Administration Of Simvastatin Research Articles

Intravenous Administration of Simvastatin Improves Cognitive Outcome following Severe Traumatic Brain Injury in Rats.

Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor commonly used to reduce serum cholesterol. The beneficial effects of oral simvastatin have been reported in pre-clinical models of traumatic brain injury (TBI). The current study was designed to evaluate the potential beneficial effects of simvastatin in a model of severe penetrating TBI using an intravenous (IV) route of administration. Rats were subjected to unilateral frontal penetrating ballistic-like brain injury (PBBI), and simvastatin was delivered intravenously at 30 min and 6 h post-injury and continued once daily for either 4 or 10 days post-PBBI. Motor function was assessed on the rotarod and cognitive performance was evaluated using the Morris water maze (MWM) task. Serum levels of inflammatory cytokines and the astrocytic biomarker, glial fibrillary acidic protein (GFAP), were quantified at 1 h, 4 h, and 24 h post-injury. Histopathological damage was assessed at the terminal end-point. Rotarod testing revealed significant motor deficits in all injury groups but no significant simvastatin-induced therapeutic benefits. All PBBI-injured animals showed cognitive impairment on the MWM test; however, 10-day simvastatin treatment mitigated these effects. Animals showed significantly improved latency to platform and retention scores, whereas the 4-day treatment regimen failed to produce any significant improvements. Biomarker and cytokine analysis showed that IV simvastatin significantly reduced GFAP, interleukin (IL)-1α, and IL-17 serum levels by 4.0-, 2.6-, and 7.0-fold, respectively, at 4 h post-injury. Collectively, our results demonstrate that IV simvastatin provides significant protection against injury-induced cognitive dysfunction and reduces TBI-specific biomarker levels. Further research is warranted to identify the optimal dose and therapeutic window for IV delivery of simvastatin in models of severe TBI.

Simvastatin use associated with low intraocular ADP levels in patients with sight-threatening diabetic retinopathy

Dear Editor, Purinergic signalling controls vascular thrombosis, remodelling and inflammation [1], and may result in disrupted blood flow and vascular function in the diabetic retina [2]. High glucose conditions increase secretion and reduce degradation of extracellular ATP in retinal cell culture [3], with increased purine concentrations being reported in the vitreous of diabetic patients suffering from proliferative retinopathy [4]. Administration of simvastatin, a lipophilic HMG-CoA reductase inhibitor, did not only promote direct vasculoprotective effects in experimental in vitro and ex vivo models [5], but was also associated with low levels of vasoactive and tissue remodelling factors in the retinas of diabetic rats [6] and vitreous of diabetic patients [7]. Here, we evaluated the vitreous accumulation of extracellular purine nucleotides in a total of 52 eyes of 52 type I and type II adult diabetic patients admitted to primary vitrectomy for the management of sight-threatening forms of diabetic retinopathy. The patients included those without statin medication (n = 41) and those with preoperative simvastatin treatment (n = 11). No difference emerged in the baseline characteristics of the patients (age, gender, HbA1c, body mass index, physical status, blood pressure, duration of diabetes) and vitrectomized eyes (intraocular pressure, lens status, intravitreal anti-VEGF treatment, macular oedema, proliferative retinopathy, vitreous haemorrhage, fibrosis) between the study groups. Vitreous samples were subjected to protein concentration measurements of adenosine 5’-triphosphate (ATP), -5’-diphosphate (ADP), -5’-monophosphate (AMP), adenosine and inosine. Intravitreal levels of proinflammatory and pro-thrombotic ADP were lower in simvastatin-treated diabetic patients (simvastatin vs. non-statin, mean ± SEM 42.9 ± 15.1 vs 7.7 ± 2.7 nM; p= 0.026, Table 1), while the data on other purinergic factors (ATP 34.5 ± 17.1 vs 6.1 ± 2.1; AMP 1974.3 ± 253.7 vs 1634.9 ± 253.4; adenosine 1066.3 ± 235.7 vs 1744.5 ± 419.5 and inosine 1163.0 ± 456.1 vs 2351.8 ± 1206.2, respectively, Table 1) led to a non-significant trend towards lower pro-inflammatory ATP and higher anti-inflammatory adenosine levels due to simvastatin treatment. These results suggest that simvastatin may favour dephosphorylation of extracellular ADP and shift the balance to an anti-inflammatory direction in the eye. Our findings are parallel with the previous report that statin use was associated with low plasma ADP levels in patients with atherosclerotic disease [8]. These data provide a novel insight into the potential vasculoprotective mechanisms of simvastatin involving extracellular purine nucleotides in patients with sight-threatening diabetic retinopathy. * Raimo Tuuminen raimo.tuuminen@helsinki.fi

Local Administration of Simvastatin Stimulates Healing of an Avascular Meniscus in a Rabbit Model of a Meniscal Defect

