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HMG-CoA Reductase Inhibitors (hmg-coa + reductase_inhibitor)
Selected AbstractsDesign and Synthesis of Hepatoselective, Pyrrole-Based HMG-CoA Reductase Inhibitors.CHEMINFORM, Issue 52 2007Jeffrey A. Pfefferkorn Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Development of a Practical Synthesis of Novel, Pyrrole-Based HMG-CoA Reductase Inhibitors.CHEMINFORM, Issue 48 2007Jeffrey A. Pfefferkorn Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Effect of naringin on bone cellsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 11 2006R.W.K. Wong Abstract Statin, a HMG-CoA reductase inhibitor, was shown to increase BMP-2 gene expression for bone formation, by blocking the mevalonate pathway in cholesterol production. We investigated the effect of naringin, a flavonoid available commonly in citrus fruits, which was also a HMG-CoA reductase inhibitor, in UMR 106 osteoblastic cell line in vitro. The control group consisted of cells cultured without any intervention for different time intervals (24 h, 48 h, and 72 h), whereas the experimental (naringin) group consisted of cells cultured with naringin of different concentrations (0.001 µmol/L, 0.01 µmol/L, and 0.1 µmol/L) for the same time intervals of the control. Colorimetric Tetrazolium (MTT) assay, total protein content assay, and alkaline phosphatase activity were used to measure the cellular activities. Results for the naringin group showed an increase in MTT assay compared with the control and the effect was dose dependent. At high concentration (0.1 µmol), the increases ranged from 60% to 80%. In the total protein content assay, naringin also showed an increase compared with control and the effect was also dose dependent. At high concentration (0.1 µmol), the increases ranged from 9% to 20%. In the alkaline phosphatase activity assay, naringin at high concentration (0.1 µmol) significantly increased the activity up to 20%. In conclusion, naringin significantly increased bone cell activities in vitro. This is the first study specifically attempted to investigate the effect of naringin on bone cell activities. Besides statin, this provided another example of mevalonate pathway blockage in the cholesterol production pathway by HMG-CoA reductase inhibition will increase the bone cell activities. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:2045,2050, 2006 [source] Neopterin induces pro-atherothrombotic phenotype in human coronary endothelial cellsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2006P. CIRILLO Summary.,Background: Inflammation plays a pivotal role in atherothrombosis. Recent data indicate that serum levels of neopterin, a marker of inflammation and immune modulator secreted by monocytes/macrophages, are elevated in patients with acute coronary syndromes and seem to be a prognostic marker for major cardiovascular events. The aim of the present study was to determine whether neopterin might affect the thrombotic and atherosclerotic characteristics of human coronary artery endothelial cells (HCAECs). Methods and results: In HCAECs, neopterin induced TF-mRNA transcription as demonstrated by real time polymerase chain reaction and expression of functionally active tissue factor (TF) as demonstrated by procoagulant activity assay, and of cellular adhesion molecules (CAMs) as demonstrated by FACS analysis, in a dose-dependent fashion. These neopterin effects were prevented by lovastatin, a HMG-CoA reductase inhibitor. Neopterin-induced TF and CAMs expression was mediated by oxygen free radicals through the activation of the transcription factor, nuclear factor-kappa B (NF- ,B), as demonstrated by electrophoretic mobility shift assay and by suppression of CAMs and TF expression by superoxide dismutase and by NF- ,B inhibitor, pyrrolidine-dithio-carbamate ammonium. Conclusions: These data indicate that neopterin exerts direct effects on HCAECs by promoting CAMs and TF expression and support the hypothesis that neopterin, besides representing a marker of inflammation, might be an effector molecule able to induce a pro-atherothrombotic phenotype in cells of the coronary circulation. [source] Liver function testing in patients on HMG-CoA reductase inhibitors,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 4 2003Susan E. Andrade ScD Abstract Purpose The Food and Drug Administration currently requires the labeling of HMG-CoA reductase inhibitors to recommend liver function tests (LFTs) before the start of therapy and at various intervals during therapy, depending on the specific agent. We sought to determine the frequency and patterns of LFT screening in patients receiving HMG-CoA reductase inhibitors. Methods A retrospective study was conducted at a staff-model health maintenance organization among 4178 new users of HMG-CoA reductase inhibitors during the period 1 January 1991 through 31 December 1996. The number and proportions of HMG-CoA reductase inhibitor therapy courses with baseline LFTs (within 180 days prior to dispensing), follow-up LFTs and LFT abnormalities were calculated. Results For the initial HMG-CoA reductase inhibitor dispensed, 1947 patients (47%) had at least one screening LFT at