Reduce Mortality from Ovarian Cancer

DTIC Science & Technology

2015-10-01

intraperitoneal (i.p.) injection twice weekly; atorvastatin (10 mg/kg per injection) was i.p. administered daily (19). Tumor Translational Relevance Recent...other lipophilic statins exerted an anti- tumor phenotype, we assessed another inhibitor of HMG-CoA reductase, atorvastatin (Brand name: Lipitor), in an...OVCAR5 tumor xenograft model. Daily injections of atorvastatin (10 mg/kg) led to significantly reduced tumor sizes as compared with vehicle control

Effects of High Intensity Statin Therapy in the Treatment of Diabetic Dyslipidemia in Patients with Coronary Artery Disease.

PubMed

Vavlukis, Marija; Kedev, Sasko

2018-01-01

Diabetic dyslipidemia has specifics that differ from dyslipidemia in patients without diabetes, which contributes to accelerated atherosclerosis equally as dysglycemia. The aim of this study was to deduce the interdependence of diabetic dyslipidemia and cardiovascular diseases (CVD), therapeutic strategies and the risk of diabetes development with statin therapy. We conducted a literature review of English articles through PubMed, PubMed Central and Cochrane, on the role of diabetic dyslipidemia in atherosclerosis, the antilipemic treatment with statins, and the role of statin therapy in newly developed diabetes, by using key words: atherosclerosis, diabetes mellitus, diabetic dyslipidemia, CVD, statins, nicotinic acid, fibrates, PCSK9 inhibitors. hyperglycemia and dyslipidemia cannot be treated separately in patients with diabetes. It seems that dyslipidemia plays one of the key roles in the development of atherosclerosis. High levels of TG, decreased levels of HDL-C and increased levels of small dense LDL- C particles in the systemic circulation are the most specific attributes of diabetic dyslipidemia, all of which originate from an inflated flux of free fatty acids occurring due to the preceding resistance to insulin, and exacerbated by elevated levels of inflammatory adipokines. Statins are a fundamental treatment for diabetic dyslipidemia, both for dyslipidemia and for CVD prevention. The use of statin treatment with high intensity is endorsed for all diabetes-and-CVD patients, while a moderate - intensity treatment can be applied to patients with diabetes, having additional risk factors for CVD. Statins alone are thought to possess a small, although of statistical significance, risk of incident diabetes, outweighed by their benefits. As important as hyperglycemia and glycoregulation are in CVD development in patients with diabetes, diabetic dyslipidemia plays an even more important role. Statins remain the cornerstone of antilipemic treatment in diabetic

PCSK9 Inhibitors: Treating the Right Patients in Daily Practice.

PubMed

King, Peta; Nicholls, Stephen J

2017-08-01

Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged as a novel approach to low-density lipoprotein cholesterol (LDL-C) lowering. The potential role of PCSK9 inhibitors in clinical practice will be reviewed. Clinical trials have demonstrated that PCSK9 inhibitors produce robust LDL-C lowering when administered either as monotherapy or in combination with statins. This provides the opportunity to achieve effective lipid lowering in familial hypercholesterolemia, patients with either established atherosclerotic cardiovascular disease or high risk primary prevention and an important opportunity to treat patients with statin intolerance. The findings from plaque imaging and patients with established atherosclerotic cardiovascular disease suggest that PCSK9 inhibition has favorable outcomes beyond improving lipid profiles, which has the opportunity to expand their use. PCSK9 inhibitors represent a new approach to achieving effective cardiovascular risk reduction in a broader number of patients. How these agents will be taken up in clinical practice remains to be determined.

Statins and Thyroid Carcinoma: a Meta-Analysis.

PubMed

Zhao, Junyu; Xu, Chunmei; Yao, Jinming; Yu, Changzhen; Liao, Lin; Dong, Jianjun

2018-06-19

Experimental studies have reported the antineoplastic effects of statins in thyroid carcinoma; however, observational studies suggested that statins might increase the risk of thyroid carcinoma. Therefore, this study evaluated the antineoplastic effects of statins in both in vitro studies and animal models, as well as the epidemiological evidence. Databases-PubMed, Cochrane Library, SinoMed, CNKI, Wanfang, and clinical trial registries- were searched. A meta-analysis was performed with sufficiently homogeneous studies. Eighteen articles were involved. In in vitro studies, statins showed a concentration-dependent inhibition of cell line growth (weighted mean difference -34.68, 95% confidence interval -36.53 to -32.83). A significant efficacy of statin-induced apoptosis was observed (weighted mean difference [95% confidence interval]: 24 h, 57.50 [55.98-59.03]; 48 h, 23.43 [22.19-24.66]; 72 h, 51.29 [47.52-55.07]). Early apoptosis was increased in a dose- and time-dependent manner. In in vivo antitumor studies, lovastatin inhibited tumor growth, as shown by a reduction in tumor volume. However, two clinical studies showed discordant results from the experimental studies. Experimental studies revealed the antineoplastic efficacy of statins but statins were associated with thyroid carcinoma in clinical studies. This discrepancy may be due to the different concentrations of statins used and the effects of hyperlipidemia interventions, and thus further study is required. © 2018 The Author(s). Published by S. Karger AG, Basel.

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.

Comparative effects of cholesteryl ester transfer protein inhibition, statin or ezetimibe on lipid factors: The ACCENTUATE trial.

PubMed

Nicholls, Stephen J; Ray, Kausik K; Ballantyne, Christie M; Beacham, Lauren A; Miller, Debra L; Ruotolo, Giacomo; Nissen, Steven E; Riesmeyer, Jeffrey S

2017-06-01

The optimal approaches to management of patients treated with moderate statin doses on lipid parameters are unknown. The ACCENTUATE study aimed to compare the effects of adding the cholesteryl ester transfer protein inhibitor (CETP) evacetrapib, ezetimibe or increasing statin dose in atorvastatin-treated high-vascular risk patients on lipid parameters. 366 patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg plus placebo, daily for 90 days at 64 centers in the United States. Lipid parameters, safety and tolerability were measured. Addition of evacetrapib significantly reduced LDL-C (-33%) compared with ezetimibe (-27%, p=0.045), increasing statin dose (-6%) and statin alone (0%, p<0.001). Evacetrapib also decreased apoB by 23% compared to 19% with ezetimibe (p=0.06) and 7% with increased statin dose (p<0.001), and reduced Lp(a) by 29% (p<0.001 vs. other groups). Evacetrapib increased HDL-C (+125%), apoA-I (+46%), apoC-III (+50%) and apoE (+28%) (p<0.001 vs. other groups). Non-ABCA1-mediated efflux increased by 53% (p<0.001 vs. other groups) with evacetrapib. ABCA1-mediated efflux also increased by 13% with evacetrapib (p<0.001 vs. ezetimibe, p=0.002 vs. increasing statin dose, and p=0.004 vs. statin alone). Addition of evacetrapib to atorvastatin produced an increase in hsCRP compared with ezetimibe (p=0.02). While evacetrapib improved traditional atherogenic and putative protective lipid measures compared with ezetimibe and increasing statin dose in patients with ASCVD and/or diabetes, it also adversely affected novel atherogenic risk factors. These findings may contribute to the lack of clinical benefit observed in the ACCELERATE trial. Copyright © 2017 Elsevier B.V. All rights reserved.

[Help me--I do not tolerate my statin].

PubMed

Nater, Harald; Perger, Ludwig; Suter, Paolo M

2015-05-06

Statins represent the most widely prescribed drugs. Accordingly, in daily practice statin-related muscle pain and other myopathic sensations are frequently seen. In this practice review the clinical approach to statin myopathy is discussed.

Effect of pretreatment with statins on ischemic stroke outcomes.

