Effects Of Simvastatin Research Articles

Simvastatin inhibits the adipogenesis of bone marrow‑derived mesenchymal stem cells through thedownregulation of chemerin/CMKLR1 signaling.

Simvastatin is effective in the treatment of osteoporosis, partly through the inhibition of the adipogenesis of bone-marrow derived mesenchymal stem cells (BMSCs). The present study focused on the mechanisms responsible for the inhibitory effects of simvastatin on adipogenesis and examined the effects of simvastatin on the expression of peroxisome proliferator-activated receptor γ (PPARγ), chemerin, chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1) and the adipocyte marker gene, adiponectin. BMSCs were isolated from 4-week-old female Sprague-Dawley (SD) rats, and adipogenesis was measured by the absorbance values at 490 nm of Oil Red O dye. The expression of each gene was evaluated by western blot analysis or reverse transcription-quantitative PCR (RT-qPCR). The expression of chemerin increased during adipogenesis, while CMKLR1 exhibited a trend towards a decreased expression. On days 7 and 14, the simvastatin-treated cells exhibited a down-regulated expression of chemerin, whereas the upregulated expression of its receptor, CMKLR1 was observed. The results also revealed that CMKLR1 is required for adipogenesis and the simvastatin-mediated inhibitory effect on adipogenesis. Simvastatin regulated adipogenesis by negatively modulating chemerin-CMKLR1 signaling. Importantly, simvastatin stimulation inhibited the upregulation of PPARγ and PPARγ-mediated chemerin expression to prevent adipogenesis. Treatment with the PPARγ agonist, rosiglitazone, partially reversed the negative regulatory effects of simvastatin. On the whole, the findings of the present study demonstrate that simvastatin inhibits the adipogenesis of BMSCs through the downregulation of PPARγ and subsequently prevents the PPARγ-mediated induction of chemerin/CMKLR1 signaling.

A Peptide Construct Mediates Focal Adhesion Pathway Through the Activation of Integrin Receptor.

The integrin family receptors stimulate the cellular proliferation and migration through the focal adhesion pathway by the activation of PTK2, VASP and TSP1 proteins. The purpose of this study was to investigate the integrin-ligated motifs through the activation of focal adhesion pathway. A chimeric peptide was predicted from the integrin-mediated ligands by bioinformatics tools. The VSMCs were treated with the chimeric peptide and simvastatin. The PTK2, VASP and TSP1 protein and gene expression levels were measured by RT-qPCR and Western Blotting techniques, respectively. AutoDock Tools were used for the docking technique. The PTK2, VASP and TSP1 protein expression levels increased significantly in the VSMCs treated with chimeric peptide in conversely with the effects of simvastatin. The docking results suggested two motifs in the chimeric peptide. In conclusion, the chimeric peptide activated the focal adhesion pathway. The motifs 1 and 2 may be directly involved in the transduction of signal by integrin family receptors.

