Simvastatin

The Penicillium Citrinum

Simvastatin (SIM), a lactone, is white, crystalline, nonhygroscopic and powdery, practically insoluble in water (30 mcg/ml), and 0.1 (N) HCl (60 mcg/ml). Its precursor is a fermentation product of Aspergillus terreus. It is used for treating coronary heart disease, hyperlipidemia, hypercholesterolemia, atherosclerosis and stroke [1] [2]. SIM is biologically inactive. Oral ingestion hydrolyzed it into the β-hydroxyacid form which is an inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase [2]. In human lung microvascular endothelial cells, it increased the amount of endothelial nitric oxide synthase mRNA [3]. Simvastatin had anti-cancer properties [1]. Its IC50 to inhibit P-glycoprotein is 9 μM [4].

HMG CoA reductase catalyses an early rate-limiting step in the biosynthesis of cholesterol [2].

In both cell lines HepG2 and Huh7, both doses of simvastatin (32 and 64 μM) had a significant inhibitory effect on tumor cell growth as compared to controls (p<0.05). This effect was time-dependent, a simvastatin pre-treatment for 48 h or 72 h significantly reduced cell growth as compared to 24 h pre-incubation (p<0.05). Simvastatin treatment for 48 or 72 h made HepG2 cells exhibit downregulation of CDK1, CDK2, CDK4 and cyclins D1 and E as compared to control tumor cells. Simvastatin treatment for 24, 48 and 72 h made relative expression of cyclin-dependent kinase inhibitors p19 and p27 enhance as compared to control tumor cells [1].

In patients with polygenic hypercholesterolemia and allocated to diet plus 20 mg/day simvastatin for 8 weeks, total cholesterol (-27%), low density lipoproteincholesterol (-33%), and monocyte expression of TNF (-49%) and IL-1( (-35%) significantly decreased (p<0.02) [5].

References:
[1].  Borna Relja, Frank Meder, Kerstin Wilhelm, et al. Simvastatin inhibits cell growth and induces apoptosis and G0/G1 cell cycle arrest in hepatic cancer cells. International Journal of Molecular Medicine, 2010, 26:735-741.
[2].  Dipika Mandal, Probir Kumar Ojha, Bankim Chandra Nandy, et al. Effect of Carriers on Solid Dispersions of Simvastatin (Sim): Physico-Chemical Characterizations and Dissolution Studies. Der Pharmacia Lettre, 2010, 2(4):47-56.
[3].  Ji-Hyun Lee, Dong-Soon Lee, Eun-Kyung Kim, et al. Simvastatin Inhibits Cigarette Smoking–induced Emphysema and Pulmonary Hypertension in Rat Lungs. American Journal of Respiratory and Critical Care Medicine, 2005, 172: 987-993.
[4].  C. Bradley Hare, Mai P. Vu, Carl Grunfeld, et al. Simvastatin-Nelfinavir Interaction Implicated in Rhabdomyolysis and Death. Clinical Infectious Diseases, 2002, 35:e111–2.
[5].  Domenico Ferro, Sandro Parrotto, Stefania Basili, et al. Simvastatin Inhibits the Monocyte Expression of Proinflammatory Cytokines in Patients With Hypercholesterolemia. Journal of the American College of Cardiology, 2000, 36(2): 427–431.

Simvastatin restored vascular reactivity, endothelial function and reduced string vessel pathology in a mouse model of cerebrovascular disease.[Pubmed:25564230]

J Cereb Blood Flow Metab. 2015 Mar;35(3):512-20.