Background: Repair of an avascular meniscus is challenging because of its low capacity for healing. Several reports have shown that simvastatin stimulates the anabolic activity of intervertebral fibrochondrocytes, suggesting that simvastatin may be used for the treatment of meniscal defects. Purpose: To test whether the local administration of simvastatin stimulates healing of an avascular meniscus in rabbits. Study Design: Controlled laboratory study. Methods: In 30 Japanese White rabbits, a cylindrical defect (1.5-mm diameter) was introduced into the avascular zone of the anterior part of the medial meniscus in bilateral knees. Either a gelatin hydrogel (control group) or simvastatin-conjugated gelatin hydrogel (simvastatin group) was implanted into the defect. Histological assessments were performed using qualitative scoring systems, and immunohistochemical analysis was performed at 12 weeks after surgery. The occupation ratio (OR) and safranin O staining occupation ratio (SOR) were evaluated quantitatively at each time point. Stiffness of the regenerated tissue was analyzed biomechanically at 12 weeks after surgery. Rabbit meniscal cells were cultured in the presence or absence of 0.5 μM simvastatin, and then real-time polymerase chain reaction was performed to evaluate gene expression. Results: The qualitative score was significantly higher in the simvastatin group after 8 and 12 weeks (P = .031 and .035, respectively). The mean OR and SOR were also significantly higher in the simvastatin group (OR at 8 weeks: 0.396 ± 0.019 [control] vs 0.564 ± 0.123 [simvastatin], P = .008; OR at 12 weeks: 0.451 ± 0.864 [control] vs 0.864 ± 0.035 [simvastatin], P = .001; SOR at 8 weeks: 0.071 ± 0.211 [control] vs 0.487 ± 0.430 [simvastatin], P = .009; SOR at 12 weeks: 0.093 ± 0.088 [control] vs 0.821 ± 0.051 [simvastatin], P = .006). Immunohistochemical analysis showed that at 12 weeks, the reparative tissue was more strongly positive for type I collagen (COL1), type II collagen (COL2), bone morphogenetic protein 2 (BMP-2), and BMP-7 in the simvastatin group than in the control group. Biomechanical analysis showed significantly higher stiffness in the simvastatin group (2.417 ± 1.593 N/ms [control] vs 5.172 ± 1.078 N/ms [simvastatin]; P = .005). In rabbit meniscal cells, BMP-2 and BMP-7 were upregulated after 4 and 8 hours and after 7 and 14 days, whereas COL1A1 and COL2A1 were significantly upregulated by simvastatin after 7 and 14 days. Conclusion: The local administration of simvastatin promotes the regeneration of an avascular meniscus in the rabbit model of a meniscal defect. The mechanism may involve the upregulation of BMPs and the subsequent upregulation of COL1 and COL2. Clinical Relevance: This study suggests that simvastatin stimulated intrinsic healing of an avascular meniscus. The local administration of simvastatin is safe and inexpensive and seems to be a promising treatment of meniscal injuries.

MP50-06 SIMVASTATIN INHIBITS THE PROLIFERATION, MIGRATION AND INVASION OF ANDROGEN INDEPENDENT HUMAN PROSTATE CANCER CELLS VIA UP-REGULATION OF ANNEXIN A10