Simvastatin ameliorates altered mechanotransduction in uterine leiomyoma cells

Uterine leiomyomas, the most common tumors of the female reproductive system, are characterized by excessive deposition of disordered stiff extracellular matrix and fundamental alteration in the mechanical signaling pathways. Specifically, these alterations affect the normal dynamic state of responsiveness to mechanical cues in the extracellular environment. These mechanical cues are converted through integrins, cell membrane receptors, to biochemical signals including cytoskeletal signaling pathways to maintain mechanical homeostasis. Leiomyoma cells overexpress β1 integrin and other downstream mechanical signaling proteins. We previously reported that simvastatin, an antihyperlipidemic drug, has antileiomyoma effects through cellular, animal model, and epidemiologic studies. This study aimed to examine the hypothesis that simvastatin might influence altered mechanotransduction in leiomyoma cells. This is a laboratory-based experimental study. Primary leiomyoma cells were isolated from 5 patients who underwent hysterectomy at the Department of Gynecology and Obstetrics of the Johns Hopkins University Hospital. Primary and immortalized human uterine leiomyoma cells were treated with simvastatin at increasing concentrations (0.001, 0.01, 0.1, and 1 μM, or control) for 48 hours. Protein and mRNA levels of β1 integrin and extracellular matrix components involved in mechanical signaling were quantified by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. In addition, we examined the effect of simvastatin on the activity of Ras homolog family member A using pull-down assay and gel contraction. We found that simvastatin significantly reduced the protein expression of β1 integrin by 44% and type I collagen by 60% compared with untreated leiomyoma cells. Simvastatin-treated cells reduced phosphorylation of focal adhesion kinase down to 26%-60% of control, whereas it increased total focal adhesion kinase protein expression. Using a Ras homolog family member A pull-down activation assay, we observed reduced levels of active Ras homolog family member A in simvastatin-treated cells by 45%-85% compared with control. Consistent with impaired Ras homolog family member A activation, simvastatin treatment reduced tumor gel contraction where gel area was 122%-153% larger than control. Furthermore, simvastatin treatment led to reduced levels of mechanical signaling proteins involved in β1 integrin downstream signaling, such as A-kinase anchor protein 13, Rho-associated protein kinase 1, myosin light-chain kinase, and cyclin D1. The results of this study suggest a possible therapeutic role of simvastatin in restoring the altered state of mechanotransduction signaling in leiomyoma. Collectively, these findings are aligned with previous epidemiologic studies and other reports and support the need for clinical trials.

SUN-657 The Effect of Simvastatin on Glucose Metabolism in Primary Human Muscle Cells

Statin use, especially treatment with simvastatin, is associated with impaired insulin secretion and whole-body insulin sensitivity, and increased risk for T2D. Here, we investigated the direct effects of lactone- and acid-forms of simvastatin on glucose metabolism in primary human skeletal muscle cells. Exposure of human myotubes to lactone-form simvastatin for 48 h increased glucose uptake and glucose incorporation into glycogen, whereas the acid-form did not affect glucose uptake and decreased glucose incorporation into glycogen. These metabolic actions were accompanied by changes in insulin signaling, as phosphorylation of AS160 and GSK3β was upregulated with lactone-, but not with acid-form simvastatin. Exposure to both lactone and acid-forms of simvastatin led to a decrease in glycolysis and glycolytic capacity, as well as to a decrease in mitochondrial respiration and ATP production. Collectively these data indicate that lactone- and acid forms of simvastatin exhibit differences such that lactone-form increases, and acid-form impairs glucose incorporation into glycogen. Exposure to either form of simvastatin, however, impairs glycolysis and mitochondrial oxidative metabolism in human skeletal muscle cells.

Simvastatin attenuated sickness behavior and fever in a murine model of endotoxemia

AimsDuring illnesses caused by infectious disease, a suite of brain-mediated responses called sickness syndrome occurs, triggering behavioral and physiological (fever) changes. Simvastatin is widely used as a lipid-lowering medication that has beneficial immunomodulatory properties. This study investigated the effects of simvastatin in a mouse model of sickness syndrome by systemic administration of lipopolysaccharide (LPS). Main methodsMale mice were pretreated with vehicle or simvastatin (40 mg/kg, p.o.) for 7 days and received LPS (200 μg/kg, i.p.) or sterile saline. We investigated the behavioral effects in male mice 2 h after LPS administration using tests screening for depressive-like behavior and locomotor activity alterations. Changes in body temperature were measured by biotelemetry probe preimplanted in the peritoneal cavity to evaluate the effect of simvastatin on the thermoregulatory response during immunological challenge. Key findingsPretreatment with simvastatin blunted most of the assessed parameters related to sickness syndrome, including depressive-like behavior and depressed locomotor activity, and attenuated LPS-induced fever. These data are consistent with simvastatin promoting alterations in peripheral febrigenic signaling (plasma levels of TNF-α, IL-1β, and IL-10). SignificanceOur data provide further evidence of the capacity of simvastatin to attenuate sickness behavior and fever induced by immunological challenge through a mechanism related to changes in the profile of cytokine production.

Investigation of the Inhibitory Effect of Simvastatin on the Metabolism of Lidocaine Both in vitro and in vivo.

