A novel osteotropic biomaterial OG-PLG: In vitro efficacy.

Satsangi N.

Department of Restorative Dentistry, Division of Biomaterials, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MSC 7890, San Antonio, Texas 78229-3900.

Previously, a novel osteotropic biomaterial, OG-PLG [simvastatin grafted to poly(lactide-co-glycolide), PLG], was synthesized and shown to have degradation-controlled release kinetics. The objective here was to determine the effect of grafting statins to PLG on bone regeneration in vitro. Rat bone marrow cells were stimulated in vitro with simvastatin dissolved in media, saponified simvastatin dissolved in media, simvastatin released through diffusion from emulsion freeze-dried scaffolds, and OG-PLG. Unstimulated cultures and cultures stimulated with dexamethasone were used as negative and positive controls, respectively. In vitro bone formation was assessed using the alkaline phosphatase (ALP) and von Kossa assays at different times up to 16 days. ALP analysis revealed that saponified simvastatin at 10(-7)M and OG-PLG significantly increased ALP expression at various time points. von Kossa assay showed that simvastatin, saponified simvastatin, and OG-PLG significantly enhanced mineralization, with the effect from OG-PLG being the most significant. In short, OG-PLG significantly enhanced in vitro bone cell mineralization beyond the effect of simvastatin or saponified simvastatin dissolved in media and simvastatin released via diffusion from scaffolds. (c) 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005.

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Simvastatin promotes cell metabolism, proliferation, and osteoblastic differentiation in human periodontal ligament cells.

Bernimoulin JP.

Department of Periodontology, Faculty of Dentistry, Campus Virchow Klinikum, Charite, University Medical School, Berlin, Germany. yazawa.peri tmd.ac.jp

BACKGROUND: Simvastatin is one of the cholesterol lowering drugs. Recent studies demonstrated that it has a bone stimulatory effect. Periodontal ligament (PDL) cells are believed to play an important role in periodontal regeneration; that is, they may differentiate into specific cells which make cementum, bone, and attachment apparatus. It would be of interest whether simvastatin has a positive effect on PDL cells. Therefore, effects of simvastatin on cell proliferation and osteoblastic differentiation in PDL cells were analyzed. METHODS: Human PDL cells were cultured in monolayer with simvastatin for 24 and 72 hours and cell metabolism and proliferation were determined. To analyze osteoblastic differentiation, human PDL cells were cultured in organoid culture for 7, 14, and 21 days and alkaline phosphatase (ALP) activity, osteopontin (OPN), bone morphogenetic protein (BMP) -2, osteocalcin (OCN), and calcium contents were measured. They were co-treated by simvastatin and mevalonate. RESULTS: Simvastatin enhanced cell proliferation and metabolism dose-dependently after 24 hours. Simvastatin also stimulated ALP activity of human PDL cells dose-dependently, and maximum effect was obtained at the concentration of 10(8) M. In time dependent analysis, 10(8) M simvastatin stimulated ALP activity and osteopontin content after 7 days and calcium contents after 21 days. BMP-2 and OCN contents were not detected. Moreover this statin-enhanced ALP activity was abolished by mevalonate. CONCLUSION: These results suggest that at low concentration, simvastatin exhibits positive effect on proliferation and osteoblastic differentiation of human PDL cells, and these effects may be caused by the inhibition of the mevalonate pathway.

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Simvastatin-induced myocardial protection against ischemia-reperfusion injury is mediated by activation of ATP-sensitive K+ channels.

Birnbaum Y.

Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-0553, USA.

OBJECTIVES: Previous studies have suggested that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors attenuate ischemia-reperfusion injury. We investigated whether pretreatment with simvastatin reduces myocardial infarct size and whether glyburide, a non-selective inhibitor of the ATP-sensitive K channels, abrogates this infarct size-limiting effect. METHODS: Sprague-Dawley rats were treated with either simvastatin (20 mg/kg per day) or saline alone for 3 days. Additional groups of rats were treated as above and on the fourth day they received intravenous glyburide (0.3 mg/kg). All rats underwent 30 min of coronary artery occlusion followed by 180 min of reperfusion. Ischemic myocardium at risk was assessed with blue dye and infarct size with triphenyltetrazolium chloride. RESULTS: Infarct size, expressed as a percentage of the myocardium at risk, was significantly smaller in the simvastatin group (n = 8, 20.8 +/- 3.4%) than in the placebo group (n = 6, 40.1 +/- 2.7%) (P = 0.001). Glyburide abolished the protective effect of simvastatin with infarct size being 34.2 +/- 6.9% and 29.7 +/- 3.9% of the area at risk in the simvastatin group (n = 7) and placebo (n = 7) group, respectively (P = 0.58). CONCLUSIONS: Simvastatin significantly reduced myocardial infarct size. The protective effect was completely abrogated by glyburide, strongly suggesting that this protective effect is mediated via activation of the ATP-sensitive K channels. Copyright 2004 Lippincott Williams & Wilkins

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Early effects of statin therapy on endothelial function and microvascular reactivity in patients with coronary artery disease.

Beanlands R.