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II1 Apr 2016MP50-06 SIMVASTATIN INHIBITS THE PROLIFERATION, MIGRATION AND INVASION OF ANDROGEN INDEPENDENT HUMAN PROSTATE CANCER CELLS VIA UP-REGULATION OF ANNEXIN A10 Yoshiyuki Miyazawa, Yoshitaka Sekine, Haruo Kato, Yosuke Furuya, Hidekazu Koike, and Kazuhiro Suzuki Yoshiyuki MiyazawaYoshiyuki Miyazawa More articles by this author , Yoshitaka SekineYoshitaka Sekine More articles by this author , Haruo KatoHaruo Kato More articles by this author , Yosuke FuruyaYosuke Furuya More articles by this author , Hidekazu KoikeHidekazu Koike More articles by this author , and Kazuhiro SuzukiKazuhiro Suzuki More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.440AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recently, statins have been being studied for their proapoptic and antimetastatic effects. However, the exact mechanisms of their anticancer action are still unclear. By using microarray, we found that up-regulation of Annexin A10 (ANXA10) was observed in PC-3 after treatment of simvastatin. ANXA10 is reported to have antitumor effects. In this study, we evaluated the effects of simvastatin on ANXA10 signaling in androgen independent prostate cancer cells. METHODS PC-3, LNCaP-LA and DU145 human PC cell lines were usey. In Gunma university hospital, prostate tissues (BPH; n = 15, Gleason score 7; n = 15 and Gleason score 8 to 10; n = 15) were collected at the time of prostate biopsy. To evaluate the effect of simvastatin and/or ANXA10 on PC-3 cells, we used a nude mouse tumor xenograft model with administration of simvastatin 5mg/kg, 50mg/kg and saline (as control group) via intraperitoneal injections. RESULTS Simvastatin inhibited proliferation of PC-3, LNCaP-LA and DU145 cells. The expressions of ANXA10 were up-regulated by simvastatin in PC-3, LNCaP-LA and DU145. Transfection with ANXA10 inhibited PC-3 cell proliferation, migration and invasion. Knockdown of ANXA10 by siRNA increased proliferation of PC-3 cells. In a nude mouse xenograft model of PC-3 cells, simvastatin induced both reductions in tumor size and up-regulations of ANXA10 expression (Fig.1). In human prostate biopsy samples, ANXA10 mRNA expression was significantly lower in prostate cancer groups than BPH group (Fig.2). Next, we focused on S100 calcium binding protein A4 (S100A4), which is reported to be correlated with aggressiveness and worse prognosis for patients with different types of carcinoma. The expression of S100A4 was down-regulated by both simvastatin and overexpression of ANXA10. Moreover, knockdown of S100A4 by siRNA inhibited proliferation, migration and invasion of PC-3 cells. CONCLUSIONS Our results suggest statins inhibit proliferation, migration and invasion of androgen independent prostate cancer cells by up-regulation of ANXA10. In addition, S100A4 plays an important role in the effects. It seems that statins may be beneficial in preventative and/or therapeutic treatment of prostate cancer. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e674 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Yoshiyuki Miyazawa More articles by this author Yoshitaka Sekine More articles by this author Haruo Kato More articles by this author Yosuke Furuya More articles by this author Hidekazu Koike More articles by this author Kazuhiro Suzuki More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Simvastatin enhances NMDA receptor GluN2B expression and phosphorylation of GluN2B and GluN2A through increased histone acetylation and Src signaling in hippocampal CA1 neurons

Simvastatin (SV) can improve cognitive deficits in Alzheimer's disease patients and mice. Herein, we report that the administration of SV (20 mg/kg) for 5 days in mice (SV-mice) or the treatment of slices with SV (10 μM) for 4 h (SV-slices) could increase the density of NMDA-evoked inward currents (INMDA) in hippocampal CA1 pyramidal cells, which were blocked by farnesol (FOH) that converts farnesyl pyrophosphate (FPP), but not geranylgeraniol (GGOH) that increases geranylgeranylpyrophosphate (GGPP). Sensitivity of INMDA to ifenprodil in SV-mice or SV-slices was significantly increased. The levels of hippocampal GluN2B and GluN2A or Src phosphorylation in SV-mice or SV-slices were higher than controls, which were sensitive to FOH. The Src inhibitor PP2 could inhibit the SV-enhanced phosphorylation of GluN2B and GluN2A and SV-augmented INMDA, but PI3K inhibitor LY294002 did not. The levels of GluN2B mRNA and protein were elevated in SV-mice, which was abolished by FOH, but not by GGOH or PP2. Furthermore, the histone H3K9 and H3K27 acetylation of GluN2B promoter was increased in SV-mice, which was suppressed by FOH rather than GGOH or PP2. In control mice and slices, the reduction of FPP by farnesyl transferase inhibitor could increase the levels of GluN2B expression, the histone H3K9 and H3K27 acetylation and enhance the phosphorylation of GluN2B, GluN2A and Src. The findings indicate that the administration of SV can enhance GluN2B expression and GluN2B and GluN2A phosphorylation leading to augmentation of NMDAR activity through reducing FPP to increase histone acetylation of GluN2B and Src signaling.

Discontinuation of simvastatin leads to a rebound phenomenon and results in immediate peri-implant bone loss.

Although administration of simvastatin has been reported to promote bone formation, the effect of short‐term simvastatin administration is not well known. Following implant installation, 10‐week‐old male Wistar rats (n = 24) were divided into two groups randomly. The experimental group received 10 mg/kg of simvastatin daily for seven days. Then simvastatin administration was discontinued, and the animals were observed up to 28 days. Animals in the control group underwent the same procedure but received saline instead of simvastatin. All animals were analyzed by micro‐computed tomography. Samples at days 14 and 21 were subjected to histological analyses. After seven days of simvastatin administration, more new bone formation around the implant was observed in the simvastatin group compared with the control group. Seven days after simvastatin discontinuation, however, the amount of peri‐implant trabecular bone began to decrease. Results from morphometric analysis also showed a reduction in new bone area after day 7, which was lowest at day 14. These results were confirmed by histological analyses. In contrast, both the peri‐implant trabecular bone and new bone area were maintained in the control group. Short‐term administration of simvastatin may affect implant stability owing to a rebound phenomenon and an immediate loss of peri‐implant bone.