BackgroundLidocaine has cardiovascular and neurologic toxicity, which is dose-dependent. Due to CYP3A4-involved metabolism, lidocaine may be prone to drug–drug interactions.Materials and MethodsGiven statins have the possibility of combination with lidocaine in the clinic, we established in vitro models to assess the effect of statins on the metabolism of lidocaine. Further pharmacokinetic alterations of lidocaine and its main metabolite, monoethylglycinexylidide in rats influenced by simvastatin, were investigated.ResultsIn vitro study revealed that simvastatin, among the statins, had the most significant inhibitory effect on lidocaine metabolism with IC50 of 39.31 µM, 50 µM and 15.77 µM for RLM, HLM and CYP3A4.1, respectively. Consistent with in vitro results, lidocaine concomitantly used with simvastatin in rats was associated with 1.2-fold AUC(0-t), 1.2-fold AUC(0-∞), and 20%-decreased clearance for lidocaine, and 1.4-fold Cmax for MEGX compared with lidocaine alone.ConclusionCollectively, these results implied that simvastatin could evidently inhibit the metabolism of lidocaine both in vivo and in vitro. Accordingly, more attention and necessary therapeutic drug monitoring should be paid to patients with the concomitant coadministration of lidocaine and simvastatin so as to avoid unexpected toxicity.

The Effect of Simvastatin on Gut Microbiota and Lipid Metabolism in Hyperlipidemic Rats Induced by a High-Fat Diet.

The objective of this study was to investigate the effects of simvastatin (SIM) on lipid metabolism disorders and gut microbiota in high-fat diet-induced hyperlipidemic rats. The obtained results revealed that feeding rats with SIM (20 mg/kg/day) significantly decreased serum lipid level and inhibited hepatic lipid accumulation and steatosis. Histological analysis further indicated that SIM reduced lipid deposition in adipocytes and hepatocytes in comparison with that of the HFD group. The underlying mechanisms of SIM administration against HFD-induced hyperlipidemia were also studied by UPLC-Q-TOF/MS-based liver metabonomics coupled with pathway analysis. Metabolic pathway enrichment analysis of liver metabolites with significant difference in abundance indicated that fatty acids metabolism and amino acid metabolism were the main metabolic pathways altered by SIM administration. Meanwhile, operational taxonomic units (OTUs) analysis revealed that oral administration of SIM altered the composition of gut microbiota, including Ruminococcaceae (OTU960) and Lactobacillus (OTU152), and so on. Furthermore, SIM treatment also regulated the mRNA levels of the genes involved in lipid and cholesterol metabolism. Immunohistochemistry (IHC) analysis of the liver-related proteins (CD36, CYP7A1 and SREBP-1C) showed that oral administration of SIM could regulate the levels of the protein expression related to hepatic lipid metabolism.

Statin downregulation of miR-652-3p protects endothelium from dyslipidemia by promoting ISL1 expression

BackgroundAberrant endothelial function is a major contributing factor in cardiovascular disease. Dyslipidemia leads to decreased nitric oxide (NO) bioavailability, an early sign of endothelial failure. Low insulin gene enhancer protein (ISL1) levels decrease healthy NO bioavailability. We hypothesized that the microRNA miR-652-3p negatively regulates endothelial ISL1 expression and that dyslipidemia-induced miR-652-3p upregulation induces aberrant endothelial functioning via ISL1 downregulation. MethodsVarious in vitro experiments were conducted in human umbilical vein endothelial cells (HUVECs). Luciferase assays were performed in HEK293 cells. We constructed a high-fat diet (HFD) Apoe−/− murine model of dyslipidemia and a rat model of low-density lipoprotein (LDL)-induced dyslipidemia to conduct in vivo and ex vivo experiments. ResultsLuciferase assays confirmed miR-652-3p's targeting of the ISL1 3′-untranslated region (3′-UTR). Simvastatin blocked oxidized LDL (ox-LDL)-induced increases in miR-652-3p and ox-LDL-induced decreases in ISL1 protein expression, endothelial NO synthase (eNOS) activation, and NO production. Simvastatin's effects were abrogated by miR-652-3p overexpression and phenocopied by miR-652-3p inhibition. The dyslipidemic mouse model exhibited increased miR-652-3p and decreased ISL1 protein levels in the endothelium, effects opposed by simvastatin or miR-652-3p inhibition. The impact of simvastatin in vivo was abolished by overexpressing miR-652-3p or knocking-down ISL1. The rat model of dyslipidemia exhibited a similar pattern of miR-652-3p upregulation, attenuated ISL1 protein levels, decreased eNOS activation, and decreased NO production, effects mitigated by simvastatin. ConclusionsDyslipidemia upregulates endothelial miR-652-3p, which decreases ISL1 protein levels, eNOS activation, and NO production. Simvastatin therapy lowers endothelial miR-652-3p expression to protect endothelial function under dyslipidemic conditions.

