• 대한치과의사협회지
• /
• 제46권9호
• /
• pp.563-573
• /
• 2008

Purpose : The purpose of this study is to investigate the effects of Simvastain, which is HMG-CoA reductase inhibitor, on proliferation and differentiation of osteoblast. Materials & Methods : Twenty-four cell culture plates containing essential medium were seeded with UMR-106 cell lines, at density of 5 x $10^4$ cells per plate. Each plates were incubated with 5% $CO^2$incubator $37^{\circ}C$. Starting from 2 days after incubation, cell culture medias were replaced with Osteogenesis induction media every 2 days, for 12 days. In some plates, 0.01, 0.1, 1, 10, $100\muM$ of Simvastatin were added with Osteogenesis induction media, and classified as "test group". Those not added with Simvastatin were classified as "control group". Results : 1. When Alrizarin Red staining was observed with naked eye, control group showed normal deep red color, but test group show rapid decrease of red color as Simvastatin concentration increased more than $0.1\muM$. 2, When observed with microscope, compared to control group, amount of osteo matrix stained with Alrizarin Red decreased rapidly in Simvastatin concentration more than $0.1\muM$. 3. In optical density analysis, regarding control group as a basis, mineral deposition decreased rapidly when Simvastatin concentration increased more than $0.1\muM$. 4. In flow cytometry analysis, survival rate of UMR-106 cell showed no changes in both control group and test group. Conclusion : From the above results, we were able to identify that Simvastatin inhibited osteogenesis without effecting survival or cell number of osteoblasts.

• 청정기술
• /
• 제13권4호
• /
• pp.237-243
• /
• 2007

고지혈증 치료제로 잘 알려져 있는 난용성 약물인 심바스타틴(Simvastatin)을 대상으로 더메틸에테르를 용매로 사용하고 초임계이산화탄소를 역용매로 사용하는 초임계 역용매 재결정법에 의해 약물 미세입자를 제조할 때, 운전조건을 설정하는데 활용될 수 있는 가이드라인을 제공하기 위하여 simvastatin/디메틸에테르/초임계이산화탄소 3성분계 혼합물의 상거동을 연구하였다. 가변부피 투시 셀이 장착된 고압 상평형장치를 사용하여 여러 가지 조건에서 3성분계 혼합물의 구름점(cloud point)을 측정함으로서 디메틸에테르와 초임계이산화탄소의 혼합용매에서 simvastatin의 용해도를 온도, 압력, 용매 조성의 함수로 결정하였다. 주어진 온도에서 simvastatin 약물의 용해도는 디메틸에테르의 조성과 압력이 증가할수록, 온도가 감소할수록 증가하였다.

• IMMUNE NETWORK
• /
• 제14권2호
• /
• pp.116-122
• /
• 2014

Macrophage death plays a role in several physiological and inflammatory pathologies such as sepsis and arthritis. In our previous work, we showed that simvastatin triggers cell death in LPS-activated RAW 264.7 mouse macrophage cells through both caspase-dependent and independent apoptotic pathways. Here, we show that the nuclear orphan receptor NR4A1 is involved in a caspase-independent apoptotic process induced by LPS and simvastatin. Simvastatin-induced NR4A1 expression in RAW 264.7 macrophages and ectopic expression of a dominant-negative mutant form of NR4A1 effectively suppressed both DNA fragmentation and the disruption of mitochondrial membrane potential (MMP) during LPS- and simvastatin-induced apoptosis. Furthermore, apoptosis was accompanied by Bcl-2-associated X protein (Bax) translocation to the mitochondria. Our findings suggest that NR4A1 expression and mitochondrial translocation of Bax are related to simvastatin-induced apoptosis in LPS-activated RAW 264.7 macrophages.

• BMB Reports
• /
• 제50권9호
• /
• pp.466-471
• /
• 2017

The results of this study show that c-Jun N-terminal kinase (JNK) activation was associated with the enhancement of docetaxel-induced cytotoxicity by simvastatin in DU145 human prostate cancer cells. To better understand the basic molecular mechanisms, we investigated simvastatin-regulated targets during simvastatin-induced cell death in DU145 cells using two-dimensional (2D) proteomic analysis. Thus, vimentin, Ras-related protein Rab-1B (RAB1B), cytoplasmic hydroxymethylglutaryl-CoA synthase (cHMGCS), thioredoxin domain-containing protein 5 (TXNDC5), heterogeneous nuclear ribonucleoprotein K (hnRNP K), N-myc downstream-regulated gene 1 (NDRG1), and isopentenyl-diphosphate Delta-isomerase 1 (IDI1) protein spots were identified as simvastatin-regulated targets involved in DU145 cell death signaling pathways. Moreover, the JNK inhibitor SP600125 significantly inhibited the upregulation of NDRG1 and IDI protein levels by combination treatment of docetaxel and simvastatin. These results suggest that NDRG1 and IDI could at least play an important role in DU145 cell death signaling as simvastatinregulated targets associated with JNK activation.