Cerebrovascular dysfunction seen in Alzheimer's disease (AD) and vascular dementia (VaD) is multifaceted and not limited to the amyloid-beta (Abeta) pathology. It encompasses structural alterations in the vessel wall, degenerating capillaries (string vessels), vascular fibrosis and calcification, features recapitulated in transgenic mice that overexpress transforming growth factor-beta1 (TGF mice). We recently found that Simvastatin rescued Abeta-mediated cerebrovascular and cognitive deficits in a transgenic mouse model of AD. However, whether Simvastatin can counteract Abeta-independent deficits remains unknown. Here, we evaluated the effects of Simvastatin in aged TGF mice on cerebrovascular reactivity and structure, and on cognitive performance. Simvastatin restored baseline levels of nitric oxide (NO), NO-, and KATP channel-mediated dilations and endothelin-1-induced contractions. Simvastatin significantly reduced vasculopathy with arteriogenic remodeling and string vessel pathology in TGF mice. In contrast, Simvastatin did not lessen gliosis, and the cerebrovascular levels of pro-fibrotic proteins and calcification markers remained elevated after treatment. The TGF mice displayed subtle cognitive decline that was not affected by Simvastatin. Our results show potent benefits of Simvastatin on endothelial- and smooth muscle cell-mediated vasomotor responses, endothelial NO synthesis and in preserving capillary integrity. We conclude that Simvastatin could be indicated in the treatment of cerebrovascular dysfunction associated with VaD and AD.

Simvastatin reduces burn injury-induced splenic apoptosis via downregulation of the TNF-alpha/NF-kappaB pathway.[Pubmed:24950285]

Ann Surg. 2015 May;261(5):1006-12.

OBJECTIVE: Recent studies have suggested that epidermal burn injuries are associated with inflammation and immune dysfunction. Simvastatin has been shown to possess potent anti-inflammatory properties. Thus, we hypothesized that Simvastatin protects against burn-induced apoptosis in the spleen via its anti-inflammatory activity. METHODS: Wild-type, tumor necrosis factor alpha knockout (TNF-alpha KO) and NF-kappaB KO mice were subjected to full-thickness burn injury or sham treatment. The mice then were treated with or without Simvastatin, and the spleen was harvested to measure the extent of apoptosis. Expression levels of TNF-alpha and NF-kappaB were also determined in spleen tissue and serum. RESULTS: Burn injury induced significant splenic apoptosis and systemic cytokine production. Simvastatin protected the spleen from apoptosis, reduced cytokine production in the serum, and increased the survival rate. Simvastatin decreased burn-induced TNF-alpha and NF-kappaB expression in the spleen and serum. TNF-alpha and NF-kappaB KO mice demonstrated lower levels of apoptosis in spleen in response to burn injury. Simvastatin did not further decrease burn-caused apoptosis and mortality in either strain of KO mice. CONCLUSIONS: Simvastatin reduces burn-induced splenic apoptosis via downregulation of the TNF-alpha/NF-kappaB pathway.

Simvastatin induces NFkappaB/p65 down-regulation and JNK1/c-Jun/ATF-2 activation, leading to matrix metalloproteinase-9 (MMP-9) but not MMP-2 down-regulation in human leukemia cells.[Pubmed:25316568]

Biochem Pharmacol. 2014 Dec 15;92(4):530-43.

The aim of the present study was to explore the signaling pathways associated with the effect of Simvastatin on matrix metalloproteinase-2 (MMP-2)/MMP-9 expression in human leukemia K562 cells. In sharp contrast to its insignificant effect on MMP-2, Simvastatin down-regulated MMP-9 protein expression and mRNA levels in K562 cells. Simvastatin-induced Pin1 down-regulation evoked NFkappaB/p65 degradation. Meanwhile, Simvastatin induced JNK-mediated c-Jun and ATF-2 activation. Over-expression of Pin1 suppressed Simvastatin-induced MMP-9 down-regulation. Treatment with SP600125 (a JNK inhibitor) or knock-down of JNK1 reduced MMP-2 expression in Simvastatin-treated cells. Simvastatin enhanced the binding of c-Jun/ATF-2 with the MMP-2 promoter. Down-regulation of c-Jun or ATF-2 by siRNA revealed that c-Jun/ATF-2 activation was crucial for MMP-2 expression. Suppression of p65 activation or knock-down of Pin1 by shRNA reduced MMP-2 and MMP-9 expression in K562 cells. Over-expression of constitutively active JNK1 rescued MMP-2 expression in Pin1 shRNA-transfected cells. Simvastatin treatment also suppressed MMP-9 but not MMP-2 expression in human leukemia U937 and KU812 cells. Taken together, our data indicate that Simvastatin-induced p65 instability leads to MMP-9 down-regulation in leukemia cells, while Simvastatin-induced JNK1/c-Jun/ATF-2 activation maintains the MMP-2 expression underlying p65 down-regulation.