Effect of Simvastatin on Iodoacetate-induced Temporomandibular Joint Osteoarthritis in Rats

Objectives: osteoarthritis (OA) is one of the harmful disorders affecting the body joint including the temporomandibular joint (TMJ). Although OA is believed to be non-inflammatory disorder, antiinflammatory agents, as simvastatin, have been used for OA treatment. Simvastatin is presumed to possess antiosteoarthritic effect beside its antilipidemic influences. The present study tried to estimate the effect of simvastatin on the monoiodoacetate (MIA)-induced TMJ osteoarthritis. Materials and methods: thirty young adult female Sprague-Dawley rats were randomly categorized into; control, osteoarthritis and osteoarthritis with simvastatin groups. Both MIA for osteoarthritis induction and simvastatin for therapy were delivered unilaterally via the intra-articular route at the right side as a single dose for each. Results: the simvastatin administration has relatively reduced the MIA-induced osteoarthritic manifestations, and/or inhibited the progress of some osteoarthritic degenerative features but it failed to control others. The most striking findings with simvastatin administration were the prominent thickening of the condylar proliferative layer, as well as the development of osteophytes at the anterior pole of mandibular condyle. The condylar cartilage matrix showed enhancement of the extracellular matrix production with simvastatin administration. Discussion: the present study has clarified the relative antiosteoarthritic effect of simvastatin intraarticular injection. Though simvastatin has valuable palliative effect, it failed to prevent the advancement of some osteoarthritic manifestations. Conclusion: temporomandibular joint osteoarthritis (TMJOA) treated by simvastatin relieve some osteoarthritic features and modulate the structure of some joint components to compensate the damaged induced structures with MIA.

Effect of Simvastatin on Iodoacetate-Induced Temporomandibular Joint Osteoarthritis in Rats

Effect of Simvastatin on Iodoacetate-Induced Temporomandibular Joint Osteoarthritis in Rats

Evaluation of the effects of topically applied simvastatin on titanium implant osseointegration

ObjectiveThe aim of this study was to evaluate the effect of topical simvastatin on the osseointegration of machined-surface titanium implants. Material & methodsSixteen female Sprague–Dawley rats were used in this study in a 4-wk experimental trial. The rats were divided into two groups: a test group (n = 8), in which local simvastatin was applied, and a control group (n = 8). In each of the 16 animals, a machined-surface titanium implant was surgically integrated into the tibial metaphysis. Prior to integration of the implants, 100 μl of ethanol solution containing 5 mg of simvastatin was applied to the bone sockets. The implants were then immediately integrated into the bone sockets. No simvastatin treatment was applied in the control group. At the end of the 4-wk period, the rats were sacrificed, and the implants and surrounding bone tissue were removed. The bone–implant contact (BIC) and bone filling (BF) ratios of nondecalcified histological sections were then determined. The BIC ratio was defined as the ratio of the implant surface directly in contact with the bone to the total implant surface length. The BF ratio was determined by measuring the bone-filled area at a distance of 0.5 mm from implant. ResultsThere were no statistically significant differences in the BIC and BF ratios of the test group and control group in terms of implant osseointegration (p > 0.05). ConclusionWithin the limitations of this study, we conclude that topically applied simvastatin to implant surfaces does not affect osseointegration.

Effect of simvastatin on c-myc, cyclin D1 and p53 expression in DMBA-induced breast cancer in mice

Effect of simvastatin on c-myc, cyclin D1 and p53 expression in DMBA-induced breast cancer in mice

Significant effect of simvastatin and/or ezetimibe-loaded nanofibers on the healing of femoral defect: An experimental study.