PubMed

Reeves, Mathew J; Gargano, Julia Warner; Luo, Zhehui; Mullard, Andrew J; Jacobs, Bradley S; Majid, Arshad

2008-06-01

Statins reduce the risk of stroke in at-risk populations and may improve outcomes in patients taking statins before an ischemic stroke (IS). Our objectives were to examine the effects of pretreatment with statins on poor outcome in IS patients. Over a 6-month period all acute IS admissions were prospectively identified in 15 hospitals participating in a statewide acute stroke registry. Poor stroke outcome was defined as modified Rankin score >/=4 at discharge (ie, moderate-severe disability or death). Multivariable logistic regression models and matched propensity score analyses were used to quantify the effect of statin pretreatment on poor outcome. Of 1360 IS patients, 23% were using statins before their stroke event and 42% had a poor stroke outcome. After multivariable adjustment, pretreatment with statins was associated with lower odds of poor outcome (OR=0.74, 95% CI 0.52, 1.02). A significant interaction (P<0.01) was found between statin use and race. In whites, statins were associated with statistically significantly lower odds of poor outcome (OR=0.61, 95% CI 0.42, 0.86), but in blacks statins were associated with a nonstatistically significant increase in poor outcome (OR=1.82, 95% CI 0.98, 3.39). Matched propensity score analyses were consistent with the multivariable model results. Pretreatment with statins was associated with better stroke outcomes in whites, but we found no evidence of a beneficial effect of statins in blacks. These findings indicate the need for further studies, including randomized trials, to examine differential effects of statins on ischemic stroke outcomes among whites and blacks.

Statins for acute coronary syndrome.

PubMed

Vale, Noah; Nordmann, Alain J; Schwartz, Gregory G; de Lemos, James; Colivicchi, Furio; den Hartog, Frank; Ostadal, Petr; Macin, Stella M; Liem, Anho H; Mills, Edward J; Bhatnagar, Neera; Bucher, Heiner C; Briel, Matthias

2014-09-01

The early period following the onset of acute coronary syndrome (ACS) represents a critical stage of coronary heart disease, with a high risk of recurrent events and deaths. The short-term effects of early treatment with statins on patient-relevant outcomes in patients suffering from ACS are unclear. This is an update of a review previously published in 2011. To assess the effects, both harms and benefits, of early administered statins in patients with ACS, in terms of mortality and cardiovascular events. We updated the searches of CENTRAL (2013, Issue 3), MEDLINE (Ovid) (1946 to April Week 1 2013), EMBASE (Ovid) (1947 to 2013 Week 14), and CINAHL (EBSCO) (1938 to 2013) on 12 April 2013. We applied no language restrictions. We supplemented the search by contacting experts in the field, by reviewing the reference lists of reviews and editorials on the topic, and by searching trial registries. Randomized controlled trials (RCTs) comparing statins with placebo or usual care, with initiation of statin therapy within 14 days following the onset of ACS, follow-up of at least 30 days, and reporting at least one clinical outcome. Two authors independently assessed risk of bias and extracted data. We calculated risk ratios (RRs) for all outcomes in the treatment and control groups and pooled data using random-effects models. Eighteen studies (14,303 patients) compared early statin treatment versus placebo or no treatment in patients with ACS. The new search did not identify any new studies for inclusion. There were some concerns about risk of bias and imprecision of summary estimates. Based on moderate quality evidence, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction, and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) or four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up when compared to placebo or no treatment. There were no statistically significant risk reductions

Differences in hypolipidaemic effects of two statins on Hep G2 cells or human hepatocytes in primary culture.

PubMed Central

Clerc, T.; Sbarra, V.; Domingo, N.; Rault, J. P.; Diaconescu, N.; Moutardier, V.; Hasselot, N.; Lafont, H.; Jadot, G.; Laruelle, C.; Chanussot, F.

1996-01-01

1. The objective of this study was to compare in cultured human hepatocytes or Hep G2 cells, changes in the fate of unesterified low density lipoprotein (LDL)-cholesterol induced by crilvastatin, a new cholesterol lowering drug and a reference statin, simvastatin. 2. The experiments were carried out for 20 h, each well contained 4.2 x 10(5)/cm2 Hep G2 cells or 0.5 x 10(5)/Cm2 human hepatocytes, 130 microM ursodeoxycholate, 0.68 microCi or 1.59 microCi unesterified human [14C]-LDL-cholesterol, crilvastatin or simvastatin at 0 or 50 microM (both cell types) or 300 microM (Hep-G2 cells). Incubation with the two drugs resulted in increased amounts of unesterified [14C]-LDL-cholesterol taken by the two cell types, compared to control. 3. Crilvastatin 50 microM led to significantly higher quantities of [14C]-glyco-tauro-conjugated bile salts, compared to simvastatin. Statins reduced the apo B100 level secreted by the two cell types (simvastatin) or human hepatocytes (crilvastatin). Crilvastatin enhanced both the level of apo A1 secreted by the Hep G2 cells and the level of APF, a high density lipoprotein (HDL) and biliary apoprotein. 4. Crilvastatin not only acts by stimulating LDL-cholesterol uptake by hepatocytes, but also by enhancing the catabolism of LDL-cholesterol in bile salts and probably by stimulating HDL and/or bile component secretion. Such a mechanism was not previously described for HMG CoA reductase inhibitors. Our results on APF show that this apoprotein could be considered also as an indicator of changes in bile and/or HDL compartments. 5. The human hepatocyte model appeared to be a suitable and relevant model in the pharmacological-metabolic experiments carried out in this study. It led to more consistent data than those obtained with Hep G2 cells. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8842455

PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future.

PubMed

Shimada, Yuichi J; Cannon, Christopher P

2015-09-21

Reduction in low-density lipoprotein cholesterol (LDL-C), mainly with statins, has decreased the risk of cardiovascular events over the last few decades. However, there are several patient populations that warrant further decrease in LDL-C by additional cholesterol-lowering therapy other than statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of drugs that have been shown to further decrease LDL-C by 50-70% when administered as a monotherapy or on a background therapy with statins. Proprotein convertase subtilisin/kexin type 9 inhibitors are also an excellent example of drug development in which discovery of gene mutations and its clinical effects have rapidly progressed into successful preclinical and clinical studies with multiple Phases 1-3 clinical trials completed or ongoing to date. This review summarizes the rapid evolution of the drug from genetic discovery to identification of targets for the drugs, to animal and human testing, and to large clinical outcomes trials, followed by discussion on foreseeable challenges of PCSK9 inhibitors. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

X-ray structural studies of quinone reductase 2 nanomolar range inhibitors

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

Pegan, Scott D.; Sturdy, Megan; Ferry, Gilles

Quinone reductase 2 (QR2) is one of two members comprising the mammalian quinone reductase family of enzymes responsible for performing FAD mediated reductions of quinone substrates. In contrast to quinone reductase 1 (QR1) which uses NAD(P)H as its co-substrate, QR2 utilizes a rare group of hydride donors, N-methyl or N-ribosyl nicotinamide. Several studies have linked QR2 to the generation of quinone free radicals, several neuronal degenerative diseases, and cancer. QR2 has been also identified as the third melatonin receptor (MT3) through in cellulo and in vitro inhibition of QR2 by traditional MT3 ligands, and through recent X-ray structures of humanmore » QR2 (hQR2) in complex with melatonin and 2-iodomelatonin. Several MT3 specific ligands have been developed that exhibit both potent in cellulo inhibition of hQR2 nanomolar, affinity for MT3. The potency of these ligands suggest their use as molecular probes for hQR2. However, no definitive correlation between traditionally obtained MT3 ligand affinity and hQR2 inhibition exists limiting our understanding of how these ligands are accommodated in the hQR2 active site. To obtain a clearer relationship between the structures of developed MT3 ligands and their inhibitory properties, in cellulo and in vitro IC{sub 50} values were determined for a representative set of MT3 ligands (MCA-NAT, 2-I-MCANAT, prazosin, S26695, S32797, and S29434). Furthermore, X-ray structures for each of these ligands in complex with hQR2 were determined allowing for a structural evaluation of the binding modes of these ligands in relation to the potency of MT3 ligands.« less

Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education.