baseline and 3063 (73%) had at least one follow-up LFT. Twenty-seven (0.9%) patients with at least one follow-up LFT performed had a level greater than 3 times the upper limit of normal. In a random sample of 100 discontinued patients, none discontinued due to elevated LFTs or liver disease. Conclusions A large proportion of patients dispensed HMG-CoA reductase inhibitors in this managed care setting did not have baseline and follow-up LFTs performed. Modest LFT abnormalities were common among users of HMG-CoA reductase inhibitors; however, in this population, serious abnormalities were rare. Copyright © 2003 John Wiley & Sons, Ltd. [source] Improvement of age-related endothelial dysfunction by simvastatin: effect on NO and COX pathwaysBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2005Maria Įlvarez De Sotomayor The effects of oral administration of the HMG-CoA reductase inhibitor, simvastatin (SV), on age-related endothelial dysfunction were investigated in the aorta of male Wistar rats. Adult (12,14 weeks) and old (60,80 weeks) rats were treated daily for 12 weeks with either vehicle or SV (1 mg kg,1). In old rats, SV treatment did not significantly affect systolic blood pressure and LDL-cholesterol, but it reduced plasma cholesterol, triglycerides and oxidised LDL though it did not affect total antioxidant status. SV improved endothelium-dependent relaxation to acetylcholine and A-23187 in vessels from aged, but not adult, rats. This effect was linked to a greater NO vasodilatation via an increased expression of endothelial NO-synthase. A mechanism sensitive to superoxide dismutase and catalase also accounts for enhanced endothelial vasodilatation. Finally, SV did not affect the release of prostacyclin, but it inhibited the generation of thromboxane (TX) A2 from COX-2 isoform. The effect of the latter was sensitive to the Tp receptor antagonist, ICI-192,605. The present study provides evidence that oral administration of SV improves endothelial dysfunction in the aorta from aged rats by mechanisms associated with enhanced NO vasodilatation, reduced release of TXA2 from cyclo-oxygenase, and increased antioxidant properties of the vessel wall. These data underscore a new therapeutic perspective for SV in age-related endothelial dysfunction. British Journal of Pharmacology (2005) 146, 1130,1138. doi:10.1038/sj.bjp.0706420 [source] HMG-CoA reductase inhibitors prevent bone loss in patients with Type 2 diabetes mellitusDIABETIC MEDICINE, Issue 9 2004A. Nakashima Abstract Aims It has been reported that 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors increase bone mineral density (BMD) in vivo. We investigated the effect of HMG-CoA reductase inhibitors on BMD in patients with Type 2 diabetes mellitus. Patients and methods We selected 122 patients with Type 2 diabetes, who were not taking active vitamin D preparations. Their mean age was 67.3 ± 9.2 years. They were divided into a control group (n = 63) without HMG-CoA reductase inhibitor therapy and an HMG-CoA group (n = 59) who were treated with these drugs. The BMD of the distal one-third of the radius was measured by dual-energy X-ray adsorptiometry at baseline and after 2 years. Results There were no significant differences between the control and HMG-CoA groups at baseline with respect to age, gender, body mass index, duration of diabetes, haemoglobin A1c, fasting plasma glucose, adjusted calcium, serum phosphorus, alkaline phosphatase, albumin excretion rate and radial BMD. However, there was a significantly smaller annual decrease of the radial BMD in the HMG-CoA group. Multiple regression analysis with a forward elimination procedure revealed a positive correlation of the radial BMD Z-score with body mass index, while there was a negative correlation with alkaline phosphatase and albumin excretion rate. In addition, the annual rate of change of the radial BMD showed a positive correlation with HMG-CoA reductase inhibitor therapy. Conclusions These findings suggest that HMG-CoA reductase inhibitors may prevent bone loss in patients with Type 2 diabetes. [source] A New and Efficient Synthesis of the HMG-CoA Reductase Inhibitor PitavastatinHELVETICA CHIMICA ACTA, Issue 6 2007Murat Acemoglu Abstract A new synthetic method for the preparation of pitavastatin is described. The approach circumvents various synthetic problems associated with the buildup of the 3,5-dihydroxy-C7 acid side chain of HMG-CoA reductase inhibitors (statins). The use of the C6 -amide derivative 5 instead of ester derivatives in the coupling reaction with carboxaldehyde 8 (Scheme,3) prevents undesired side reactions, such as eliminations and retro -aldol reactions. The method provides synthetic statins, such as pitavastatin, in >99% ee and exceptionally high overall yield. The enantiomerically pure starting material, (3S)-3-{[(tert -butyl)dimethylsilyl]oxy}-5-oxo-5-{[(1S)-1-phenylethyl]amino}pentanoic acid (3c), is prepared by an improved procedure from 3-{[(tert -butyl)dimethylsilyl]oxy}glutaric anhydride (1) and (1S)-1-phenylethylamine (2c; Scheme,1). [source] Evidence-based medicine: Review of guidelines and trials in the prevention of secondary stroke,JOURNAL OF HOSPITAL MEDICINE, Issue S4 