Fracture healing complications are associated with significant healthcare and economic burden. In this study, we aimed to investigate how the combined administration of local simvastatin and ezetimibe into the femoral defect of the animal model affects the bone-healing process in comparison with their monotherapy. A total of 32 four-month-old adult male Wistar rats were randomized into the four study groups: simvastatin + ezetimibe-loaded nanofibers (group 1), simvastatin-loaded nanofibers (group 2), ezetimibe-loaded nanofibers (group 3), and non-loaded nanofibers (group 4). After the generation of femoral defects, the predesigned nanofibers were locally administered into the defect site. The healing measures were serum and bone osteoprotegerin (OPG) expression, pathologic evaluation of union (Allen's fracture healing scores), and radiographic evaluation of bone density (Hounsfield scale) at weeks 2 and 4. The improvement of all evaluated healing measures was remarkably superior in rats that were treated with loaded nanofibers in comparison with the control group. Also, the improvement of all evaluated healing measures was considerably more in the simvastatin-ezetimibe combination therapy group compared to their monotherapy. All the evaluated measures were superior in the ezetimibe monotherapy group compared to the simvastatin monotherapy group. The cumulative effect of simvastatin and ezetimibe on the induction of bone healing is more significant than the individual effect of these drugs. Therefore, local administration of nanofibers loaded with simvastatin and ezetimibe could be regarded as a promising osteoinductive compound for the acceleration of bone repair.

Simvastatin decreases the silver resistance of E. faecalis through compromising the entrapping function of extracellular polymeric substances against silver.

Enterococcus faecalis (E. faecalis) is a Gram-positive bacterium closely related to many refractory infections of human and shows the resistant ability against the antibacterial effects of silver. Simvastatin is a semisynthetic compound derived from lovastatin and a hydroxymethyl glutaryl coenzyme A(HMG-COA) reductase inhibitor showing certain inhibitive effects on bacteria. The main purpose of this study was to establish and characterize the Ag+/silver nanoparticles (AgNPs)-resistant E. faecalis, and further evaluate the function of extracellular polymeric substances (EPS) in the silver resistance and the effect of simvastatin on the silver-resistance of E. faecalis. The results showed that the established silver-resistant E. faecalis had strong resistance against both Ag+ and AgNPs and simvastatin could decrease the silver-resistance of both original and Ag+/AgNPs-resistant E. faecalis. The Transmission electron microscopy (TEM), High-angle annular dark-field (HAADF) and mapping images showed that the silver ions or particles aggregated and confined in the EPS on surface areas of the cell membrane when the silver-resistant E. faecalis were incubated with Ag+ or AgNPs. When the simvastatin was added, the silver element was not confined in the EPS and entered the bacteria. These findings may indicate that the silver resistance of E. faecalis was derived from the entrapping function of EPS, but simvastatin could compromise the function of EPS to decrease the silver resistant ability of E. faecalis.

Different Drugs Effect on Mesenchymal Stem Cells Isolated From Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a progressive dilation of the aortic wall, determined by the unbalanced activity of matrix metalloproteinase (MMPs). Invitro and invivo studies support the pivotal role of MMP-9 to AAA pathogenesis. In our experience, we elucidated the expression of MMP-9 in an exvivo model of human mesenchymal stem cells isolated from AAA specimen (AAA-MSCs). Thus, MMP-9 inhibition could be an attractive therapeutic strategy for inhibiting AAA degeneration and rupture. Our study was aimed at testing the effect of 3 different drugs (pioglitazone, doxycycline, simvastatin) on MMP-9 and peroxisome proliferator-activated receptor (PPAR)-γ expression in AAA-MSCs. Aneurysmal aortic wall segments were taken from AAA patients after the open surgical treatment. MSCs were isolated from AAA (n=20) tissues through enzymatic digestion. AAA-MSCs were exposed to different doses of pioglitazone (5-10-25μM), doxycycline (10-25μM), and simvastatin (10μM) for 24h. The effect of each drug was evaluated in terms of cell survival, by crystal violet stain. MMP-9 and PPAR-γ mRNA were analyzed using real-time PCR. AAA-MSCs were not affected by the exposure to the selected drugs, as shown by the analysis of cell viability. Interestingly, MMP-9 mRNA resulted significantly decreased after each treatment, recording a downregulation of 50% in presence of pioglitazone, 90% with doxycycline, and 40% with exposed to simvastatin, in comparison to untreated cells. We further analyzed the expression of PPAR-γ, target of pioglitazone, observing an upregulation in exposed AAA-MSCs to controls. Our data support the potential therapeutic effect of pioglitazone, doxycycline, and simvastatin on AAA by reducing the MMP-9 expression in a patient-specific model (AAA-MSCs). In addition, pioglitazone drives the increase of PPAR-G, another promising target for AAA therapy. Further studies are necessary to elucidate the mechanism drivingthis inhibitory pathway, which can reduces the mortality risk associated with AAA rupture.

