Tissue selectivity of the cholesterol-lowering agents lovastatin, simvastatin and pravastatin in rats in vivo

Germershausen, John; Hunt, Vincent M.; Bostedor, Richard G.; Bailey, Philip J.; Karkas, John D.; Alberts, Alfred W.

doi:10.1016/0006-291x(89)92773-3

Cited by 163 publications

(47 citation statements)

References 9 publications

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“…Presumably, only the unbound drug can penetrate the tissues (18). Tissue distribution studies with rats demonstrated that concentrations of simvastatin and lovastatin were 50% higher than that of pravastatin in liver during the 24 h after drug administration and were three to six times lower than pravastatin concentrations in peripheral tissues (3). The antiparasitic activities of pravastatin on the intraerythrocytic development of P. falciparum are under in-VOL.…”

Section: Discussionmentioning

confidence: 99%

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit in vitro development of Plasmodium falciparum and Babesia divergens in human erythrocytes

Grellier

Valentin

Millerioux

et al. 1994

Antimicrob Agents Chemother

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The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit the in vitro intraerythrocytic development of Plasmodium falciparum and Babesia divergens, with concentrations inhibiting parasite growth by 50% in the ranges of 10 to 20 and 5 to 10 ug -ml-', respectively. For P.falciparum, the 50% inhibitory concentrations were in the same range whatever the chloroquine susceptibility of the strains tested (strain F32/Tanzania [chloroquine susceptible] or FcB.1/Columbia [resistant]). The stage-dependent susceptibility of P. falciparum to simvastatin was studied by subjecting synchronized cultures to 6-h pulses of drug throughout the 48-h erythrocytic life cycle. The most important inhibitory effects were observed between the 12th and 30th hours of the cycle, corresponding to the trophozoite stage. This period precedes the S phase and the nuclear divisions. Parasites in the newly formed ring stage (time zero to the 6th hour of the cycle) and the schizont stage (30th to 48th hour of the cycle) were weakly or not susceptible to simvastatin pulses.The Apicomplexa hemoparasites Plasmodium falciparum and Babesia divergens, the causative agents of human malaria and bovine babesiosis, respectively, still constitute major health and economic problems in most developing countries (12,24). The (8,21,22) and depend on their import from the host's plasma. With the use of a serum-free medium, we have recently found a unidirectional transfer of phospholipids from human high-density lipoproteins to the intraerythrocytic P. falciparum by ducts and vesicles moving from the erythrocyte to the parasitophorous vacuole membranes (6). A similar phospholipid transfer was observed in B. divergensinfected erythrocytes (RBC), but no ducts or vesicles were observed (21). High-density lipoproteins support the in vitro growth of B. divergens and P. falciparum in the absence of other major serum components and appeared to be a lipid source for the parasites (6,7,21 by P. falciparum-infected RBC, we have shown evidence for an isoprenoid metabolisnm until, at least, the farnesyl PPi step (16).This pathway, with numerous end products, is essential for various cellular functions such as mitochondrial electron transport, tRNA synthesis, control of cell growth, protein glycosylation, and intracellular targeting (4). In both prokaryotic and eukaryotic cells, the isoprenoid pathway is highly regulated through feedback regulations at the level of two sequential enzymes involved in the synthesis of mevalonate: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and HMGCoA reductase (4). HMG-CoA reductase inhibitors are available as hypocholesterolemic agents in humans. The goal of our study was to establish whether the HMG-CoA reductase inhibitors lovastatin and simvastatin are able to inhibit the in vitro development of P. falciparum and B. divergens. MATERIALS AND METHODSLovastatin and simvastatin, both in the lactone form, were kindly provided by J. C. Mazi&re (Hopital St-Antoine, Paris, France) and by C. Fous...

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Section: Discussionmentioning

confidence: 99%

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit in vitro development of Plasmodium falciparum and Babesia divergens in human erythrocytes

Grellier

Valentin

Millerioux

et al. 1994

Antimicrob Agents Chemother

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“…These differences in tissue permeability and metabolism may account for some of the observed differences in their peripheral side effects (27). Lipophilic statins, such as simvastatin, are considered more likely to enter endothelial cells by passive diffusion than hydrophilic statins, such as pravastatin and rosuvastatin, which are primarily targeted to the liver.…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic Effects of Statins

Liao

Laufs

2005

Annu. Rev. Pharmacol. Toxicol.

1,611

1,198

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Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, 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 pleiotropic effects of statins.

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“…This drug, besides being commonly prescribed to decrease hepatic cholesterol biosynthesis [24], has also been reported to potentially improve bone healing [25].…”

Section: Introductionmentioning

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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Tissue selectivity of the cholesterol-lowering agents lovastatin, simvastatin and pravastatin in rats in vivo

Cited by 163 publications

References 9 publications

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit in vitro development of Plasmodium falciparum and Babesia divergens in human erythrocytes

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit in vitro development of Plasmodium falciparum and Babesia divergens in human erythrocytes

Pleiotropic Effects of Statins

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

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