PubMed

Wei, Melissa Y; Ito, Matthew K; Cohen, Jerome D; Brinton, Eliot A; Jacobson, Terry A

2013-01-01

Although statins have been shown to reduce cardiovascular disease mortality, less than half of U.S. adults achieve their low-density lipoprotein cholesterol goal. In many patients initiated on a statin, adherence rates decrease over time. To characterize current and former statin users, identify reasons for the discontinuation or switching of statins, and identify factors associated with adherence. The USAGE survey is a cross-sectional, self-administered Internet-based survey of 10,138 U.S. adults fielded September to October 2011. The following statin users were identified and compared: adherent nonswitchers, adherent switchers, non-adherent switchers, and discontinuers. Univariate and multivariate models using a priori covariates for adherence and discontinuation were examined. Most participants were current statin users who adhered with their prescribed statin (82.5%, n = 8371). Former statin users or discontinuers (12%, n = 1220) cited muscle pain, a side effect, as the primary reason for discontinuation (60%), followed by cost (16%), and then perceived lack of efficacy (13%). Discontinuers were less satisfied with their physicians' explanation of cholesterol treatment, more likely to use the Internet to research statins, and less likely to undergo frequent cholesterol monitoring. Among adherent statin users, the primary reasons for switching were muscle side effects (33%) and cost (32%). Individuals at risk for non-adherence included those with low household income, those who experienced muscle pain as a side effect while on statin therapy, and those taking medication for cardiovascular disease. Statin-related muscle side effects are common and contribute significantly to rates of discontinuation, switching, and non-adherence. Improved physician patient communication about side effects and benefits of statins are necessary to improve both adherence and outcomes. Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Statins Improve the Resolution of Established Murine Venous Thrombosis: Reductions in Thrombus Burden and Vein Wall Scarring

PubMed Central

Kessinger, Chase W.; Kim, Jin Won; Henke, Peter K.; Thompson, Brian; McCarthy, Jason R.; Hara, Tetsuya; Sillesen, Martin; Margey, Ronan J. P.; Libby, Peter; Weissleder, Ralph; Lin, Charles P.; Jaffer, Farouc A.

2015-01-01

Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins—lipid-lowering agents with anti-thrombotic and anti-inflammatory properties—in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy. PMID:25680183

Inhibitory effect of rhetsinine isolated from Evodia rutaecarpa on aldose reductase activity.

PubMed

Kato, A; Yasuko, H; Goto, H; Hollinshead, J; Nash, R J; Adachi, I

2009-03-01

Aldose reductase inhibitors have considerable potential for the treatment of diabetic complications, without increased risk of hypoglycemia. Search for components inhibiting aldose reductase led to the discovery of active compounds contained in Evodia rutaecarpa Bentham (Rutaceae), which is the one of the component of Kampo-herbal medicine. The hot water extract from the E. rutaecarpa was subjected to distribution or gel filtration chromatography to give an active compound, N2-(2-methylaminobenzoyl)tetrahydro-1H-pyrido[3,4-b]indol-1-one (rhetsinine). It inhibited aldose reductase with IC(50) values of 24.1 microM. Furthermore, rhetsinine inhibited sorbitol accumulation by 79.3% at 100 microM. These results suggested that the E. rutaecarpa derived component, rhetsinine, would be potentially useful in the treatment of diabetic complications.

Statins Do Not Alter the Incidence of Mesothelioma in Asbestos Exposed Mice or Humans

PubMed Central

Robinson, Cleo; Alfonso, Helman; Woo, Samantha; Walsh, Amy; Olsen, Nola; Musk, Arthur W.; Robinson, Bruce W. S.; Nowak, Anna K.; Lake, Richard A.

2014-01-01

Mesothelioma is principally caused by asbestos and may be preventable because there is a long latent period between exposure and disease development. The most at-risk are a relatively well-defined population who were exposed as a consequence of their occupations. Although preventative agents investigated so far have not been promising, discovery of such an agent would have a significant benefit world-wide on healthcare costs and personal suffering. Statins are widely used for management of hypercholesterolemia and cardiovascular risk; they can induce apoptosis in mesothelioma cells and epidemiological data has linked their use to a lower incidence of cancer. We hypothesised that statins would inhibit the development of asbestos-induced mesothelioma in mice and humans. An autochthonous murine model of asbestos-induced mesothelioma was used to test this by providing atorvastatin daily in the feed at 100 mg/kg, 200 mg/kg and 400 mg/kg. Continuous administration of atorvastatin did not alter the rate of disease development nor increase the length of time that mice survived. Latency to first symptoms of disease and disease progression were also unaffected. In a parallel study, the relationship between the use of statins and development of mesothelioma was investigated in asbestos-exposed humans. In a cohort of 1,738 asbestos exposed people living or working at a crocidolite mine site in Wittenoom, Western Australia, individuals who reported use of statins did not have a lower incidence of mesothelioma (HR = 1.01; 95% CI = 0.44–2.29, p = 0.99). Some individuals reported use of both statins and non-steroidal anti-inflammatory drugs or COX-2 inhibitors, and these people also did not have an altered risk of mesothelioma development (HR = 1.01; 95% CI = 0.61–1.67, p = 0.97). We conclude that statins do not moderate the rate of development of mesothelioma in either a mouse model or a human cohort exposed to asbestos. PMID:25093718

Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus

DOE PAGES

Wang, Hui; Lu, Yang; Liu, Li; ...

2014-09-06

Here we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of PT119, a potent Staphylococcus aureus enoyl-ACP reductase (saFabI) inhibitor with a K i value of 0.01 nM and a residence time of 750 min on the enzyme target in mice. PT119 was found to have promising antibacterial activity in two different S. aureus infection models: it caused a 3 log reduction in the CFU’s in a mouse thigh muscle infection model and increased the survival rate from 0% to 50% in a mouse systemic infection model. PT119 was then radiolabeled with carbon-11 to evaluate its biodistribution and PK in bothmore » healthy and S. aureus infected mice using positron emission tomography (PET). The biodistribution of [ 11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ~1 h of analysis permitted by the carbon-11 half life. This approach provides important data for PK/PD modeling and is the first step in identifying radiotracers that can non-invasively image bacterial infection in vivo.« less

Radiosynthesis and biological evaluation of a novel enoyl-ACP reductase inhibitor for Staphylococcus aureus

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

Wang, Hui; Lu, Yang; Liu, Li

Here we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of PT119, a potent Staphylococcus aureus enoyl-ACP reductase (saFabI) inhibitor with a K i value of 0.01 nM and a residence time of 750 min on the enzyme target in mice. PT119 was found to have promising antibacterial activity in two different S. aureus infection models: it caused a 3 log reduction in the CFU’s in a mouse thigh muscle infection model and increased the survival rate from 0% to 50% in a mouse systemic infection model. PT119 was then radiolabeled with carbon-11 to evaluate its biodistribution and PK in bothmore » healthy and S. aureus infected mice using positron emission tomography (PET). The biodistribution of [ 11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ~1 h of analysis permitted by the carbon-11 half life. This approach provides important data for PK/PD modeling and is the first step in identifying radiotracers that can non-invasively image bacterial infection in vivo.« less

Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases.

PubMed

Healy, David; Le Noury, Joanna; Mangin, Derelie

2018-05-01

To investigate clinical reports of post-SSRI sexual dysfunction (PSSD), post-finasteride syndrome (PFS) and enduring sexual dysfunction following isotretinoin. Data from RxISK.org, a global adverse event reporting website, have been used to establish the clinical features, demographic details and clinical trajectories of syndromes of persistent sexual difficulties following three superficially different treatment modalities.RESULTSWe report on 300 cases of enduring sexual dysfunction from 37 countries following 14 different drugs comprised of serotonin reuptake inhibiting antidepressants, 5α-reductase inhibitors and isotretinoin. While reports of certain issues were unique to the antidepressants, such as the onset of premature ejaculation and persistent genital arousal disorder (PGAD), there was also a significant overlap in symptom profile between the drug groups, with common features including genital anaesthesia, pleasureless or weak orgasm, loss of libido and impotence. Secondary consequences included relationship breakdown and impaired quality of life.CONCLUSIONSThese data point to a legacy syndrome or syndromes comprising a range of disturbances to sexual function. More detailed studies will require developments in coding systems that recognise the condition(s). Further exploration of these tardive sexual syndromes may yield greater understanding of tardive syndromes in general.

Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases

PubMed Central

Healy, David; Le Noury, Joanna; Mangin, Derelie

2018-01-01

OBJECTIVE: To investigate clinical reports of post-SSRI sexual dysfunction (PSSD), post-finasteride syndrome (PFS) and enduring sexual dysfunction following isotretinoin. METHODS: Data from RxISK.org, a global adverse event reporting website, have been used to establish the clinical features, demographic details and clinical trajectories of syndromes of persistent sexual difficulties following three superficially different treatment modalities. RESULTS We report on 300 cases of enduring sexual dysfunction from 37 countries following 14 different drugs comprised of serotonin reuptake inhibiting antidepressants, 5α-reductase inhibitors and isotretinoin. While reports of certain issues were unique to the antidepressants, such as the onset of premature ejaculation and persistent genital arousal disorder (PGAD), there was also a significant overlap in symptom profile between the drug groups, with common features including genital anaesthesia, pleasureless or weak orgasm, loss of libido and impotence. Secondary consequences included relationship breakdown and impaired quality of life. CONCLUSIONS These data point to a legacy syndrome or syndromes comprising a range of disturbances to sexual function. More detailed studies will require developments in coding systems that recognise the condition(s). Further exploration of these tardive sexual syndromes may yield greater understanding of tardive syndromes in general. PMID:29733030

Androgen Regulation of 5α-Reductase Isoenzymes in Prostate Cancer: Implications for Prostate Cancer Prevention

PubMed Central

Li, Jin; Ding, Zhiyong; Wang, Zhengxin; Lu, Jing-Fang; Maity, Sankar N.; Navone, Nora M.; Logothetis, Christopher J.; Mills, Gordon B.; Kim, Jeri

2011-01-01

The enzyme 5α-reductase, which converts testosterone to dihydrotestosterone (DHT), performs key functions in the androgen receptor (AR) signaling pathway. The three isoenzymes of 5α-reductase identified to date are encoded by different genes: SRD5A1, SRD5A2, and SRD5A3. In this study, we investigated mechanisms underlying androgen regulation of 5α-reductase isoenzyme expression in human prostate cells. We found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type–specific manner, that such regulation occurs at the transcriptional level, and that AR is necessary for this regulation. In addition, our results suggest that AR is recruited to a negative androgen response element (nARE) on the promoter of SRD5A3 in vivo and directly binds to the nARE in vitro. The different expression levels of 5α-reductase isoenzymes may confer response or resistance to 5α-reductase inhibitors and thus may have importance in prostate cancer prevention. PMID:22194926

SRD5A1 and SRD5A2 are associated with treatment for benign prostatic hyperplasia with the combination of 5α-reductase inhibitors and α-adrenergic receptor antagonists.

PubMed

Gu, Xin; Na, Rong; Huang, Tao; Wang, Li; Tao, Sha; Tian, Lu; Chen, Zhuo; Jiao, Yang; Kang, Jian; Zheng, Siqun; Xu, Jianfeng; Sun, Jielin; Qi, Jun

2013-08-01

Common treatments for benign prostatic hyperplasia include 5α-reductase inhibitors and α-adrenergic receptor antagonists. However, these treatments can only partially decrease the risk of benign prostatic hyperplasia progression. SRD5A1 and SRD5A2 are 5α-reductase inhibitor targets. We investigated the association between drug efficacy and single nucleotide polymorphisms in the SRD5A1 and SRD5A2 genes in a Chinese population. We genotyped 11 tagging single nucleotide polymorphisms in the SRD5A1 and SRD5A2 genes in a total of 426 benign prostatic hyperplasia cases and 1,008 controls from Xinhua Hospital, Shanghai, People's Republic of China. Cases were treated with type II 5α-reductase inhibitors and α-adrenergic receptor antagonists. We tested the association of tagging single nucleotide polymorphisms with benign prostatic hyperplasia risk/progression, clinical characteristics at baseline, including the I-PSS (International Prostate Symptom Score) and total prostate volume, and changes in clinical characteristics after treatment. The 11 tagging single nucleotide polymorphisms were not significantly associated with benign prostatic hyperplasia risk or progression (each p >0.05). In the SRD5A1 gene rs6884552 and rs3797177 were significantly associated with baseline I-PSS (p = 0.04 and 0.003, respectively). In the SRD5A2 gene rs523349 (V89L) and rs9332975 were significantly associated with baseline total prostate volume (p = 0.01 and 0.001, respectively). In SRD5A1 rs166050 was significantly associated with the posttreatment change in total prostate volume (p = 0.04). In SRD5A2 rs523349 and rs612224 were significantly associated with the posttreatment I-PSS change (p = 0.03 and 0.009, respectively). SRD5A1 and SRD5A2 single nucleotide polymorphisms are significantly associated with the clinical characteristics of benign prostatic hyperplasia and the efficacy of benign prostatic hyperplasia treatment. Copyright © 2013 American Urological Association Education and

Recent developments in the effects of nitric oxide-donating statins on cardiovascular disease through regulation of tetrahydrobiopterin and nitric oxide.

PubMed

Ma, Sze; Ma, Christopher Cheng-Hwa

2014-11-01

Since the discovery of the importance of nitric oxide (NO) to the human body three decades ago, numerous laboratory and clinical studies have been done to explore its potential therapeutic actions on many organs. In the cardiovascular system, NO works as a volatile signaling molecule regulating the vascular permeability and vascular tone, preventing thrombosis and inflammation, as well as inhibiting the smooth muscle hyperplasia. Thus, NO is important in the prevention and treatment of cardiovascular disease. NO is synthesized by NO synthase (NOS) with tetrahydrobiopterin (BH4) as the crucial cofactor. Many studies have been done to form nitric oxide donors so as to deliver NO directly to the vessel walls. In addition, NO moieties have been incorporated into existing therapeutic agents to enhance the NO bioavailability, including statins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA), the rate-limiting enzyme of the mevalonate pathway. By inhibiting this pathway, statins lower blood cholesterol and exert their pleiotropic effects through activity in reaction cascades, such as Rho/ROCK and Rac 1/NADPH oxidase pathways. Statins have also been observed to implement their non-lipid effects by promoting BH4 synthesis with increase of NO bioavailability. Furthermore, NO-donating statins in laboratory studies have demonstrated to produce better therapeutic effects than their parent's drugs. They offer better anti-inflammatory, anti-proliferative and antithrombotic actions on cardiovascular system. They also cause better revascularization in peripheral ischemia and produce greater enhancement in limb reperfusion and salvage. In addition, it has been shown that NO-donating statin caused less myotoxicity, the most common side effect related to treatment with statins. The initial studies have demonstrated the superior therapeutic effects of NO-donating statins while producing fewer side effects. Crown Copyright © 2014. Published by Elsevier Inc. All

Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase)

PubMed Central

Miyadera, Hiroko; Shiomi, Kazuro; Ui, Hideaki; Yamaguchi, Yuichi; Masuma, Rokuro; Tomoda, Hiroshi; Miyoshi, Hideto; Osanai, Arihiro; Kita, Kiyoshi; Ōmura, Satoshi