Sesamol protects MIN6 pancreatic beta cells against simvastatin-induced toxicity by restoring mitochondrial membrane potentials.

Statins, the drugs for the treatment of dyslipidemia, have been suggested to impact insulin sensitivity, resulting in pancreatic β-cell dysfunction, and consequently, lead to new onset of diabetes. Taking this as a clue, the present study was designed to evaluate the protective effect of sesamol (a known antioxidant, antidiabetic and antidyslipidemic agent) against the diabetogenic potential of simvastatin. The toxic effects of simvastatin and sesamol on MIN6 insulinoma (Mouse pancreatic β cells) cells were evaluated separately by MTT assay. The protective effect of sesamol was evaluated at the IC50 value of simvastatin at doses ranging from 7.8 to 62.5 micromolar (µM). Further, the reversal of the impact of simvastatin on cell cycle and mitochondrial membrane potential by sesamol pretreatment was studied. The IC50 for simvastatin and sesamol were found to be 70.05 ± 2.34μM and 2134 ± 8.41μM, respectively, after 48h and 72h of incubation. Sesamol pretreatment protected the MIN6 cells from simvastatin toxicity (70µM) in a dose-dependent manner from 7.8 to 31.25µM. Simvastatin induced cell cycle arrest in G0/G1 phase. However, when cells were preincubated with sesamol for 24h, a reversal in the cell cycle arrest was observed in simvastatin-treated cells (G0/G1). Pretreatment with sesamol also reduced the mitochondrial membrane potential loss compared to simvastatin treatment alone. These in vitro findings indicate that sesamol has a protective effect against simvastatin-induced toxicity on the pancreatic beta cells.

Pleiotropic Effects of Simvastatin on the Regulation of Potassium Channels in Monocytes.

PurposeThe underlying mechanism of pleiotropic effects of statins on atherosclerosis is still unclear. Kv1.3 and KCa3.1 are two potassium channels that might be involved in monocyte migration and atherosclerosis formation. The aim of this study was to investigate the effect of simvastatin on the Kv1.3 and KCa3.1 in monocyte.Methods and ResultsIn human monocytic THP-1 cells, simvastatin significantly inhibited Kv1.3 mRNA and protein expression by real-time quantitative PCR analysis and western blotting. However, simvastatin had no effects on KCa3.1 mRNA and protein expression. By whole-cell patch clamp, simvastatin (10 μM) remarkably inhibited the current intensity of Kv1.3, but had no effect on KCa3.1. Simvastatin (10 μM) treatment significantly reduced the monocyte chemoattractant protein 1 (MCP-1)-induced monocyte migration. This inhibition was only partially reversed by mevalonate (1mM). In human peripheral blood mononuclear cells (PBMCs), both Kv1.3 and KCa3.1 mRNA expression were increased in patients with coronary artery diseases (CAD) (n = 20) compared to healthy controls (n = 22). However, simvastatin (40 mg per day) significantly inhibited the Kv1.3 but not KCa3.1 mRNA expression after 1 month and 3 months therapy in CAD patients.ConclusionOur data suggested Kv1.3 in monocytes was a potential molecular target of the pleiotropic effects of statins. KCa3.1 might be another marker of CAD, but not associated with statins treatment.

Synergic effect of simvastatin in combination with amphotericin B against environmental strains of Cryptococcus neoformans from northeastern Brazil: a prospective experimental study.