Simvastatin prevents vascular complications in the chronic reactive oxygen species murine model of systemic sclerosis

ABSTRACTAims Systemic sclerosis (SSc) is characterized by vasculopathy and organ fibrosis. Although microvascular alterations are very well characterized, structural and functional abnormalities of large vessels are not well defined. Therefore, we evaluated the effect of simvastatin administration on aortic and small renal arteries thickening, and on myofibroblasts differentiation in a murine model of SSc. Methods and results SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl, 100 μl) for 6 weeks. Mice (n = 23) were randomized to receive: HOCl (n = 10); HOCl plus simvastatin (40 mg/kg; n = 8); or vehicle (n = 5). Simvastatin administration started 30 min after HOCl injection, and up to week 6. Aortic and small renal arteries intima–media thickness was evaluated by histological analysis. Immunostaining for α-smooth muscle actin (SMA), vascular endothelial growth factor receptor 2 (VEGFR2), and CD31 in aortic tissues was performed to evaluate myofibroblast differentiation and endothelial markers.In HOCl-treated mice, intima–media thickening with reduced lumen diameter was observed in the aorta and in small renal arteries and simvastatin administration prevented this increase. Aortic and renal myofibroblasts count, as expressed by α-SMA + density, was lower in the group of mice treated with simvastatin compared to HOCl-treated mice. Simvastatin prevented the reduction in VEGFR2 and CD31 expression induced by HOCl. Conclusions The administration of simvastatin regulates collagen deposition in the aortic tissues and in the small renal arteries by modulating myofibroblasts differentiation and vascular markers. Further studies are needed to better address the effect of statins in the macrovascular component of SSc.

Low-density lipoprotein receptors play an important role in the inhibition of prostate cancer cell proliferation by statins.

BackgroundThere are some reports about the antitumor effects of statins in these days. Statins decrease the level of cholesterol in the blood by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Inhibition of this enzyme decreases intracellular cholesterol synthesis. Thus, the expression of low-density lipoprotein receptor (LDLr) is increased to import more cholesterol from the bloodstream. In this study, we assessed the effects of statins on the proliferation of prostate cancer cells, and studied the relationship between the expression of LDLr and the effects of statins.MethodsSimvastatin was used in the experiments. We studied the effect of simvastatin on PC-3 and LNCaP cell proliferation using the MTS assay, and evaluated the expression of LDLr after administration of simvastatin by quantitative polymerase chain reaction and Western blotting. Intracellular cholesterol levels in the prostate cancer cells were measured after administration of simvastatin. Furthermore, small interfering RNA (siRNA) was used to knockdown the gene expression of LDLr.ResultsIn PC-3 cells, simvastatin inhibited cell proliferation. In LNCaP cells, only a high concentration of simvastatin (100μM) inhibited cell proliferation. In LNCaP cells, the protein level of LDLr was increased by simvastatin. In PC-3 cells, the protein levels of LDLr were unregulated. In PC-3 cells, but not in LNCaP cells, intracellular cholesterol levels were significantly decreased by simvastatin. After knocking down LDLr expression by siRNA, intracellular cholesterol levels were decreased, and cell proliferation was inhibited by simvastatin in LNCaP cells.ConclusionSimvastatin inhibited prostate cancer cell growth by decreasing cellular cholesterol and could be more effective in androgen-independent prostate cancer, where there is loss of regulation of LDLr expression. LDLr was shown to play an important role in the statin-induced inhibition of prostate cancer cell proliferation. These results suggest that future studies evaluating the cholesterol-lowering effects of statin may lead to new approaches to the prevention and treatment of prostate cancer.

Statins are not associated with short-term improved aneurysm healing in a rabbit model of unruptured aneurysms

BackgroundOwing to their anti-inflammatory effects and ability to stimulate production of extracellular matrix and chemotactic migration of mesenchymal progenitor cells, statins could potentially improve aneurysm healing after endovascular treatment.ObjectiveTo test...

Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice.