2003-01-01

Enzymes in the mitochondrial respiratory chain are involved in various physiological events in addition to their essential role in the production of ATP by oxidative phosphorylation. The use of specific and potent inhibitors of complex I (NADH-ubiquinone reductase) and complex III (ubiquinol-cytochrome c reductase), such as rotenone and antimycin, respectively, has allowed determination of the role of these enzymes in physiological processes. However, unlike complexes I, III, and IV (cytochrome c oxidase), there are few potent and specific inhibitors of complex II (succinate-ubiquinone reductase) that have been described. In this article, we report that atpenins potently and specifically inhibit the succinate-ubiquinone reductase activity of mitochondrial complex II. Therefore, atpenins may be useful tools for clarifying the biochemical and structural properties of complex II, as well as for determining its physiological roles in mammalian tissues. PMID:12515859

Statins in Acute Ischemic Stroke: A Systematic Review

PubMed Central

Hong, Keun-Sik; Lee, Ji Sung

2015-01-01

Background and Purpose Statins have pleiotropic effects of potential neuroprotection. However, because of lack of large randomized clinical trials, current guidelines do not provide specific recommendations on statin initiation in acute ischemic stroke (AIS). The current study aims to systematically review the statin effect in AIS. Methods From literature review, we identified articles exploring prestroke and immediate post-stroke statin effect on imaging surrogate markers, initial stroke severity, functional outcome, and short-term mortality in human AIS. We summarized descriptive overview. In addition, for subjects with available data from publications, we conducted meta-analysis to provide pooled estimates. Results In total, we identified 70 relevant articles including 6 meta-analyses. Surrogate imaging marker studies suggested that statin might enhance collaterals and reperfusion. Our updated meta-analysis indicated that prestroke statin use was associated with milder initial stroke severity (odds ratio [OR] [95% confidence interval], 1.24 [1.05-1.48]; P=0.013), good functional outcome (1.50 [1.29-1.75]; P<0.001), and lower mortality (0.42 [0.21-0.82]; P=0.0108). In-hospital statin use was associated with good functional outcome (1.31 [1.12-1.53]; P=0.001), and lower mortality (0.41 [0.29-0.58]; P<0.001). In contrast, statin withdrawal was associated with poor functional outcome (1.83 [1.01-3.30]; P=0.045). In patients treated with thrombolysis, statin was associated with good functional outcome (1.44 [1.10-1.89]; P=0.001), despite an increased risk of symptomatic hemorrhagic transformation (1.63 [1.04-2.56]; P=0.035). Conclusions The current study findings support the use of statin in AIS. However, the findings were mostly driven by observational studies at risk of bias, and thereby large randomized clinical trials would provide confirmatory evidence. PMID:26437994

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

5α-Reductase inhibitor is less effective in men with small prostate volume and low serum prostatic specific antigen level.

PubMed

Lin, Victor C; Liao, Chun-Hou; Wang, Chung-Cheng; Kuo, Hann-Chorng

2015-09-01

Large total prostate volumes (TPVs) or high serum prostate-specific antigen (PSA) levels indicate high-risk clinical progression of benign prostatic hyperplasia. This prospective study investigated the treatment outcome of combined 5α-reductase inhibitor and α-blocker in patients with and without large TPVs or high PSA levels. Men aged ≥ 45 years with International Prostate Symptom scores (IPSS) ≥ 8, TPV ≥ 20 mL, and maximum flow rate ≤ 15 mL/s received a combination therapy (dutasteride plus doxaben) for 2 years. Patients with baseline PSA ≥ 4 ng/mL underwent prostatic biopsy for excluding malignancy. The changes in the parameters from baseline to 24 months after combination therapy were compared in those with and without TPV ≥ 40 mL or PSA levels ≥ 1.5 ng/mL. A total of 285 patients (mean age 72 ± 9 years) completed the study. Combination therapy resulted in significant continuous improvement in IPSS, quality of life index, maximum flow rate, and postvoid residual (all p < 0.0001) regardless of baseline TPV or PSA levels. However, only patients with baseline TPV ≥ 40 mL had significant improvements in IPSS-storage subscore, voided volume, reduction in TPV, transitional zone index, and PSA levels. In addition, patients with baseline TPV < 40 mL and PSA < 1.5 ng/mL had neither a reduction in TPV nor a decrease in serum PSA level. A high TPV indicates more outlet resistance, whereas elevated serum PSA level reflects glandular proliferation. Thus, patients with TPV<40 mL and low PSA levels has less benefit from 5α-reductase inhibitor therapy. The therapeutic effect of combined treatment may arise mainly from the α-blocker in these patients. Copyright © 2013. Published by Elsevier B.V.

Statins for stroke prevention: disappointment and hope.

PubMed

Amarenco, Pierre; Tonkin, Andrew M

2004-06-15

The occurrence of stroke increases with age, particularly affecting the older elderly, a population also at higher risk for coronary heart disease (CHD). Epidemiological and observational studies have not shown a clear association between cholesterol levels and all causes of stroke. Nonetheless, large, long-term statin trials in patients with established CHD or at high risk for CHD have shown that statins decrease stroke incidence in these populations. Combined data from 9 trials including 70,070 patients indicated relative and absolute risk reductions for stroke of 21% and 0.9%, respectively, with statins. The number of strokes prevented per 1000 patients treated for 5 years in patients with CHD is 9 for statins, compared with 17.3 for antiplatelet agents. Statins have not yet been shown to reduce stroke risk in the typical general population without known CHD, nor have they been shown to prevent recurrent stroke in patients with prior stroke. Potential reasons for the effects of statins on stroke and the non-cholesterol-lowering mechanisms that may be involved are discussed. Treatment strategies based on global cardiovascular risk may be most effective. Additional studies in patients representative of the typical stroke population are needed.

Muscular effects of statins in the elderly female: a review

PubMed Central

Bhardwaj, Shilpa; Selvarajah, Shalini; Schneider, Eric B

2013-01-01

Statins have demonstrated substantial benefits in supporting cardiovascular health. Older individuals are more likely to experience the well-known muscle-related side effects of statins compared with younger individuals. Elderly females may be especially vulnerable to statin-related muscle disorder. This review will collate and discuss statin-related muscular effects, examine their molecular and genetic basis, and how these apply specifically to elderly women. Developing strategies to reduce the incidence of statin-induced myopathy in older adult women could contribute to a significant reduction in the overall incidence of statin-induced muscle disorder in this vulnerable group of patients. Reducing statin-related muscle disorder would likely improve overall patient compliance, thereby leading to an increase in improved short- and long-term outcomes associated with appropriate use of statins. PMID:23355775

The 5α-reductase inhibitor finasteride is not associated with alterations in sleep spindles in men referred for polysomnography

PubMed Central

Goldstein, Michael R.; Cook, Jesse D.; Plante, David T.

2015-01-01

Objective Endogenous neurosteroids that potentiate the GABAA receptor are thought to enhance the generation of sleep spindles. This study tested the hypothesis that the 5α-reductase inhibitor finasteride, an agent associated with reductions in neurosteroids, would be associated with reduced sleep spindles in men referred for polysomnography. Methods Spectral analysis and spindle waveform detection were performed on electroencephalographic (EEG) sleep data in the 11–16Hz sigma band, as well as several subranges, from 27 men taking finasteride and 27 matched comparison patients (ages 18 to 81 years). Results No significant differences between groups were observed for spectral power or sleep spindle morphology measures, including spindle density, amplitude, duration, and integrated spindle activity. Conclusions Contrary to our hypothesis, these findings demonstrate that finasteride is not associated with alterations in sleep spindle range activity or spindle morphology parameters. PMID:26494125

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.

An update on the relationship between statins and physical activity.

PubMed

Panza, Gregory A; Taylor, Beth A; Thompson, Paul D

2016-09-01

This review examined studies published within the last 16 months that investigated the relationship between statins and physical activity. These recent studies suggest that statins do not adversely affect cardiorespiratory fitness, muscle strength, athletic performance, or physical activity adherence. One recent study comparing patients with statin-associated myalgia and nonstatin-using controls did report that statins are associated with a slowing of time to peak power output, increased abdominal adiposity, and insulin resistance. Statin users also had different muscle gene expression than controls, but conclusions are limited by the design of that study. Previous reports suggest that statin-associated muscle symptoms such as myalgia, cramps, and weakness occur more frequently in physically active individuals, but the recent studies we reviewed do not provide additional support for this possibility. Well-designed clinical trials are needed to determine whether different statins or statin doses evoke statin-associated muscle symptoms or muscle damage that may reduce cardiorespiratory fitness and adherence to physical activity.