• Archives of Plastic Surgery
• /
• 제36권5호
• /
• pp.525-530
• /
• 2009

Purpose: The hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are widely used in the treatment of dyslipidemia for the lowering of cholesterol. And studies about simvastatins have been shown to enhance bone formation in vitro and in vivo in rodents. But some other researchers have reported that there was no anabolic effect abouts simvastatins on bone. The peripheral distribution beyond the liver represents a small fraction of an orally administered dose. We hypothesize that this poor peripheral distribution is the likely reason that simvastatins, yield ambiguous results as anabolic agents. We therefore investigated whether the effects of simvastatins on bone may be enhanced by subcutaneous administration, providing better peripheral delivery of these drugs. Methods: 36 rat unilaterally mandible fractured models were prepared and divided into two groups. The simvastatin treated group where 1 mg/kg of simvastatin was daily injected subcutaneously. The same dose of normal saline was injected on the control group. And 3 rats in each group were sacrificed and taken bone samples in each week. Bone sample was evaluated with tensile strength and histological morphology after 1, 2, 3, 4, 5 and 6 weeks. Results: In simvastatin treated group, the fracture healing process, chondrocyte aggregation, collagen formation and trabecular bone formation was rapidly proceeded than the control group in histologically. The tensile strength of the simvastatin treated group was 1.02, 2.25, 3.95, 4.42, 5.49 and $6.00N/mm^2$ by weeks. The control group data was 0.60, 1.05, 2.17, 3.75, 4.15 and $5.17N/mm^2$ by weeks. The average tensile strength was higher by $1.04N/mm^2$ in simvastatin treated group. Conclusion: The currently available data on the effects of simvastatin on bone has done to confirm the finding that simvastatin helps fracture healing. And the potential for simvastatin to be used as anabolic agents for bone when delivered by the subcutaneous route.

• Asian Pacific Journal of Cancer Prevention
• /
• 제16권16호
• /
• pp.7103-7110
• /
• 2015

The present study was conducted to investigate the effect of ${\gamma}$-radiation alone or combined with a cytotoxic drug, simvastatin, on viability and cell cycling of a myeloma cell line. P3NS1 myeloma cells were treated with the selected dose of simvastatin ($0.1{\mu}M/l$) 24 hours prior to ${\gamma}$-irradiation (0.25, 0.5 and 1Gy). The cell viability, induction of apoptosis, cell death, cell cycling, generation of ROS, and expression of P53, Bax, Bcl2, caspase3, PARP1 and Fas genes were estimated. The results indicated that simvastatin ($0.1{\mu}M/l$) treatment for 24 hours prior to ${\gamma}$-irradiation increased cell death to 37.5% as compared to 4.81% by radiation (0.5Gy) alone. It was found that simvastatin treatment before irradiation caused arrest of cells in G0/G1 and G2/M phases as assessed using flow cytometry. Interestingly, simvastatin treatment of P3NS1 cells increased the intracellular ROS production and decreased antioxidant enzyme activity with increased P53, Bax and Caspase3 gene expression while that of Bcl2 was decreased. Consequently, our results indicated that pre-treatment with simvastatin increased radio sensitivity of myeloma tumor cells in addition to apoptotic effects through an intrinsic mitochondrial pathway.

• Nutritional Sciences
• /
• 제7권4호
• /
• pp.214-217
• /
• 2004

Dietary intervention and simvastatin is beneficial in the prevention cardiovascular diseases by lowering plasma lipid levels. Endothelial dysfunction is associated with coronary artery disease and its risk factors and is reversed by dietary intervention. It has been suggested that hyperlipidemia contributes to the development of atherosclerosis by increasing inducible nitric oxide synthase (iNOS) expression via intimal thickening. Statins treatment has been found to decrease iNOS expression and atherogenensis in animal models. We hypothesized that dietary intervention and simvastatin therapy could decrease plasma nitric oxide in hypercholesterolemic patients, which would suggest the opportunity for modulation of iNOS expression through the use of statins in a clinical situation. We measured the plasma levels of nitrite and nitrate (NOx) in 19 hyperlipidemia patients. The subjects were under dietary intervention following simvastatin therapy for 12 weeks. As a result, the plasma level of NOx, stable metabolites of nitric oxide (NO), saw a two-fold elevation in hyperlipidemic patients as compared to normal levels. Although 12 weeks of dietary intervention did not lower NOx levels, subsequent 12-week simvastatin (10 mg/day) treatment, along with dietary intervention, lowered NOx levels significantly. This NOx reduction, induced by simvastatin therapy, positively correlated with lowered coronary risk factors (r=0.40, p=0.02). It indicated that simvastatin therapy decreases plasma NOx levels by, perhaps, decreasing iNOS expression or activity leading to the attenuation of the development of neointima.