PurposeLipid nanoemulsions (LDEs) that bind to low-density lipoprotein (LDL) receptors used as carriers of paclitaxel (PTX) can decrease toxicity and increase PTX antitumoral action. The administration of simvastatin (Simva), which lowers LDL-cholesterol, was tested as an adjuvant to commercial PTX and to PTX associated with LDE (LDE-PTX).Materials and methodsB16F10 melanoma-bearing mice were treated with saline solution or LDE (controls), Simva, PTX, PTX and Simva, LDE-PTX, and LDE-PTX and Simva: PTX dose 17.5 μmol/kg (three intraperitoneal injections, 3 alternate days): Simva 50 mg/kg/day by gavage, 9 consecutive days.ResultsCompared with saline controls, 95% tumor-growth inhibition was achieved by LDE-PTX and Simva, 61% by LDE-PTX, 44% by PTX and Simva, and 43% by PTX. Simva alone had no effect. Metastasis developed in only 37% of the LDE-PTX and Simva, 60% in LDE-PTX, and 90% in PTX and Simva groups. Survival rates were higher in LDE-PTX and Simva and in LDE-PTX groups. The LDE-PTX and Simva group presented tumors with reduced cellular density and increased collagen fibers I and III. Tumors from all groups showed reduction in immunohistochemical expression of ICAM, MCP-1, and MMP-9; LDE-PTX and Simva presented the lowest MMP-9 expression. Expression of p21 was increased in the Simva, LDE-PTX, and LDE-PTX and Simva groups. In the Simva and LDE-PTX and Simva groups, expression of cyclin D1, a proliferation and survival promoter of tumor cells, was decreased. Therapy with LDE-PTX and Simva showed negligible toxicity compared with PTX and Simva, which resulted in weight loss and myelosuppression.ConclusionSimva increased the antitumor activity of PTX carried in LDE but not of PTX commercial presentation, possibly because statins increase the expression of LDL receptors that internalize LDE-PTX.

Simvastatin Effect on Calcium and Silicon Plasma Levels in Postmenopausal Women with Osteoarthritis.

Postmenopausal women more often suffered from knee osteoarthritis and its pathogenesis still remains unclear. Calcium and silicon are significant elements involved in bone and joint metabolism, especially in older people. Cardiovascular diseases are common worldwide and simvastatin is the most prescribed drug in such population of patients. The purpose of this study was to evaluate the effect of simvastatin administration on calcium and silicon concentration in the plasma of postmenopausal women with osteoarthritis. Sixty postmenopausal mild hypercholesterolemic women (mean age 61.4 years, range 54–68) were enrolled. Thirty patients received simvastatin (20 or 40 mg/day) for at least 1 year before being enrolled (simvastatin “+” group). Control group consists of remaining 30 women (simvastatin “−“group). Silicon and calcium concentrations were measured spectrophotometrically. Plasma simvastatin level was determined 3 h after the drug administration using HPLC-UV-Vis. Calcium but not silicon level was significantly lower in patients receiving simvastatin in comparison with non-statin group (1.91 ± 0.32 vs. 2.33 ± 0.19 mmol/l, p < 0.05). A weak but significant positive correlation between plasma silicon and simvastatin levels (r = 0.3, p < 0.05) was observed; this may be due to the fact that simvastatin contains silicon dioxide as an inactive ingredient. The mean simvastatin concentration was 9.02 ng/ml. All hypotheses were verified at the significance level of p < 0.05. A statistically significant decrease in the plasma calcium concentration of postmenopausal women, treated with simvastatin suggests that simvastatin may play a role in calcium metabolism in postmenopausal women with osteoarthritis. Positive correlation of simvastatin concentration with silicon level in the plasma suggests that both might prompt the positive effect of osteoarthritis treatment.

Effects of simvastatin, ezetimibe and simvastatin/ezetimibe on mitochondrial function and leukocyte/endothelial cell interactions in patients with hypercholesterolemia

BackgroundCholesterol-lowering therapy has been related with several beneficial effects; however, its influence on oxidative stress and endothelial function is not fully elucidated. AimsTo investigate the effect of simvastatin and ezetimibe on mitochondrial function and leukocyte–endothelium interactions in polymorphonuclear cells of hyperlipidemic patients. MethodsThirty-nine hyperlipidemic patients were randomly assigned to one of two groups: one received simvastatin (40 mg/day) and the other received ezetimibe (10 mg/day) for 4 weeks, after which both groups were administered combined therapy for an additional 4-week period. Lipid profile, mitochondrial parameters (oxygen consumption, reactive oxygen species (ROS) and membrane potential), glutathione levels, superoxide dismutase activity, catalase activity and leukocyte/endothelial cell interactions and adhesion molecules -VCAM-1, ICAM-1, E-selectin, were evaluated. ResultsAn improvement in lipid profile was observed after administration of simvastatin or ezetimibe alone (LDLc: −40.2 vs −19.6%, respectively), though this effect was stronger with the former (p < 0.001), and a further reduction was registered when the two were combined (LDLc: −50.7% vs −56.8%, respectively). In addition to this, simvastatin, ezetimibe and simvastatin + ezetimibe significantly increased oxygen consumption, membrane potential and glutathione content, and decreased levels of ROS, thereby improving mitochondrial function. Furthermore, simvastatin + ezetimibe increased catalase activity. In addition, simvastatin and simvastatin/ezetimibe improved leukocyte/endothelium interactions by decreasing leukocyte rolling and adhesion and increasing leukocyte rolling velocity. Finally, simvastatin, ezetimibe and simvastatin + ezetimibe reduced levels of the adhesion molecule ICAM-1, and ezetimibe + simvastatin significantly decreased levels of E-selectin. ConclusionCo-administration of simvastatin and ezetimibe has an additive cholesterol-lowering effect and beneficial consequences for mitochondrial function and leukocyte/endothelium interactions in leukocytes of hypercholesterolemic patients.