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

Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update.

PubMed

Reiner, Z

2013-09-01

Cardiovascular disease (CVD) is a significant cause of death in Europe. In addition to patients with proven CVD, those with type 2 diabetes (T2D) are at a particularly high-risk of CVD and associated mortality. Treatment for dyslipidaemia, a principal risk factor for CVD, remains a healthcare priority; evidence supports the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary objective of dyslipidaemia management. While statins are the treatment of choice for lowering LDL-C in the majority of patients, including those with T2D, many patients retain a high CVD risk despite achieving the recommended LDL-C targets with statins. This 'residual risk' is mainly due to elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Following statin therapy optimisation additional pharmacotherapy should be considered as part of a multifaceted approach to risk reduction. Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated TG or low HDL-C levels. Currently, the strongest evidence of benefit is for the addition of fenofibrate to statin treatment in high-risk patients with T2D and dyslipidaemia. An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy. Here, addition of fibrates and niacin to statin therapy is discussed, and novel approaches being developed for HDL-C and TG management, including cholesteryl ester transfer protein inhibitors, Apo A-1 analogues, mipomersen, lomitapide and monoclonal antibodies against PCSK9, are reviewed. Copyright © 2013 Elsevier B.V. All rights reserved.

Cytochrome P450 drug interactions with statin therapy.

PubMed

Goh, Ivanna Xin Wei; How, Choon How; Tavintharan, Subramaniam

2013-03-01

Statins are commonly used in the treatment of hyperlipidaemia. Although the benefits of statins are well-documented, they have the potential to cause myopathy and rhabdomyolysis due to the complex interactions of drugs, comorbidities and genetics. The cytochrome P450 family consists of major enzymes involved in drug metabolism and bioactivation. This article aims to highlight drug interactions involving statins, as well as provide updated recommendations and approaches regarding the safe and appropriate use of statins in the primary care setting.

Managing statin-induced muscle toxicity in a lipid clinic.

PubMed

Blaier, O; Lishner, M; Elis, A

2011-06-01

Muscle toxicity is the most significant adverse effect related to statins. The aim of the study was to analyse the clinical course and achievement of LDL-C target levels in patients with statin-induced muscle toxicity. All patients who were referred to the lipid clinic because of statin-induced muscle toxicity, or developed it during follow-up, or did not reach LDL-C target levels because of its previous occurrence, and attended the clinic for at least three follow-up visits, were eligible. Files were reviewed for demographic and clinical parameters, coronary heart disease risk level, the severity of muscle injury, the type of statin and dose that caused the adverse effects, the clinical approach and outcome, and whether the LDL-C target level was achieved. The study group consisted of 54 patients. Twenty-three (43%) patients complained of myalgia, 23 (43%) had asymptomatic serum creatine kinase (CK) level elevation, five (9%) had myopathy and three (5%) had rhabdomyolysis. Fifty of the patients (93%) continued statin therapy and 43 (80%) achieved the LDL-C target level. We show that for the majority of patients with statin-induced muscle toxicity, statin therapy can be safely and effectively continued. In cases of asymptomatic CK levels <3-5 upper limit of normal (ULN), statin treatment should not be interrupted. When CK levels >3-5 ULN or when various symptomatic muscle adverse reactions are present, statins rechallenge, after a recovery period, should be individualized either by a low dose of a potent statin or by a less potent statin. An additional lipid medication is advised if the target levels are not achieved. © 2011 Blackwell Publishing Ltd.

Effect of statins on skeletal muscle function.

PubMed

Parker, Beth A; Capizzi, Jeffrey A; Grimaldi, Adam S; Clarkson, Priscilla M; Cole, Stephanie M; Keadle, Justin; Chipkin, Stuart; Pescatello, Linda S; Simpson, Kathleen; White, C Michael; Thompson, Paul D

2013-01-01

Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied. The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00609063.

Relative adrenal insufficiency in mice deficient in 5α-reductase 1

PubMed Central

Livingstone, Dawn E W; Di Rollo, Emma M; Yang, Chenjing; Codrington, Lucy E; Mathews, John A; Kara, Madina; Hughes, Katherine A; Kenyon, Christopher J; Walker, Brian R; Andrew, Ruth

2014-01-01

Patients with critical illness or hepatic failure exhibit impaired cortisol responses to ACTH, a phenomenon known as ‘relative adrenal insufficiency’. A putative mechanism is that elevated bile acids inhibit inactivation of cortisol in liver by 5α-reductases type 1 and type 2 and 5β-reductase, resulting in compensatory downregulation of the hypothalamic–pituitary–adrenal axis and adrenocortical atrophy. To test the hypothesis that impaired glucocorticoid clearance can cause relative adrenal insufficiency, we investigated the consequences of 5α-reductase type 1 deficiency in mice. In adrenalectomised male mice with targeted disruption of 5α-reductase type 1, clearance of corticosterone was lower after acute or chronic (eightfold, P<0.05) administration, compared with WT control mice. In intact 5α-reductase-deficient male mice, although resting plasma corticosterone levels were maintained, corticosterone responses were impaired after ACTH administration (26% lower, P<0.05), handling stress (2.5-fold lower, P<0.05) and restraint stress (43% lower, P<0.05) compared with WT mice. mRNA levels of Nr3c1 (glucocorticoid receptor), Crh and Avp in pituitary or hypothalamus were altered, consistent with enhanced negative feedback. These findings confirm that impaired peripheral clearance of glucocorticoids can cause ‘relative adrenal insufficiency’ in mice, an observation with important implications for patients with critical illness or hepatic failure, and for patients receiving 5α-reductase inhibitors for prostatic disease. PMID:24872577

Primary Prevention With Statins: ACC/AHA Risk-Based Approach Versus Trial-Based Approaches to Guide Statin Therapy.

PubMed

Mortensen, Martin B; Afzal, Shoaib; Nordestgaard, Børge G; Falk, Erling

2015-12-22

Guidelines recommend initiating primary prevention for atherosclerotic cardiovascular disease (ASCVD) with statins based on absolute ASCVD risk assessment. Recently, alternative trial-based and hybrid approaches were suggested for statin treatment eligibility. This study compared these approaches in a direct head-to-head fashion in a contemporary population. The study used the CGPS (Copenhagen General Population Study) with 37,892 subjects aged 40 to 75 years recruited in 2003 to 2008, all free of ASCVD, diabetes, and statin use at baseline. Among the population studied, 42% were eligible for statin therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) risk assessment and cholesterol treatment guidelines approach, versus 56% with the trial-based approach and 21% with the hybrid approach. Among these statin-eligible subjects, the ASCVD event rate per 1,000 person-years was 9.8, 6.8, and 11.2, respectively. The ACC/AHA-recommended absolute risk score was well calibrated around the 7.5% 10-year ASCVD risk treatment threshold and discriminated better than the trial-based or hybrid approaches. Compared with the ACC/AHA risk-based approach, the net reclassification index for eligibility for statin therapy among 40- to 75-year-old subjects from the CGPS was -0.21 for the trial-based approach and -0.13 for the hybrid approach. The clinical performance of the ACC/AHA risk-based approach for primary prevention of ASCVD with statins was superior to the trial-based and hybrid approaches. Our results indicate that the ACC/AHA guidelines will prevent more ASCVD events than the trial-based and hybrid approaches, while treating fewer people compared with the trial-based approach. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Motivational effects of coronary artery calcium scores on statin adherence and weight loss.