Statins are used as cholesterol-lowering drugs and may also have direct antimicrobial effects. To evaluate synergic interactions between simvastatin and both amphotericin B and fluconazole, against environmental strains of Cryptococcus neoformans isolated from captive birds' droppings. Experimental study conducted at Federal University of Piauí, Parnaíba, in collaboration with Federal University of Triângulo Mineiro, Uberaba, Brazil. Statin susceptibility tests of Cryptococcus neoformans samples were performed as prescribed in standards. Interactions of simvastatin with amphotericin and fluconazole were evaluated using the checkerboard microdilution method. Presence of these interactions was quantitatively detected through determining the fractional inhibitory concentration index (FICI). Isolates of Cryptococcus neoformans were obtained from 30 of the 206 samples of dry bird excreta (14.5%) that were collected from pet shops and houses. Ten isolates were selected for susceptibility tests. All of them were susceptible to amphotericin and fluconazole. All presented minimum inhibitory concentration (MIC) > 128 µg/ml and, thus, were resistant in vitro to simvastatin. An in vitro synergic effect was shown through combined testing of amphotericin B and simvastatin, such that six isolates (60%) presented FICI < 0.500. Two isolates showed considerable reductions in MIC, from 1 µg/ml to 0.250 µg/ml. No synergic effect was observed through combining fluconazole and simvastatin. These results demonstrate that simvastatin should be considered to be a therapeutic alternative, capable of potentiating the action of amphotericin B. However, further studies are necessary to clarify the real effect of simvastatin as an antifungal agent.

Effect of Simvastatin Use in Free Tissue Transfer: An Experimental Study in a Rat Epigastric Free Flap Model.

Statins are traditionally used in lowering cholesterol and low-density lipoprotein biosynthesis, but recent reports show their beneficial effect on microcirculation. The aim of this study was to investigate the effect of simvastatin on the microcirculation and in conjunction with aspirin in a rat free epigastric flap model. Thirty-six Sprague-Dawley rats were divided into group A (control, n = 12), group B (simvastatin treated, n = 12), and group C (simvastatin and aspirin, n = 12). Bilateral free epigastric skin flap was used to evaluate the effect. At 48 hours, flaps biopsies were evaluated for inflammatory activity, nitric oxide content, and thrombomodulin regulation in the endothelial lining of microvessels. Flap survival was evaluated on day 7. The diameter of microvessels and nitric oxide activity in groups B and C were significantly higher than in group A (p < 0.005 and 0.015, respectively). The perivascular inflammatory cell infiltrates and intravascular adhesions were predominant in group A compared with groups B and C (p < 0.005). Groups B and C demonstrated significant higher degree of thrombomodulin expression. The flap survival rate on day 7 was 70.8% for group A, and 87.5% and 91.7%, respectively, for groups B and C without significance between the two (p = 0.675). Simvastatin significantly improves the free flap survival by effective anti-inflammatory, vasodilator, and anticoagulant activities. Combined therapy did not have an antagonistic effect and further study is needed to see synergistic action through different mechanisms.

Effect of Simvastatin on Bone Regeneration: A Histologic and Histomorphometric Analysis

The purpose of the present study was to evaluate the efficacy of simvastatin administration as an osteoinductive agent combined with bovine bone material (BBM) for augmentation of human maxillary sinuses. In the present randomized clinical trial with a split-mouth design, 24 maxillary sinuses in 12 patients were augmented using BBM alone or BBM combined with simvastatin. Biopsy samples were taken 9months after maxillary sinus floor augmentation for histologic and histomorphometric analyses. A total of 44 implants were placed in the augmented bone. The results of the microscopic assessment of most samples revealed no inflammation or only mild chronic inflammation. Lamellation was detectable in old bone trabeculae under polarized light microscopy but was not observed in newly formed bone. Osteocytes were found with a lower frequency in the lacunae of newly formed bone compared with normal bone. No significant differences were found in the amount of newly formed bone and the amount of residual particles between the 2 groups. Despite the greater mean percentage of newly formed bone in the test group, the histomorphometric analysis results did not show a significant positive effect for the use of simvastatin in maxillary sinus augmentation.