Simvastatin prevents and reverses depigmentation in a mouse model of vitiligo.[Pubmed:25521459]

J Invest Dermatol. 2015 Apr;135(4):1080-1088.

Vitiligo is a common autoimmune disease of the skin that results in disfiguring white spots. There are no Food and Drug Administration (FDA)-approved treatments, and current treatments are time-consuming, expensive, and of low efficacy. We sought to identify new treatments for vitiligo, and first considered repurposed medications because of the availability of safety data and expedited regulatory approval. We previously reported that the IFN-gamma-induced chemokine CXCL10 is expressed in lesional skin from vitiligo patients, and that it is critical for the progression and maintenance of depigmentation in our mouse model of vitiligo. We hypothesized that targeting IFN-gamma signaling might be an effective new treatment strategy. Activation of signal transducer and activator of transcription 1 (STAT1) is required for IFN-gamma signaling and recent studies revealed that Simvastatin, an FDA-approved cholesterol-lowering medication, inhibited STAT1 activation in vitro. Therefore, we hypothesized that Simvastatin may be an effective treatment for vitiligo. We found that Simvastatin both prevented and reversed depigmentation in our mouse model of vitiligo, and reduced the number of infiltrating autoreactive CD8(+) T cells in the skin. Treatment of melanocyte-specific, CD8(+) T cells in vitro decreased proliferation and IFN-gamma production, suggesting additional effects of Simvastatin directly on T cells. Based on these data, Simvastatin may be a safe, targeted treatment option for patients with vitiligo.

Potential anticancer effects of statins: fact or fiction?[Pubmed:12699077]

Endothelium. 2003;10(1):49-58.

Deregulation of any of the steps in cell growth, proliferation and apoptosis may result in its malignant transformation. Statins, along with their lipid-lowering potential, modify several processes in the cell cycle. These agents inhibit cell proliferation and arrest cell cycle progression by interrupting growth-promoting signals. Statins selectively induce proapoptotic protential in tumor cells and synergistically enhance proapoptotic potential of several cytotoxic agents. Statins alter angiogenic potential of cells by modulating apoptosis inhibitory effects of VEGF and decrease secretion of metalloproteases. Statins also alter adhesion and migration of tumor cells, thereby inhibiting tumor invasion and metastasis. Statins suppress rate of activation of multiple coagulation factors and thus prevent coagulation-mediated angiogenesis. Statins have been shown to have anti-tumor activity in experimental models. Various anti-neoplastic properties of statins are probably a result of inhibition of posttranslational modifications of growth regulatory proteins. Molecular mechanisms of antiproliferative, proapoptotic and antiangiogenic effects of statins are reviewed in this chapter.

Preclinical pharmacokinetics of statins.[Pubmed:12616706]

Methods Find Exp Clin Pharmacol. 2002 Nov;24(9):593-613.

This review summarizes the pharmacokinetic properties of HMG-CoA reductase inhibitors (or statins) reported in animals. Lovastatin and Simvastatin are administered as lactone prodrugs in contrast to other statins, which are generally formulated in the pharmacological active hydroxy acid form. Pharmacokinetics vary with the statin and animal species considered. Oral absorption is rapid and the bioavailability low due to an extensive first-pass metabolism. Pitavastatin is the exception, with high bioavailability in all species except monkeys (80% vs. 18%). Plasma protein binding is high for all statins (> 95%) except pravastatin (60%). Regardless of the dosing schedule (single or multiple), animal species and statin, the highest tissue levels are found in the liver--the target organ. Elimination is rapid with metabolism being the main elimination route for all statins, except for pitavastatin, which is only slightly metabolized, and pravastatin, which aside from metabolism is also eliminated by renal excretion. Statins undergo enterohepatic circulation and are recovered mainly in feces via bile, the extent of which is species-dependent. Metabolism varies with the statin and animal species, particularly the beta-oxidation of the dihydroxy heptanoic side chain that occurs primarily in rodents.

