Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions

Kaesemeyer, Wayne H.; Caldwell, Ruth B.; Huang, Jianzhong; Caldwell, Robert W.

doi:10.1016/s0735-1097(98)00514-2

Cited by 323 publications

(205 citation statements)

References 32 publications

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“…More hydrophilic molecules can give a higher local concentration. Therefore, the approach used for enhancing simvastatin solubility was hydrolysis to cleave the lactone ring and convert the molecule to its β-hydroxyacid form (Kaesemeyer et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Bioerodible devices for intermittent release of simvastatin acid

Jeon

Thomas

Puleo

2007

International Journal of Pharmaceutics

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The association polymer system of cellulose acetate phthalate (CAP) and Pluronic F-127 (PF-127) was used to create intermittent release devices for mimicking the daily injection of simvastatin that has been reported to stimulate bone formation. To enhance solubility in water, prodrug simvastatin was modified by lactone ring opening, which converts the molecule to its hydroxyacid form. CAP/ PF-127 microspheres incorporating simvastatin acid were prepared by a water-acetone-oil-water (W/ A/O/W) triple emulsion process. Devices were then fabricated by pressure-sintering UV-treated blank and drug-loaded microspheres. Using a multilayered fabrication approach, pulsatile release profiles were obtained. Delivery was varied by changing loading, number of layers, blend ratio, and incubation conditions. To determine the cellular effects of intermittent exposure to simvastatin acid, MC3T3-E1 cells were cultured with either alternating or sustained concentrations of simvastatin acid in the medium, and DNA content, alkaline phosphatase activity, and osteocalcin secretion were measured. For all three cell responses, cultures exposed to simvastatin acid showed higher activity than did control cultures. Furthermore, cell activity was greater for cells cultured with intermittent concentrations of simvastatin acid compared to cells that were constantly treated. These results imply that devices intermittently releasing simvastatin acid warrant further study for locally promoting osteogenesis.

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Section: Discussionmentioning

confidence: 99%

“…The solution was heated at 50°C for 2 hours. Then the final solution was neutralized to pH 7.2 with 0.1 M HCl, and the volume was brought to 10 ml with deionized water (Kaesemeyer et al, 1999). Simvastatin acid (10 mM) was stored frozen at −20°C.…”

Section: Hydrolysis Of Simvastatinmentioning

confidence: 99%

Bioerodible devices for intermittent release of simvastatin acid

Jeon

Thomas

Puleo

2007

International Journal of Pharmaceutics

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“…Whereas lipophilic molecules of simvastatin (lactone) are metabolized in the liver for the reduction of cholesterol, a more hydrophilic form (hydroxyacid) is needed in hard tissues applications to potentiate its pharmacological effect [30,31]. The simvastatin was therefore hydrolysed to convert its isolated β-hydroxyacid form into an open ring by adding the simvastatin in an alkaline solution of ethanol/NaOH 0.1 M and heating it at 50 ºC for 2 h [32]. The simvastatin solution was then neutralized to pH 7.4 and stored at -20 ºC.…”

Section: Cement Preparationmentioning

confidence: 99%

Changes in the drug release pattern of fresh and set simvastatin-loaded brushite cement

Mestres

Kugiejko

Pastorino

et al. 2016

Materials Science and Engineering: C

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Calcium phosphate cements are synthetic bone graft substitutes able to set at physiological conditions. They can be applied by minimally invasive surgery and can also be used as drug delivery systems.Consequently, the drug release pattern from the cement paste (fresh cement) is of high clinical interest.However, previous studies have commonly evaluated the drug release using pre-set cements only.Therefore, the aim of this work was to determine if the time elapsed from cement preparation until immersion in the solution (3 min for fresh cements, and 1 h and 15 h for pre-set cements) had an influence on its physical properties, and correlating these to the drug release profile. Simvastatin was selected as a model drug, while brushite cement was used as drug carrier. This study quantified how the setting of a material reduces the accessibility of the release media to the material, thus preventing drug release. A shift in the drug release pattern was observed, from a burst-release for fresh cements to a sustained release for pre-set cements.

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“…To date, there are several categories of drugs used in CVD that diminish indirectly the endothelial dysfunction by upstream effect. Statins, independent of their action on lipid metabolism, have been shown experimentally to increase the expression of eNOS possible acting at the level of gene expression 79 and improve endothelial dependent vasomotion after acute coronary syndrome. 80 In hyperlipemic hamsters, simvastatin increases the plasma antioxidant potential, reduces transcytosis of LDL, and restores the endothelium-dependent relaxation, 81 an effect likely caused by an increase in endothelial NO synthesis.…”

Section: Simionescu Endothelial Implications In Vascular Diseasementioning

confidence: 99%

Implications of Early Structural-Functional Changes in the Endothelium for Vascular Disease

Simionescu¹

2007

ATVB

229

152

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Abstract-By location, between the blood and tissues and the multiple functions, the endothelial cells (ECs) play a major role in securing body homeostasis. The ECs sense all variations occurring in the plasma and interstitial fluid, and respond (function of intensity), initially by modulation of their constitutive functions, then by dysfunction, expressed by temporarily altered functions and a phenotypic shift, and ultimately by injury/death. In dyslipidemia/hyperglycemia, the initial response of EC is the modulation of 2 constitutive functions: permeability and biosynthesis. Increased transcytosis of plasma ␤-lipoproteins leads to their accumulation within the hyperplasic basal lamina, interaction with matrix proteins, and conversion to modified and reassembled lipoproteins (MRL). This generates a multipart inflammatory process and EC dysfunction characterized by expression of new cell adhesion molecules and MCP-1 that trigger T-lymphocytes and monocyte recruitment, diapedesis, and homing within the subendothelium where activated macrophages become foam cells. The latter, together with the subendothelial accrual of MRL, growth factors, cytokines, and chemokines, and accretion of smooth muscle cells of various sources lead to atheroma formation; in advanced disease, the EC overlaying atheroma take up lipids, become EC-derived foam cells, and the cytotoxic ambient ultimately conducts to EC apoptosis. Understanding the mechanisms of EC dysfunction is a prerequisite for EC-targeted therapy to reduce the incidence of cardiovascular diseases.

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Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions

Abstract: Both PRA and SIM activate eNOS, but SIM is much less effective. Clinical benefits with PRA not explained by LDL reductions may be the result of an independent action of PRA on eNOS activation.

Cited by 323 publications

References 32 publications

Bioerodible devices for intermittent release of simvastatin acid

Bioerodible devices for intermittent release of simvastatin acid

Changes in the drug release pattern of fresh and set simvastatin-loaded brushite cement

Implications of Early Structural-Functional Changes in the Endothelium for Vascular Disease

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