2008David J. Likosky MD Abstract Transient ischemic attack (TIA) carries a substantial short-term risk for stroke, which is a leading cause of disability and death in the United States. Despite the existing evidence-based guidelines for secondary prevention of stroke, variability in the assessment, diagnostic testing, and treatment of patients with TIA in actual clinical practice remains. Identification of stroke etiology via radiological examination is of paramount importance for the appropriate treatment of patients after TIA or stroke. Management of ischemic stroke or TIA includes lifestyle modifications, reduction of modifiable risk factors (eg, hypertension, diabetes, and elevated cholesterol), and appropriate therapeutic treatments. Antiplatelet therapy is the cornerstone of secondary prevention of stroke; guidelines for its use for noncardioembolic cases have been developed from a solid evidence base. Additional therapeutic approaches include HMG-CoA reductase inhibitors (statins), antihypertensives, and anticoagulants. The results of ongoing large trials will further clarify the role of specific antiplatelet agents for the secondary prevention of stroke in patients with noncardioembolic ischemic stroke or TIA. Journal of Hospital Medicine 2008;3(4 Suppl):S6,S19. © 2008 Society of Hospital Medicine. [source] Statins and osteoporosis: new role for old drugsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2006Satyawan B. Jadhav Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case,control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted. [source] Simvastatin and lovastatin, but not pravastatin, interact with MDR1JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2002Toshiyuki Sakaeda The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, was compared with simvastatin and lovastatin from the viewpoint of susceptibility to interaction with or via the multidrug transporter, MDR1 (P-glycoprotein). This was carried out using the MDR1-overexpressing cell line LLC-GA5-COL150, established by transfection of MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells, and [3H]digoxin, which is a well-documented substrate for MDR1. Pravastatin, at 25,100 ,M, had no effect on the transcellular transport of [3H]digoxin whereas simvastatin and lovastatin suppressed the basal-to-apical transport of [3H]digoxin and increased the apical-to-basal transport. It was suggested that recognition by MDR1 was due to the hydrophobicity. In conclusion, simvastatin and lovastatin are susceptible to interaction with or via MDR1, but pravastatin is not. This is important information when selecting the HMG-CoA reductase inhibitors for patients taking drugs that are MDR1 substrates. [source] Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy,,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 7 2004Jennie T. Chang PharmD Abstract Context Elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) levels are established risk factors for cardiovascular disease (CVD). HMG-CoA reductase inhibitors (statins) are effective cholesterol-lowering drugs that are commonly prescribed to treat this condition. These drugs are often combined with another class of drugs, fibric acid derivatives, to lower both cholesterol and triglyceride levels. Rhabdomyolysis is a known, rare serious side effect of statin monotherapy and of statin-fibrate combination therapy. Objective To examine Food and Drug Administration's (FDA's) postmarketing database for cases of rhabdomyolysis in relation to monotherapy and combination use and calculate reporting rates for this event. Design Domestic cases of statin- and statin/gemfibrozil-associated rhabdomyolysis were culled from FDA's database and reviewed. Rhabdomyolysis was defined by CPK,,,10,000 IU/L, myopathic signs and symptoms and clinical diagnosis of rhabdomyolysis. Reporting rates, consisting of number of reported cases/number of prescriptions for each drug, were then calculated to determine whether the reporting of rhabdomyolysis cases was commensurate with extent of use of each statin in the population. Setting Cases were obtained from the FDA adverse event reporting system (AERS) database. Patients NA. Main Outcome Measures Number of rhabdomyolysis cases were evaluated, along with outcomes, such as renal failure, dialysis and death. Results Of 866 total reported cases, 482 (56%) were associated with monotherapy and 384 (44%) related to combination therapy. More than 80% of reported cases for each drug resulted in hospitalization for renal failure and dialysis. 