Statins and bone formation.[Pubmed:11405194]

Curr Pharm Des. 2001 May;7(8):715-36.

The main therapy needed most in the bone field is an anabolic agent for the treatment of osteoporosis. Current drugs on the market, which included bisphosphonates, calcitonin, estrogen and related compounds, vitamin D analogues trabecular microarchitecture. Therefore, it would be desirable to have a satisfactory and universally and iprifalvone, are essentially bone resorption inhibitors that mainly act to stabilize bone mass. Patients with established osteoporosis have lost more than 50% of their bone mass at critical sites in the skeleton, and more over have marked disruption of acceptable drug that would stimulate new bone formation and correct this disturbance of trabecular microarchitecture characteristic of established osteoporosis. Recently inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which controls the first step in the biosynthesis of cholesterol, have been shown to stimulate bone formation in rodents both in vitro and in vivo. The effect is associated with an increased expression of the bone morphogenetic protein-2 (BMP-2) gene in bone cells. These statins drugs are widely used agents for lowering cholesterol and reducing heart attacks, however they are also known to elicit numerous pleiotropic effects including inhibition of proliferation and migration of smooth muscle cells, inhibition of tumor growth and anti-inflammatory activity. Some of these effects have been attributed to not only to the reduction of cholesterol synthesis by inhibition of the HMG-CoA reductase enzyme but also by the concurrent reduction in downstream metabolites of the mevalonate pathway such as mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. The findings that statins are capable of increasing bone formation and bone mass in rodents suggests a potential new action for the statins, which may be beneficial in patients with established osteoporosis where marked bone loss has occurred. Recent clinical data suggests that they may reduce the risk of fracture in patients taking these drugs. However, their precise role can only be determined by appropriate randomized clinical trials, which demonstrate their efficacy in this regard in patients.

Pharmacological effects of HMG CoA reductase inhibitors other than lipoprotein modulation.[Pubmed:11563401]

J Clin Pharmacol. 1999 Feb;39(2):111-8.

The HMG CoA reductase inhibitors reduce levels of low-density lipoproteins, raise high-density lipoproteins, and lower triglycerides. However, there are other pharmacological effects derived from HMG CoA reductase inhibitor therapy. Certain HMG CoA reductase inhibitors affect atherosclerotic plaque composition, endothelial function, platelet and clotting factors, and immune functioning. The unique extrahepatic pharmacological profile of agents in this class has not been fully characterized. All of the HMG CoA reductase inhibitors studied have improved endothelium-dependent vasodilatation. Vascular smooth muscle proliferation is not significantly affected by pravastatin but is by the other agents. Of all the HMG CoA reductase inhibitors, cerivastatin is the most potent inhibitor of vascular smooth muscle proliferation. Pravastatin is the only agent proven to significantly reduce platelet-thrombus formation and fibrinogen levels. Simvastatin has no effect on platelet-thrombus formation or fibrinogen levels, while atorvastatin and lovastatin have been shown to increase fibrinogen in some studies. Plasminogen activator inhibitor-1 levels are decreased by pravastatin, are not affected by atorvastatin, and are significantly increased by lovastatin and Simvastatin. Pravastatin also has clinical benefits in transplant medicine as a result of inhibiting natural killer cell function, an effect that has not been explored with other HMG CoA reductase inhibitors.

HMG-CoA reductase inhibitor,Simvastatin is a competitive inhibitor of HMG-CoA reductase with Ki of 0.1-0.2 nM in cell-free assays.

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