New insights into the pharmacodynamic and pharmacokinetic properties of statins

Corsini, Alberto; Bellosta, Stefano; Baetta, Roberta; Fumagalli, R.; Paoletti, Rodolfo; Bernini, Franco

doi:10.1016/s0163-7258(99)00045-5

Cited by 716 publications

(558 citation statements)

References 157 publications

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“…In our study, and in order to validate the peroral feeding method, we examined the levels of fluvastatin in the blood of mice after 2 hours of ingestion of the drug. The levels of fluvastatin obtained, although higher than the values reported in humans receiving typical doses (52), are comparable with the levels obtained in humans after administration of high doses of the drug (45). These differences may be due to several factors, including differences in absorption, kinetics, and metabolism of the drug in rodents, and differences in food ingestion, among other factors.…”

Section: Discussionsupporting

confidence: 71%

“…One possible mechanism of this effect includes the inhibition of tissue factor expression (51,52). In a recent report, thrombogenicity of the arterial wall of hypercholesterolemic rabbits was decreased by fluvastatin and this was accompanied by a reduction in tissue factor expression and decrease in NF-B activation in the aortic arch (53).…”

Section: Discussionmentioning

confidence: 99%

“…The enzyme HMG-CoA reductase is responsible for the conversion of HMG-CoA to mevalonate. Since mevalonic acid is the precursor not only of cholesterol, but also of many nonsteroidal isoprenoid compounds critical for several cellular processes of eukaryotic cells, inhibition of the mevalonate pathway by statins has pleiotropic effects (52). Many of these pleiotropic effects of statins are mediated by their ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules and have been shown to occur in the absence of a reduction of the cholesterol levels (54)(55)(56).…”

Section: Discussionmentioning

confidence: 99%

“…Many of these pleiotropic effects of statins are mediated by their ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules and have been shown to occur in the absence of a reduction of the cholesterol levels (54)(55)(56). In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall (22,(52)(53)(54)(55)(56).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Ferrara¹,

Liu²,

Espinola³

et al. 2003

Arthritis & Rheumatism

138

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Methods. Two groups of CD-1 male mice, each comprising ϳ18 mice, were fed either normal saline solution or 15 mg/kg fluvastatin for 15 days. Each of the 2 groups was further subdivided to receive either purified IgG from patients with the antiphospholipid syndrome (IgG-APS) or normal IgG from healthy subjects. Analysis of thrombus dynamics was performed in treated and control mice, using a standardized thrombogenic injury procedure, and the area (size) of the thrombus was measured. Adhesion of leukocytes to ECs was analyzed with a microcirculation model of exposed cremaster muscle. Baseline and posttreatment soluble intercellular adhesion molecule 1 (sICAM-1) levels were determined by enzyme-linked immunosorbent assay.Results. IgG-APS mice treated with fluvastatin showed significantly smaller thrombi, a reduced number of adherent leukocytes, and decreased levels of sICAM-1 compared with IgG-APS animals treated with placebo.Conclusion. These findings indicate that fluvastatin significantly diminishes aPL-mediated thrombosis and EC activation in vivo. These results may have important implications for the design of new treatment strategies aimed at preventing recurrent thrombosis in patients with APS.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Ferrara¹,

Liu²,

Espinola³

et al. 2003

Arthritis & Rheumatism

138

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“…30 The lowest concentration of SS (0.1 µM) used in the present study is similar to the serum levels measured in patients' receiving regular doses of SS for therapy (usually less than 90 nM). 31,32 Given our present results and the earlier findings of others, one might expect a clinical dose of SS to increase chemokine secretion from OBs at sites of bone inflammation, though it remains unclear whether higher doses of SS are cytotoxic to bone tissues in vivo.…”

Section: Discussionsupporting

confidence: 64%

Dose-Specific Biphasic Effects of Simvastatin on the Expression of CXCL10 and CX3CL1 by Human Osteoblasts

Kasama

Isozaki

Sato

et al. 2009

Immunol Immunogenet Insights

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Objective: To better understand the effects of simvastatin (SS) on the expression and secretion of two chemokines, CXCL10 and CX3CL1, by osteoblasts, and to test whether inhibition of isoprenoid intermediates of cholesterol biosynthesis were involved in the effects of SS.Methods: Human osteoblasts were incubated in the presence or absence of the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), with and without SS (0.1-100 µM). Culture supernatants were then collected, and expression of CXCL10 and CX3CL1 mRNA in osteoblasts was examined using quantitative TaqMan real-time polymerase chain reaction. The levels of CXCL10 and CX3CL1 were measured using enzyme-linked immunosorbent assays.Results: At a high concentration (100 µM), SS inhibited expression and secretion of the chemokines and showed cytotoxity, whereas at lower concentrations (0.1-1 µM) SS stimulated the expression and secretion of the chemokines. Expression and secretion of CXCL10 or CX3CL1 from osteoblasts were induced by stimulation with TNF-α  and IFN-γ. In addition, SS exerted a biphasic effect on the evoked induction of CXCL10 and CX3CL1. Chemokine expression and secretion was also assayed in the presence of mevalonate (MEV), geranylgeranyl pyrophosphate (GGPP) or farnesyl pyrophosphate (FPP). MEV abolished both the inhibitory effect of high-dose SS and the stimulatory effect of low-dose SS. On the other hand, GGPP abolished only the inhibitory effects of high-dose SS, and FPP had no effect at all.Conclusions: These findings suggest that osteoblasts are an important cellular source of CXCL10 and CX3CL1, and that statins such as SS may modulate the inflammatory process in bone tissues to inhibit bone resorption and stimulate bone formation through biphasic modulation chemokine synthesis.

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Risk for Myopathy With Statin Therapy in High-Risk Patients

Ballantyne¹,

Corsini²,

Davidson³

et al. 2003

Arch Intern Med

Self Cite

408

273

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Emerging data suggest that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) offer important benefits for the large population of individuals at high risk for coronary heart disease. This population encompasses a sizable portion of individuals who are also at high risk for drug-drug interactions due to their need for multiple medications. In general, statins are associated with a very small risk for myopathy (which may progress to fatal or nonfatal rhabdomyolysis); however, the potential for drug-drug interactions is known to increase this risk in specific high-risk groups. The incidence of myopathy associated with statin therapy is dose related and is increased when statins are used in combination with agents that share common metabolic pathways. Of particular concern is the potential for interactions with other lipid-lowering agents such as fibrates and niacin (nicotinic acid), which may be used in patients with mixed lipidemia, and with immunosuppressive agents, such as cyclosporine, which are commonly used in patients after transplantation. Clinicians should be alert to the potential for drug-drug interactions to minimize the risk of myopathy during long-term statin therapy in patients at high risk for coronary heart disease.

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New insights into the pharmacodynamic and pharmacokinetic properties of statins

Cited by 716 publications

References 157 publications

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model

Dose-Specific Biphasic Effects of Simvastatin on the Expression of CXCL10 and CX3CL1 by Human Osteoblasts

Risk for Myopathy With Statin Therapy in High-Risk Patients

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