Simvastatin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Simvastatin, the fourth drug selected for testing by Operation Brain Trauma Therapy (OBTT), is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor used clinically to reduce serum cholesterol. In addition, simvastatin has demonstrated potent antineuroinflammatory and brain edema reducing effects and has shown promise in promoting functional recovery in pre-clinical models of traumatic brain injury (TBI). The purpose of this study was to assess the potential neuroprotective effects of oral administration of simvastatin on neurobehavioral, biomarker, and histopathological outcome measures compared across three pre-clinical TBI animal models. Adult male Sprague-Dawley rats were exposed to either moderate fluid percussion injury (FPI), controlled cortical impact injury (CCI), or penetrating ballistic-like brain injury (PBBI). Simvastatin (1 or 5 mg/kg) was delivered via oral gavage at 3 h post-injury and continued once daily out to 14 days post-injury. Results indicated an intermediate beneficial effect of simvastatin on motor performance on the gridwalk (FPI), balance beam (CCI), and rotarod tasks (PBBI). No significant therapeutic benefit was detected, however, on cognitive outcome across the OBTT TBI models. In fact, Morris water maze (MWM) performance was actually worsened by treatment in the FPI model and scored full negative points for low dose in the MWM latency and swim distance to locate the hidden platform. A detrimental effect on cortical tissue loss was also seen in the FPI model, and there were no benefits on histology across the other models. Simvastatin also produced negative effects on circulating glial fibrillary acidic protein biomarker outcomes that were evident in the FPI and PBBI models. Overall, the current findings do not support the beneficial effects of simvastatin administration over 2 weeks post-TBI using the oral route of administration and, as such, it will not be further pursued by OBTT.

Simvastatin induces the apoptosis of normal vascular smooth muscle through the disruption of actin integrity via the impairment of RhoA/Rac-1 activity.

Statins, lipid-lowering agents for the prevention of atherosclerosis and fatal coronary heart diseases, have pleiotropic modalities on the function and physiology of vascular smooth muscle that include anti-contractile and pro-apoptotic effects. These effects were suggested to stem from the inhibition of small GTPase Rho A, but they are largely regarded as distinct and unrelated. Recently, we discovered that simvastatin causes both contractile dysfunction and apoptosis of vascular smooth muscle cells (VSMCs), reflecting that they may be closely related, yet their connecting link remains unexplained. Here, we elaborated the mechanism underlying simvastatin-induced apoptosis of normal VSMCs in connection with contractile dysfunction. Repeated oral administration of simvastatin to rats in vivo resulted in contractile dysfunction and apoptosis of vascular smooth muscle, of which pattern was well reproduced in rat VSMCs in vitro. Of note, contractile dysfunction and apoptosis occurred in concerted manners both in vivo and in vitro in the aspects of time course and dose of exposure. In rat VSMCs, simvastatin impaired the activation of small GTPases, RhoA along with Rac-1, which resulted in the disruption of actin integrity, a pivotal factor both for the generation of contractile force and survival of VSMCs. In line with the disruption of actin integrity, Bmf, a pro-apoptotic factor bound to intact actin, dissociated and translocated into mitochondria, which corresponded well with the dissipation of mitochondrial membrane potential, caspase-3 activation and ultimately apoptosis. These events were all rescued by an actin stabilisation agent, jasplakinolide as well as geranylgeraniol, indicating that damages of the actin integrity from disrupted activation of RhoA/Rac-1 lies at the center of simvastatin-induced contractile dysfunction and apoptosis in vascular smooth muscle.

THE EFFECTIVENESS OF OUTPATIENT AND HOSPITAL LIPID-LOWERING THERAPY IN PATIENTS WITH HIGH AND VERY HIGH CARDIOVASCULAR RISK DURING 2011-2015