PubMed

Kalia, Nove K; Cespedes, Lucas; Youssef, George; Li, Dong; Budoff, Matthew J

2015-05-01

The aim of this study was to assess the effect on adherence to statin therapy and assess the effect of beneficial changes in behavior that resulted in weight loss in patients who underwent coronary artery calcium (CAC) scoring with cardiac computed tomography. Despite convincing data demonstrating the benefits of HmGCoA inhibitors for both primary and secondary prevention of coronary heart disease, they remain underused. Also, despite convincing data demonstrating the benefits of weight loss for both primary and secondary prevention of coronary heart disease, it remains difficult to motivate behavioral changes resulting in weight loss. In this study, we assess whether higher CAC scores are associated with increased compliance with statin medication and whether higher CAC scores are associated with beneficial lifestyle behaviors resulting in weight loss. We retrospectively analyzed patients that had undergone baseline CAC testing and returned for a follow-up scan. All patients had weight documented and were administered a questionnaire regarding compliance to medications. The primary endpoint was measurable weight loss between visit one and visit two and the self-reported compliance to statin use. The study population with data regarding statin compliance consisted of 2608 individuals (72% men, mean age 58±8 years) who were followed for a mean of 4.1±3.2 years after an initial CAC scan. Overall, statin compliance was lowest (27.4%) among those with CAC=0, and gradually increased with higher CAC scores (1-99, 39.2%; 100-399, 53.6%; ≥400, 58.8%; P<0.001 for trend). In the group analyzed for weight loss the study population consisted of 1078 individuals (68% men, mean age 60±8 years) who were followed for a mean of 4.1±3.2 years after an initial CAC scan. Overall, behavioral modification resulting in weight loss was lowest (19.8%) among those with CAC=0, and gradually increased with higher CAC scores (1-99, 23.4%; 100-399, 30.8%; ≥400, 33.6%; P<0.001 for trend

Clinical review: impact of statin substitution policies on patient outcomes.

PubMed

Atar, Dan; Carmena, Rafael; Clemmensen, Peter; K-Laflamme, Annik; Wassmann, Sven; Lansberg, Peter; Hobbs, Richard

2009-01-01

The increasing awareness of cost issues in health care has led to the increasing use of policy-driven substitution of branded for generic medications, particularly relative to statin treatment for cardiovascular diseases. While there are potential short-term health care savings, the consequences for primary care are under-researched. Our objective was to review data on intensive statin therapy and generic substitution in patients at high cardiovascular risk. Current treatment guidelines for the prevention of cardiovascular disease are consistent in their recommendations regarding statin therapy and treatment targets. Clinical trials demonstrate that to reduce cardiovascular events, a statin is more effective than placebo, intensive statin therapy is more effective than moderate statin therapy in patients with established coronary disease, and in patients receiving intensive statin therapy the lowest risk is associated with the lowest low-density lipoprotein levels. However, in clinical practice, patients at high cardiovascular risk are prone to be undertreated. Observational studies suggest that mandatory statin substitution may increase the gap between achieved and recommended therapeutic targets. Substitution of generic statins may be cost-saving, particularly at the primary prevention level. However, statin substitution policies have not been adequately studied on a population level. Data raise concern that mandated statin substitution may lead to unfavourable treatment choices at the level of the individual high-risk patient.

Price and utilisation differences for statins between four countries.

PubMed

Thai, Loc Phuoc; Vitry, Agnes Isabelle; Moss, John Robert

2018-02-01

Australia, England, France and New Zealand use different policies to regulate their medicines market, which can impact on utilisation and price. To compare the prices and utilisation of statins in Australia, England, France and New Zealand from 2011 to 2013. Utilisation of statins in the four countries was compared using Defined Daily Doses (DDD) per 1000 inhabitants per year. Pairwise Laspeyres and Paasche index comparisons were conducted comparing the price and utilisation of statins. The results showed that the price of statins in New Zealand was the cheapest. The price of statins in Australia was most expensive in 2011 and 2012 but France was more expensive in 2013. There were large differences between the Laspeyres index and Paasche index when comparing the price and utilisation of England with Australia and France. The policies that regulate the New Zealand and England medicines markets were more effective in reducing the price of expensive statins. The relative utilisation of cheaper statins was greatest in England and had a large effect on the differences between the two index results. The pricing policies in Australia have been only partly effective in reducing the price of statins compared to other countries.

Statin and Atrial Fibrilation: When does it work?

PubMed

Fauchier, Laurent; Clementy, Nicolas; Pierre, Bertrand; Babuty, Dominique

2012-01-01

In the recent years, some clinical and experimental studies have suggested that the use of statins may protect against atrial fibrillation (AF). A relation between inflammation and the development of AF has been described, and the potent anti-inflammatory and antioxidant properties of statins may make them effective in preventing the development of AF. A global analysis of the literature suggests that the use of statins is associated with a decreased risk of incidence or recurrence of AF in some cases. However, this beneficial effect is not seen for all types of AF in all the patients. The use of statins seems associated 1) with a lack of benefit in primary prevention of AF, 2) with a significant but heterogeneous decreased risk of recurrence of AF in secondary prevention, and 3) with a very significant and homogeneous reduction for the risk of post operative AF. An intensive lipid lowering statin regimen does not provide greater protection against AF. Patients with coronary heart disease are curr ently treated with statins in most cases, and this may not have an impact on their treatment. In contrast, it remains to determine more accurately if statins may bring a significant benefit for some AF patients without any type of established atherosclerotic disease or with a low risk of atherogenesis. Since it remains uncertain whether the suppression of AF in these patients is beyond doubt beneficial, prescribing statins for this purpose alone should not be recommended at the present time.

Clinical outcome of statin plus ezetimibe versus high-intensity statin therapy in patients with acute myocardial infarction propensity-score matching analysis.

PubMed

Ji, Mi Seon; Jeong, Myung Ho; Ahn, Young Keun; Kim, Sang Hyung; Kim, Young Jo; Chae, Shung Chull; Hong, Taek Jong; Seong, In Whan; Chae, Jei Keon; Kim, Chong Jin; Cho, Myeong Chan; Rha, Seung-Woon; Bae, Jang Ho; Seung, Ki Bae; Park, Seung Jung

2016-12-15

It is unclear whether simvastatin-ezetimibe could be an alternative therapy to high-intensity statin therapy in high-risk patients. The aim of this study was to compare the clinical outcomes of simvastatin-ezetimibe and high-intensity statin therapy in patients with acute myocardial infarction (AMI), and especially in those with high-risk factor. A total of 3520 AMI patients in the KAMIR (Korea Acute Myocardial Infarction Registry) were classified into simvastatin-ezetimibe group (n=1249) and high-intensity statin group (n=2271). Multivariate analysis and propensity-score matching analysis were performed. The primary endpoint was major adverse cardiac events (MACE) at 12-months follow-up. In overall AMI patients, MACE occurred in 116 patients (9.3%) in simvastatin-ezetimibe group and 116 patients (5.1%) in high-intensity statin group. The difference in MACE between groups was driven by repeat revascularization (5.9% vs. 2.2%). After propensity matching analysis, simvastatin-ezetimibe was associated with a higher incidence of MACE than high-intensity statin therapy (adjusted hazard ratio: 3.090, 95% confidence interval: 1.715 to 5.566, p<0.001). However, in patients with high-risk factors, such as diabetes, old age, or heart failure, simvastatin-ezetimibe had similar incidence of MACE compared with high-intensity statin therapy in further adjusted analysis. In overall AMI patients, high-intensity statin therapy had better clinical outcomes than simvastatin-ezetimibe. However, in patients with high-risk factor, simvastatin-ezetimibe had comparable clinical outcomes to high-intensity statin therapy. Therefore, simvastatin-ezetimibe could be used as an alternative to high-intensity statin therapy in such patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mipomersen: a safe and effective antisense therapy adjunct to statins in patients with hypercholesterolemia.

