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      Evaluation of Simvastatin Grafting Around Immediate Dental Implants in Dogs :

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          Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation.

          Statins such as simvastatin are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that inhibit cholesterol synthesis. We presently investigated statin effects on vascular endothelial growth factor (VEGF) expression in osteoblastic cells. Hydrophobic statins including simvastatin, atorvastatin, and cerivastatin-but not a hydrophilic statin, pravastatin-markedly increased VEGF mRNA abundance in nontransformed osteoblastic cells (MC3T3-E1). Simvastatin (10(-6) M) time-dependently augmented VEGF mRNA expression in MC3T3-E1 cells, mouse stromal cells (ST2), and rat osteosarcoma cells (UMR-106). According to heterogeneous nuclear RNA and Northern analyses, 10(-6) M simvastatin stimulated gene expression for VEGF in MC3T3-E1 cells without altering mRNA stability. Transcriptional activation of a VEGF promoter-luciferase construct (-1128 to +827), significantly increased by simvastatin administration. As demonstrated by gel mobility shift assay, simvastatin markedly enhanced the binding of hypoxia-responsive element-protein complexes. These results indicate that the stimulation of the VEGF gene by simvastatin in MC3T3-E1 cells is transcriptional in nature. VEGF secretion into medium was increased in MC3T3-E1 by 10(-6) M simvastatin. Pretreating MC3T3-E1 cells with mevalonate or geranylgeranyl pyrophosphate, a mevalonate metabolite, abolished simvastatin-induced VEGF mRNA expression; manumycin A, a protein prenylation inhibitor, mimicked statin effects on VEGF expression. The effect of simvastatin was blocked by pretreatment with wortmannin and LY294002, specific phosphatidylinositide-3 kinase inhibitors. Simvastatin enhanced mineralized nodule formation in culture, whereas coincubation with mevalonate, geranylgeranyl pyrophosphate, LY294002, or VEGF receptor 2 inhibitor (SU1498) abrogated statin-induced mineralization. Thus, statins stimulate VEGF expression in osteoblasts via reduced protein prenylation and the phosphatidylinositide-3 kinase pathway, promoting osteoblastic differentiation.
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            Clinical effect of subgingivally delivered simvastatin in the treatment of patients with chronic periodontitis: a randomized clinical trial.

            Periodontitis is an inflammatory disease that results in bone resorption creating bony defects, which may cause tooth loss. Various drugs have been studied using local delivery to improve the periodontal health and to achieve periodontal regeneration. Simvastatin (SMV) is a specific competitive inhibitor of 3-hydroxy-2-methyl-glutaryl coenzyme A reductase. The present study was designed to investigate the effectiveness of SMV, 1.2 mg, in an indigenously prepared biodegradable controlled-release gel as an adjunct to scaling and root planing (SRP) in the treatment of chronic periodontitis. Sixty patients were categorized into two treatment groups: SRP plus placebo (group 1) and SRP plus SMV, 1.2 mg (group 2). Clinical parameters were recorded at baseline before SRP and at 1, 2, 4, and 6 months; they included modified sulcus bleeding index (mSBI), probing depth (PD), and clinical attachment level (CAL). At baseline and after 6 months, radiologic assessment of intrabony defect (IBD) fill was done using computer-aided software. The mean concentration of SMV in gingival crevicular fluid was estimated by reverse-phase high-performance liquid chromatography. All subjects tolerated the drug, without any postapplication inflammation. Both therapies resulted in significant improvements. The decrease in mSBI score at 6 months was greater in group 2 (2.3267 +/- 0.8017) compared to group 1 (0.5033 +/- 0.6815). The mean decrease in PD from baseline to 6 months was 1.20 +/- 1.24 mm and 4.26 +/- 1.59 mm in groups 1 and 2, respectively. Mean CAL gain from baseline to 6 months was 1.63 +/- 1.99 mm and 4.36 +/- 1.92 mm in groups 1 and 2, respectively. In group 2, there was greater decrease in mean IBD (1.41 +/- 0.74 mm or 32.54%) compared to group 1 (0.09 +/- 0.58 mm or 2.16%). There was a greater decrease in gingival index and PD and more CAL gain with significant IBD fill at sites treated with SRP plus locally delivered SMV in patients with chronic periodontitis.
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              Effects of simvastatin gels on murine calvarial bone.

              The cholesterol-lowering drug simvastatin has been shown to stimulate murine calvarial bone growth after multiple injections. The purpose of this study was to test if similar bone stimulation could be induced by 2 single-dose drug delivery systems appropriate to periodontal therapy. ICR Swiss mice were treated with the following protocols: 1) injection of methylcellulose gel alone, subcutaneously over the calvarium (INJ-GEL; n = 8); 2) injection of gel with simvastatin (INJ-SIM; 2.2 mg, n = 16); 3) polylactide membrane (PLA) containing gel alone implanted over calvarium (MEM-GEL; n = 10); 4) implanted PLA membrane containing gel and simvastatin (MEM-SIM; n = 10); and 5) untreated mice (n = 12). Animals were sacrificed after 22 or 44 days, calvaria decalcified and stained with hematoxylin and eosin, and images digitized and measured for bone thickness and area. Data were compared using analysis of variance. INJ-SIM stimulated a 53% (P = 0.02) increase at the thickest point of calvarial bone, while MEM-SIM caused a highly significant (P < or = 0.0005) increase in bone thickness (159% to 172%) and bone area (144% to 180%) compared to gel controls. Simvastatin gels caused soft tissue inflammation, which appeared to be related to bone increases. If INJ-SIM animals showing leakage of gel and/or no inflammation were excluded from analysis, INJ-SIM resulted in more bone (58% to 83%) than gel controls. An insignificant amount of SIM-stimulated bone was lost over the long term (44 days). A single, high dose of simvastatin gel can stimulate murine cranial bone apposition, particularly when delivered under an occlusive membrane. Both approaches should be investigated further for possible development for periodontal therapy.
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                Author and article information

                Journal
                Implant Dentistry
                Implant Dentistry
                Ovid Technologies (Wolters Kluwer Health)
                1056-6163
                2014
                April 2014
                : 23
                : 2
                : 195-199
                Article
                10.1097/ID.0000000000000051
                35c4a5a1-4f78-46a9-8ae5-91c480e149e9
                © 2014

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