Aim. To estimate the effectiveness of lipid-lowering therapy (LLT) at outpatient and hospital treatment stages in patients at high and very high cardiovascular risk during 2011-2015. Material and methods . In a cross-sectional epidemiological study we analyzed LLT in hospital patients for the period April-May 2011, 2012 and 2015. All data were obtained from randomly selected case-records of patients (n=548; 20% of all hospital patients over the study period). Risk categories of patients as well as target levels of low density lipoprotein (LDL) cholesterol were determined according to the current clinical guidelines for the respective year. Outpatient LLT was administered in local out-patient clinics and hospital one – in the clinic of State Research Centre for Preventive Medicine. Results . The most commonly prescribed group of lipid-lowering drugs was statins, while combined treatment or monotherapy with other lipid-lowering agents were used only in rare cases. From 2011 to 2015 the proportion of patients taking statins before admission increased from 20% to 49.8% (from 23.1% up to 29.6% of patients at high cardiovascular risk and from 28% up to 68.5% of patients at very high cardiovascular risk, respectively). During hospitalization the proportion of individuals receiving statins increased from 49.8% to 72.9%, from 29.6% to 74% and from 68.5% to 95.3% in general group, among patients at high and very high cardiovascular risk, respectively. In 2015 LDL cholesterol target levels were achieved in 14.8% and 7.1% of patients at high and very high risk, respectively. In-hospital rate of simvastatin administration reduced from 33.6% to 0.5%, whereas prescription of atorvastatin and rosuvastatin increased from 31.4% to 64.5% and from 3.6% to 9.9%, respectively. Average dose of statins (in conversion to atorvastatin) increased from 10 mg to 20 mg in high-risk patients and from 10 mg to 40 mg – in very high risk group. Conclusion . Positive trend in frequency of LLT prescription was demonstrated in patients at high and very high cardiovascular risk during 2011-2015. Nevertheless, significant number of patients in out-patient clinics still remains under non-optimal treatment.

Lack of Potential Pharmacokinetic and Pharmacodynamic Interactions Between Piragliatin, a Glucokinase Activator, and Simvastatin in Patients With Type 2 Diabetes Mellitus.

To evaluate the potential pharmacokinetic (PK) and pharmacodynamic (PD, glucose-lowering effect) interaction between simvastatin and piragliatin, both CYP3A substrates, 30 patients with type 2 diabetes mellitus participated in this open-label, randomized, 6-sequence, 3-way crossover (William's design) study. During 3 periods, patients were randomized to receive a single dose of 80 mg simvastatin alone, a single dose of 100 mg piragliatin alone, as well as single doses of 80 mg simvastatin and 100 mg piragliatin together. Primary PK and PD parameters were AUCs on dosing days. The ratio of geometric means (90% confidence intervals) of the AUCinf of piragliatin coadministered with simvastatin compared with piragliatin alone was 0.98 (0.92-1.05), whereas that of the AUCinf of simvastatin acid (active metabolite) coadministered with piragliatin compared with simvastatin alone, was 1.02 (0.90-1.16), suggesting lack of pharmacokinetic interaction between piragliatin and simvastatin. Piragliatin's glucose-lowering effect was not affected by coadministration of simvastatin. Overall, administration of piragliatin with simvastatin was without additional clinically relevant adverse effects as well as abnormality in laboratory tests, vital signs, and electrocardiogram parameters. Concomitant administration of simvastatin and piragliatin, both CYP3A substrates, has no clinically relevant effect on the pharmacokinetics of either piragliatin or simvastatin or on the pharmacodynamics for piragliatin.

Comparison of Metformin and Simvastatin Administration in Women With Polycystic Ovary Syndrome Before Intra-Cytoplasmic Sperm Injection Cycle: A Prospective, Randomized, Clinical Trial Study.

Background:Drugs administration as a pretreatment regiment before ICSI cycle in PCOs patients could enhance the success rate.Objectives:The aim of this study was to compare the effectiveness of metformin with Simvastatin in patients with polycystic ovary syndrome (PCOs) candidates for intra-cytoplasmic sperm injection (ICSI) before starting the cycle.Patients and Methods:In this prospective, double blind, randomized clinical trial the efficacy of these drugs was evaluated in 40 women with PCO syndrome (20 patients in each group; A: simvastatin and B: metformin) candidates for ICSI. In the both groups, metformin and simvastatin administrated for eight weeks before starting the ICSI cycle. Endocrine, metabolic and clinical parameters were measured before and after drug therapy; also, the results of ICSI cycle evaluated in the both groups.Results:Both drugs improved hirsutism score significantly, but simvastatin better than metformin (Group A, 24.5 ± 3.6 P: 0.0001 VS Group B, 22.9 ± 5.9 P: 0.003). The reduction in body mass index (BMI) was not significant in the groups. Simvastatin reduced some biochemical parameters such as FSH, LH, testosterone, total cholesterol, LDL and increased HDL level significantly, whereas metformin decreased FSH, TG, testosterone and total cholesterol significantly. Overall, respectively 35% and 30% of patients treated with metformin and Simvastatin became pregnant. There was no significant difference between the effects of these two drugs on ICSI cycle results like oocyte in meiosis2 (M2) phase (1.35 ± 1.6 vs. 2 ± 3.87, P value: 0.4) and the number of Grade A, embryo (1.2 ± 1.3 vs. 1.1 ± 1.4, P value: 0.7).Conclusions:Simvastatin effectively improved hyperandrogenism signs and symptoms in patients with PCO, but this effect as a pretreatment regiment was not more expressive than metformin in ICSI cycle outcome.

Protective effect of simvastatin on impaired intestine tight junction protein ZO-1 in a mouse model of Parkinson's disease.