• Journal of Korean Neurosurgical Society
• /
• 제50권5호
• /
• pp.403-408
• /
• 2011

Objective : Contrary to some clinical belief, there were quite a few studies regarding animal models of intracerebral hemorrhage (ICH) $in$ $vivo$ suggesting that prior use of statins may improve outcome after ICH. This study reports the effect of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, simvastatin given before experimental ICH. Methods : Fifty-one rats were subjected to collagenase-induced ICH, subdivided in 3 groups according to simvastatin treatment modality, and behavioral tests were done. Hematoma volume, brain water content and hemispheric atrophy were analyzed. Immunohistochemical staining for microglia (OX-42) and endothelial nitric oxide synthase (eNOS) was performed and caspase-3 activity was also measured. Results : Pre-simvastatin therapy decreased inflammatory reaction and perihematomal cell death, but resulted in no significant reduction of brain edema and no eNOS expression in the perihematomal region. Finally, prior use of simvastatin showed less significant improvement of neurological outcome after experimental ICH when compared to post-simvastatin therapy. Conclusion : The present study suggests that statins therapy after ICH improves neurological outcome, but prior use of statins before ICH might provide only histological improvement, providing no significant impact on neurological outcome against ICH.

• 한국식품영양과학회지
• /
• 제33권1호
• /
• pp.52-58
• /
• 2004

배추김치의 생리활성물질인 3-(4-hydroxyl-3',5'-dimethoxyphenyl)propionic acid의 고지혈증 치료효과를 살펴보기 위하여 고콜레스테롤 혈증을 유발시킨 토끼에게 1차 실험에서는 정상식이를 공급하고 2차 실험에서는 고콜레스테롤 식이를 공급하면서 각각 16일간 정맥으로 투여하여 혈장지질 농도 변화를 살펴보았고, 그 효과는 고지혈증 치료제로 사용되고 있는 Simvastatin과 비교하였다. 정상식이 공급시 Kimchi군 및 Simvastatin군에 의한 총콜레스테롤 감소는 대조군에 비해 18.65%와 29.67%이었고 고콜레스테롤 식이 공급시에는 각각 33.79%및 21.81%이었다. LDL-C의 저하현상은 정상식이 공급시에는 미미하게 관찰되었고, 고콜레스테롤 식이 공급시에는 Kimchi군 및 Simvastatin군에서 약 130%정도의 감소 효과가 관찰되었다. 중성지방의 감소효과는 정상식이시에는 거의 관찰되지 않았고, 고콜레스테롤 식이시에는 Kimchi군에서 약 105%, 그리고 Simvastatin군에서 약 62%정도의 감소가 관찰되었다. HDL-C의 변화는 모든 군에서 관찰되지 않았다. 고콜레스테롤 식이를 섭취한 토끼간의 HMG-CoA reductase 활성을 살펴보았을 때 Kimchi군 및 Simvastatin군의 활성이 48.44% 그리고 139.06% 증가하였다. 본 연구결과 Kimchi군은 고지혈증을 치료하는 효과가 있음이 관찰되었고, 그 효과는 Simvastatin군과 유사하였다. Kimchi군 및 Simvastatin군에서 관찰된 HMG-CoA reductase 활성의 증가는 지질저하 현상에 대한 보상 작용으로 생체 항상성 유지를 위한 현상으로 사료된다 3-(4-hydroxyl-3',5'-dimethoxyphenyl)propionic acid의 고지혈증 치료기전은 Simvastatin과 유사할 것으로 예상된다.

• Journal of Pharmaceutical Investigation
• /
• 제41권4호
• /
• pp.239-247
• /
• 2011

Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol. Simvastatin has good permeability, but it also has low solubility (BCS class II), which reduces its bioavailability. To overcome this problem, a solid dispersion is formed using a spray-dryer with polymeric material carrier to potentially enhance the dissolution rate and extend drug absorption. As carriers for solid dispersion, Gelucire$^{(R)}$44/14 and Gelucire$^{(R)}$ 50/13 are semisolid excipients that greatly improve the bioavailability of poorly-soluble drugs. To avoid any toxic effects of an organic solvent, we used aqueous medium to melt Tween$^{(R)}$ 80 and distilled water. The structural behaviors of the raw materials and the solid dispersion were analyzed by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The DSC and PXRD data indicated that the crystalline structure of simvastatin was transformed to an amorphous structure through solid dispersion. Then, solid dispersion-based tablets containing 20 mg simvastatin were prepared with excipients. Dissolution tests were performed in distilled water and artificial intestinal fluid using the USP paddle II method. Compared with that of the commercial tablet (Zocor$^{(R)}$ 20 mg), the release of simvastatin from solid dispersion based-tablet was more efficient. Although the stability study is not complete, this solid dispersion system is expected to deliver poorly water-soluble drugs with enhanced bioavailability and less toxicity.