PubMed

Ricotta, Daniel N; Frishman, William

2012-01-01

Mipomersen is an antisense oligonucleotide inhibitor of apolipoprotein (apo) B-100 currently in phase 3 of development for the treatment of hyperlipidemia in patients with a high risk for cardiovascular disease. The drug acts by inhibiting the production of apoB-100, which is the structural core for all atherogenic lipids, including low-density lipoprotein cholesterol (LDL-C). The agent has been shown to produce significant reductions in LDL-C from baseline values compared with placebos. Clinical trials have demonstrated that mipomersen reduces LDL-C up to 44% in patients with familial hypercholesterolemia and patients with significantly elevated LDL despite taking maximum doses of statins. Unlike other medications that target apoB-100, such as microsomal triglyceride transfer proteins, mipomersen does not cause hepatic steatosis or intestinal steatosis and does not affect dietary fat absorption. Adverse side effects encountered with mipomersen include flu-like symptoms, injection site reactions, and elevated liver transaminases. If future studies continue to show such promising results, mipomersen would likely be a viable additional lipid-lowering therapy for patients who are at high cardiovascular risk, intolerant to statins, and/or not at target lipid levels despite maximum doses of statin therapy. Clinical outcome studies looking at cardiovascular disease end points still need to be done.

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

Statins and oxidative stress in the cardiovascular system.

PubMed

Margaritis, Marios; Sanna, Fabio; Antoniades, Charalambos

2017-09-26

Statins are widely established as an important class of medications for primary and secondary prevention of cardiovascular disease. In addition to their lipid-lowering effects, mounting evidence suggests that statins exhibit non-lipid-lowering mediated effects in the cardiovascular system. These so called "pleiotropic" effects are partly due to antioxidant properties of statins. These are mediated by inhibition of the mevalonate pathway, which interferes with small GTP-ase protein prenylation. This, in turn, leads to anti-oxidant effects of statins via a plethora of mechanisms. Statins prevent the activation of the pro-oxidant enzyme NADPH-oxidase by interfering with Rac1 activation and translocation to the membrane, as well as reducing expression of crucial subunits of NADPH-oxidase. Statins also enhance the expression, enzymatic activity and coupling of endothelial nitric oxide synthase (eNOS), through mevalonate-dependent effects. The net result is a restoration of the redox balance in the cardiovascular system, with subsequent anti-atherosclerotic and cardioprotective effects. While the evidence from basic science studies and animal models is strong, more clinical trials are required to establish the relevance of these pleiotropic effects to human cardiovascular disease and potentially lead to expanded indications for statin treatment or alternative therapeutic strategies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing.

PubMed

Shrivastava-Ranjan, Punya; Flint, Mike; Bergeron, Éric; McElroy, Anita K; Chatterjee, Payel; Albariño, César G; Nichol, Stuart T; Spiropoulou, Christina F

2018-05-01

Ebola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013-2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection in vitro Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD. IMPORTANCE Treatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune

The Effect of Ezetimibe/Statin Combination and High-Dose Statin Therapy on Thyroid Autoimmunity in Women with Hashimoto's Thyroiditis and Cardiovascular Disease: A Pilot Study.

PubMed

Krysiak, R; Szkróbka, W; Okopień, B

2016-10-01

Background: Intensive statin therapy was found to reduce thyroid autoimmunity in women with Hashimoto's thyroiditis. No similar data are available for other hypolipidemic agents. Methods: The participants of the study were 16 women with Hashimoto's thyroiditis and coronary artery disease. On the basis of statin tolerance, they were divided into 2 groups. 8 patients who did not tolerate high-dose statin therapy were treated with a statin, the dose of which was reduced by half, together with ezetimibe. The remaining 8 patients tolerating the treatment continued high-dose statin therapy. Plasma lipids, serum levels of thyrotropin, free thyroxine and free triiodothyronine, as well as titers of thyroid peroxidase and thyroglobulin antibodies were measured at the beginning of the study and 6 months later. Results: Replacing high-dose statin therapy with ezetimibe/statin combination therapy increased serum titers of thyroid peroxidase as well as led to an insignificant increase in serum titers of thyroglobulin antibodies. At the end of the study, thyroid peroxidase and thyroglobulin antibody titers were higher in patients receiving the combination therapy than in those treated only with high-dose statin. Conclusions: Our study shows that high-dose statin therapy produces a stronger effect on thyroid autoimmunity than ezetimibe/statin combination therapy. © Georg Thieme Verlag KG Stuttgart · New York.

Effects of bezafibrate and of 2 HMG-CoA reductase inhibitors on lipoprotein (a) level in hypercholesterolemic patients.

PubMed

Branchi, A; Rovellini, A; Fiorenza, A M; Sommariva, D

1995-06-01

Lp(a) level is relatively stable in each individual and is mainly under genetic control. Attempts made to lower Lp(a) with pharmacological means gave conflicting results. In order to further evaluate the effect of hypocholesterolemic drugs on Lp(a) level, 66 patients with primary hypercholesterolemia were selected. The vast majority of the patients had Lp(a) concentration at the low end of the range of distribution, 7 had undetectable Lp(a) levels and only 2 had Lp(a) higher than 30 mg/dl. No relationship was found between Lp(a) level and serum and lipoprotein lipids. In 12 patients serum cholesterol was well controlled by diet alone and the patients continued the diet for up to 8 months. The other patients were randomly subdivided into 3 groups of therapy. The first group received slow release bezafibrate 400 mg once a day, the second one pravastatin 20 mg once a day and the third one simvastatin 10-40 mg once a day. Drug therapy lasted for 8 months. At the end of the period, 22 of 29 patients treated with the 2 HMG-CoA reductase inhibitors had Lp(a) higher than baseline. The difference was statistically significant in both groups of patients. No significant change in Lp(a) was observed in diet and in bezafibrate group. Serum and LDL cholesterol significantly decreased in all the 3 drug groups. The increase in Lp(a) after the 2 HMG-CoA reductase was small enough to have negligible effects on cardiovascular risk, but raises the problem of the role of LDL receptor in the catabolism of Lp(a).

Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease.

PubMed

Rosenson, Robert S; Kent, Shia T; Brown, Todd M; Farkouh, Michael E; Levitan, Emily B; Yun, Huifeng; Sharma, Pradeep; Safford, Monika M; Kilgore, Meredith; Muntner, Paul; Bittner, Vera

2015-01-27

National guidelines recommend use of high-intensity statins after hospitalization for coronary heart disease (CHD) events. This study sought to estimate the proportion of Medicare beneficiaries filling prescriptions for high-intensity statins after hospital discharge for a CHD event and to analyze whether statin intensity before hospitalization is associated with statin intensity after discharge. We conducted a retrospective cohort study using a 5% random sample of Medicare beneficiaries between 65 and 74 years old. Beneficiaries were included in the analysis if they filled a statin prescription after a CHD event (myocardial infarction or coronary revascularization) in 2007, 2008, or 2009. High-intensity statins included atorvastatin 40 to 80 mg, rosuvastatin 20 to 40 mg, and simvastatin 80 mg. Among 8,762 Medicare beneficiaries filling a statin prescription after a CHD event, 27% of first post-discharge fills were for a high-intensity statin. The percent filling a high-intensity statin post-discharge was 23.1%, 9.4%, and 80.7%, for beneficiaries not taking statins pre-hospitalization, taking low/moderate-intensity statins, and taking high-intensity statins before their CHD event, respectively. Compared with beneficiaries not on statin therapy pre-hospitalization, multivariable adjusted risk ratios for filling a high-intensity statin were 4.01 (3.58-4.49) and 0.45 (0.40-0.52) for participants taking high-intensity and low/moderate-intensity statins before their CHD event, respectively. Only 11.5% of beneficiaries whose first post-discharge statin fill was for a low/moderate-intensity statin filled a high-intensity statin within 365 days of discharge. The majority of Medicare beneficiaries do not fill high-intensity statins after hospitalization for CHD. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.