Recently, several studies showed that gastrointestinal tract may be associated with pathophysiology of Parkinson's disease (PD). Intestine tight junction protein zonula occluden-1 (ZO-1) is an important component of intestinal barrier which can be degraded by matrix metallopeptidase 9 (MMP-9). In our previous study, a significant decline in ZO-1 was observed along with enhanced MMP-9 activity in the duodenum and distal colon of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. In this study, the protective effect of simvastatin on ZO-1 was investigated using an MPTP mouse model of PD. Seven days after the end of MPTP application, the expression level of ZO-1 was evaluated by immunohistochemistry. The protein expression levels of ZO-1 and MMP9 were detected by Western blotting. Meanwhile, MMP-9 activity was analyzed by gelatin zymography. MPTP treatment led to a decrease in the expression of ZO-1, which was accompanied by elevated MMP-9 activity. Treatment with simvastatin could partly reverse the MPTP-induced changes in ZO-1 expression and reduce MMP-9 protein and activity. Taken together, these findings suggest that simvastatin administration may partially reverse the impairment of ZO-1 induced by MPTP via inhibiting the activity of MMP9, fortify the impaired intestinal barrier and limit gut-derived toxins that pass across the intestinal barrier.

Retinoic acid promotes the endogenous repair of lung stem/progenitor cells in combined with simvastatin after acute lung injury: a stereological analysis.

BackgroundThe treatment of acute respiratory distress syndrome (ARDS), most commonly seen during the organ dysfunction remains unsatisfied. Presently, the stem/progenitor cell-based endogenous repair has been aroused attention enormously. This report investigated the effects of retinoic acid (RA) plus simvastatin (SS) with respect to dynamics of lung repair cells as well as to elucidate the underlying mechanism.Materials and methodsThe experimental Sprague–Dawley rats were divided randomly into normal control (control), sham operated (sham), ARDS, ARDS + vehicle and ARDS + RA + SS groups. ARDS was reproduced through hemorrhagic shock/resuscitation (shock) and subsequent intratracheal LPS (4.5 mg/kg, Escherichia coli serotype O55: B5) injection. The rats were treated by intragastric administration of RA (2 mg/kg/day) and SS (2 mg/kg/day) for 5 days in the ARDS + RA + SS group. Seven days after the first RA-SS injection, a right lower lobe of lung was sampled for histological analysis concerning systemic uniform random sampling method. Immunohistochemistry of inflation-fixed lungs for alveolar type 1 (AT1), alveolar type 2 (AT2) and Clara cells was measured by AQP5, Pro-SPC and CCSP staining respectively. The alveolar cell proliferation and apoptosis were analyzed with Ki67 staining and terminal deoxylnucleotidyl transferase mediated-dUTP nick end labeling (TUNEL) method. Meanwhile, the alveolar cell numerical and surface density (alveolar cells, AT1, AT2, Clara, proliferating and apoptotic cells) were evaluated by stereology.ResultsRA-SS compound exerted anti-inflammatory and pro-repairing effects on respiratory tracts in ARDS induced by hemorrhagic-endotoxin shock. The numerical density and surface density of alveolar cells, AT1 cell fraction, and numerical density of AT2 and Clara cells were significantly increased after treatment with RA-SS compound in ARDS. Concurrently, the Ki67+ alveolar cells were obviously increased while the TUNEL+ alveolar cells were reduced, which was correlated with the attenuation of inflammatory injury and functional repair in injured lung tissues.ConclusionsOur data convincingly indicated that the prophylactic and therapeutic treatment of RA plus SS had obvious beneficial effect on the remodeling/regeneration of injured pulmonary tissues, suggesting that the underlying mechanisms are related to the re-balance between regeneration and apoptosis in lung stem/progenitor cells.

Simvastatin decreases steroid production in the H295R cell line and decreases steroids and FSH in female rats.

Endocrine modulating effects of Simvastatin (SV) and its metabolite, Simvastatin β-hydroxy acid (SVA), were investigated in H295R cells and in female Sprague-Dawley (SPRD) rats. H295R cells were exposed to SV and SVA concentrations from 0 to 10μM for 48h. Four groups of SPRD rats received 0 (CT), 1.3 (L), 5.0 (M), and 20.0 (H)mg SV/kg bw/day for 14 days. 10 Steroids were investigated in H295R growth media, and in tissues and plasma from rats using GC-MS/MS. Plasma LH and FSH were quantified by ELISA. In the H295R assay, SV and SVA particularly decreased progestagens with IC50-values from 0.10-0.13μM for SV and from 0.019-0.055μM for SVA. In rats, SV decreased progestagens in ovaries, brain and plasma, and plasma FSH in the M (72.4% decrease) and H group (76.6% decrease). Because progestagens and gonadotropins are major players in fertility, administration of SV might exert negative effects on female reproduction.