80 patients expired from events related directly to rhabdomyolysis. Reporting rates for all statins, except for cerivastatin, were similar and much lower than 1 per 100,000 prescriptions. The cerivastatin-reporting rate was much higher at 4.24/100,000 prescriptions. Conclusions Rhabdomyolysis is a rare, serious side effect of statin monotherapy and of statin-fibrate combination therapy. Clinicians need to remain cognizant of this potential adverse event and discuss signs and symptoms of muscle toxicity with patients in order improve the benefits-to-risks of treating dyslipidemia with statins. Copyright © 2004 John Wiley & Sons, Ltd. [source] Liver function testing in patients on HMG-CoA reductase inhibitors,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 4 2003Susan E. Andrade ScD Abstract Purpose The Food and Drug Administration currently requires the labeling of HMG-CoA reductase inhibitors to recommend liver function tests (LFTs) before the start of therapy and at various intervals during therapy, depending on the specific agent. We sought to determine the frequency and patterns of LFT screening in patients receiving HMG-CoA reductase inhibitors. Methods A retrospective study was conducted at a staff-model health maintenance organization among 4178 new users of HMG-CoA reductase inhibitors during the period 1 January 1991 through 31 December 1996. The number and proportions of HMG-CoA reductase inhibitor therapy courses with baseline LFTs (within 180 days prior to dispensing), follow-up LFTs and LFT abnormalities were calculated. Results For the initial HMG-CoA reductase inhibitor dispensed, 1947 patients (47%) had at least one screening LFT at baseline and 3063 (73%) had at least one follow-up LFT. Twenty-seven (0.9%) patients with at least one follow-up LFT performed had a level greater than 3 times the upper limit of normal. In a random sample of 100 discontinued patients, none discontinued due to elevated LFTs or liver disease. Conclusions A large proportion of patients dispensed HMG-CoA reductase inhibitors in this managed care setting did not have baseline and follow-up LFTs performed. Modest LFT abnormalities were common among users of HMG-CoA reductase inhibitors; however, in this population, serious abnormalities were rare. Copyright © 2003 John Wiley & Sons, Ltd. [source] Colesevelam: Potential Uses for the Newest Bile ResinCARDIOVASCULAR THERAPEUTICS, Issue 1 2005Karen L. Steinmetz ABSTRACT Colesevelam is the newest bile resin with a unique chemical structure. It binds to bile acids with higher affinity than traditional bile acid sequestrants and has fewer gastrointestinal side effects and drug interactions. Colesevelam is safe and efficacious alone or in combination with HMG-CoA reductase inhibitors (statins) in reducing low-density lipoprotein cholesterol (LDL-C) levels. Despite this, the role of colesevelam in the treatment of hyperlipidemia remains limited, particularly in the face of new lipid lowering agents. As guidelines for cholesterol control become more stringent, the need to maximize therapeutic benefit through combination therapy will become increasingly more important. Colesevelam has a dose-sparing effect on statin therapy, potentially decreasing the risk of unwanted side effects or drug-drug interactions associated with statin use. This makes colesevelam a viable option for addition to a statin regimen when goal LDL-C levels cannot be achieved with a statin alone. Additionally, anecdotal reports indicate that colesevelam may have potential benefits in certain patient populations that cannot tolerate other lipid lowering therapies, including organ transplant recipients, cholestatic liver disesase, and end-stage renal disease. By recognizing the potential utility of colesevelam, clinicians can better manage those patients who are not able to tolerate first-line therapies. [source] The potential antigoitrogenic effect of HMG-CoA reductase inhibitors (statins) in manCLINICAL ENDOCRINOLOGY, Issue 1 2008Laszlo Hegedüs No abstract is available for this article. [source] Vertical bone augmentation with fluvastatin in an injectable delivery system: a rat studyCLINICAL ORAL IMPLANTS RESEARCH, Issue 8 2009Yohei Jinno Abstract Objectives: HMG-CoA reductase inhibitors (statins) are widely used for hyperlipidemia. Previous studies demonstrate that statins stimulate bone morphogenetic protein-2 (BMP-2) expression and lead to bone formation. The aim of this study was to evaluate whether percutaneously injected statin with a novel statin delivery system achieved vertical bone augmentation. Material and methods: As experimental groups, atelocollagen-,-tricalcium phosphate (,TCP) composites containing 3.3 mg (low dose) or 6.7 mg (high dose) of fluvastatin were injected (one shot) subcutaneously over the calvarial periosteum of rats. The animals were then sacrificed 1, 2, and 4 weeks after injection. Vertically augmented bone was assessed by histomorphometric procedures, i.e., by measuring new bone thickness (NBT) and bone density (BD). Results: In control groups, no newly formed bone could be seen over the calvarial bone. In the experimental groups, in contrast, a large amount of newly formed bone could be seen over the preexisting calvarial bone. The newly formed bone was seen to be in direct contact with the preexisting bone. During the entire observation, significant NBT was observed in the experimental groups (P<0.05). At the final stage of observation (4 weeks), NBT was 66.7% (low-dose group) and 59.7% (high-dose group), while they were from 1% to 16.3% in the control groups. In the experimental groups, BD significantly increased in a time-dependent manner. Conclusion: Percutaneously applied fluvastatin (one shot) with a composite of ,TCP and collagen has great potential to augment the height of the bone. 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