Division of Cardiology, Department of Medicine, Cardiac PET Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

BACKGROUND: Recent data suggest an early outcome benefit with reduction in cholesterol using statin therapy in patients with coronary artery disease (CAD). This may be caused by effects of low-density lipoprotein cholesterol (LDL-C) reduction on endothelial function and vascular reactivity in the coronary bed. The aim of this randomized placebo-controlled study was to examine the early effects of important reductions in LDL-C on myocardial perfusion and peripheral endothelial function. METHODS AND RESULTS: Seventy-two patients with CAD and LDL-C between 3.0 and 5.9 mmol/L (116-228 mg/dL) were randomized to receive simvastatin 20 mg daily, pravastatin 40 mg daily, or placebo for 8 weeks. At baseline, 2 weeks, and 8 weeks, patients underwent dynamic positron emission tomography perfusion imaging to quantify the retention of rubidium-82 as a measure of myocardial flow at rest and after dipyridamole stress. Patients also underwent brachial artery ultrasound to measure endothelium-dependent flow-mediated vasodilatation. At 2 and 8 weeks, the simvastatin and pravastatin groups showed a significant reduction (P < .001) in LDL-C compared with placebo. At 8 weeks, simvastatin led to an improvement in flow-mediated vasodilatation compared with placebo (6.86% +/- 4.4% vs 3.44% +/- 4.0%, P < .05), whereas pravastatin was not significantly different than placebo (5.62% +/- 4.1% vs 3.44% +/- 4.0%, P = NS). Despite this improvement in peripheral endothelial function with simvastatin, there were no significant differences observed in global stress flow and coronary flow reserve at 8 weeks with either drug. CONCLUSIONS: Short-term LDL reduction with simvastatin therapy improves peripheral endothelial function in patients with stable CAD, although an early effect on coronary vascular reactivity could not be demonstrated.

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A novel osteotropic biomaterial OG-PLG: Synthesis and in vitro release.

Satsangi N.

Department of Restorative Dentistry, Division of Biomaterials, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MSC 7890, San Antonio, Texas 78229-3900.

Statins (e.g., simvastatin) have shown to induce expression of the bone morphogenic protein-2 gene in bone cells, but they are not used clinically because of a lack of a suitable delivery device. The overall objective is to develop optimized statin delivery devices for bone regeneration. The specific objective was to determine the effect of grafting statins to biodegradable poly[lactide-co-glycolide] (PLG) on release kinetics. Simvastatin was grafted to PLG (OG-PLG) and characterized using contact-angle measurements, attenuated total reflectance-Fourier transform infrared, and ultraviolet-visible spectroscopy to determine success of the synthesis. An ultraviolet-visible assay for measuring release of statins and degraded OG-PLG in media was also developed. In vitro release studies using films and scaffolds made with PLG, PLG blended with simvastatin (PLG + Sim), and OG-PLG (simvastatin grafted to PLG) blended into PLG at different concentrations showed that release rate of OG-PLG from films was significantly greater than that of PLG + Sim. However, release rate from scaffolds showed PLG + Sim to be significantly higher than that of OG-PLG. The diffusion-controlled release kinetics of simvastatin from PLG + Sim seems to be more heavily affected by device morphology, whereas the degradation-controlled release kinetics seem to be less affected. In short, release kinetics can be modulated by grafting statins to PLG. (c) 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005.

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Effect of co-administering ezetimibe with on-going simvastatin treatment on LDL-C goal attainment in hypercholesterolemic patients with coronary heart disease.

Allen C.

Point Medical, Rond Point de la Nation, 21000 Dijon, France.

OBJECTIVE: To determine whether co-administering ezetimibe with on-going simvastatin treatment was more effective than placebo plus on-going simvastatin in achieving an LDL-C treatment target of </=2.60 mmol/l (100 mg/dl) in hypercholesterolemic patients with coronary heart disease (CHD). METHODS: Men and women (age >/=18 years) with documented CHD and on a stable dose of simvastatin 10 mg or 20 mg for at least 6 weeks were recruited for this study. After a 4-week simvastatin 10 or 20 mg plus placebo and diet run-in period, patients were eligible for randomization if LDL-C >2.60 and </=4.20 mmol/l and triglycerides (TG) </=4.00 mmol/l. Eligible patients were randomized to a double-blind comparative study with ezetimibe 10 mg co-administered with on-going simvastatin 10 mg or 20 mg (n=181) versus placebo to match ezetimibe co-administered with simvastatin 10 mg or 20 mg (n=191) for 6 weeks. RESULTS: At baseline, mean LDL-C was comparable between the ezetimibe (3.14 mmol/l) and placebo (3.19 mmol/l) groups. With the addition of ezetimibe or placebo to on-going simvastatin therapy, the percentage of patients achieving the LDL-C goal of </=2.60 mmol/l after 6 weeks of treatment was significantly (p</=0.001) greater in the ezetimibe group (74.3%) than in the placebo group (16.7%). The addition of ezetimibe to on-going simvastatin treatment also resulted in a significantly (p</=0.001) larger mean percent reduction in LDL-C from baseline (25.2%) compared with placebo (0.9%). Ezetimibe was generally well tolerated compared to placebo when added to on-going simvastatin treatment. CONCLUSIONS: Co-administering ezetimibe with on-going simvastatin 10 or 20 mg treatment allowed more hypercholesterolemic patients with CHD to reach the LDL-C treatment target of </=2.60 mmol/l.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15982505&dopt=Abstract simvastatin, Zocor