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Clin Orthop Relat Res. 2006 Sep 28;
Chang JK, Ho ML, Yeh CH, Chen CH, Wang GJ.
From the *Departments of Orthopedics and daggerPhysiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; double daggerOrthopedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; section sig
Osteogenic Gene Expression Decreases in Stromal Cells of Patients with Osteonecrosis.
Nontraumatic osteonecrosis is related to alcohol and glucocorticoid with unknown pathogenesis. Increased adipogenesis decreases bone morphogenetic protein 2 (BMP2) gene expression after glucocorticoid treatment. Lovastatin enhances BMP2 gene expression in rodents, reverses the effects of glucocorticoids on bone, and prevents glucocorticoid-induced osteonecrosis in chickens and humans. We hypothesized patients with osteonecrosis are more susceptible to glucocorticoid treatment than patients without osteonecrosis. Marrow stromal cell cultures from 14 patients with osteonecrosis, and 10 patients without osteonecrosis were treated with dexamethasone (0.1 mumol/L), lovastatin (1 mumol/L), or combined treatment. BMP2 and osteocalcin gene expression were evaluated by reverse-transcriptase polymerase chain reaction and real-time polymerase chain reaction. The suppression of BMP2 by dexamethasone was more pronounced and the enhancement by lovastatin was less pronounced in the osteonecrosis group. Dexamethasone suppressed osteocalcin in the osteonecrosis group. Among the subgroups of osteonecrosis, suppression of BMP2 and osteocalcin by dexamethasone occurred in glucocorticoid-induced osteonecrosis group. Our data suggest individuals who are more susceptible to a glucocorticoid-induced decreases in BMP2 and osteocalcin gene expression are more likely to have osteonecrosis, especially glucocorticoid-induced osteonecrosis.
Metabolism. 2004 Jun;53(6):744-8.
Lupattelli G, Scarponi AM, Vaudo G, Siepi D, Roscini AR, Gemelli F, Pirro M, Latini RA, Sinzinger H, Marchesi S, Mannarino E.
Internal Medicine, Angiology and Atherosclerosis, Department of Clinical and Experimental Medicine, University of, Perugia, Italy.
Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women.
Statins are able to reduce cardiovascular morbility and mortality mainly through their hypocholesterolemic effect. Beyond the inhibition of cholesterol synthesis, the identification of "ancillary" mechanisms has motivated studies evaluating the relationship between the use of statins and the modification of bone mineral density (BMD). To date, clinical trials have provided discordant results. The aim of our study was to evaluate whether simvastatin treatment (40 mg/d) could modify BMD in hypercholesterolemic women (n = 40) after a 2-year treatment as compared with a control group treated only with diet (n = 20) and matched by gender, age, body mass index (BMI), lipids, menopausal age, and BMD and the number of osteopenic, osteoporotic, and normal women (on the basis of T-score value). Exclusion criteria were secondary hyperlipemias and osteoporosis and current or previous therapy with statins, bisphosphonates, and estrogens. The BMD was measured at the lumbar spine and hip by dual energy x-ray absorpiometry (DEXA). In the group treated by simvastatin, BMD, both on the spine and femoral hip, showed a significant increase after 8 and 24 months, respectively (0.878 +/- 0.133 v 0.893 +/- 0.130 and 0.907 +/- 0.132; 0.840 +/- 0.101 v 0.854 +/- 0.101; and 0.863 +/- 0.10, P <.001); there was a percentage increase of 1.7% after 8 months and 3.3% after 24 months at the spine; at the femoral hip, BMD increased 1.6% after 8 months and 2.7% after 24 months. The group treated only with hypolipidic diet demonstrated after 8 and 24 months a slight decrease in BMD both on the spine and femoral hip (respectively, 0.884 +/- 0.175 v 0.872 +/- 0.174 and 0.861 +/- 0.164; 0.860 +/- 0.110 v 0.853 +/- 0.096 and 0.847 +/- 0.095; P <.05). In conclusion, as partly suggested by retrospective or observational data, this longitudinal study indicates that simvastatin treatment exerts a beneficial effect on BMD.
Am J Cardiol. 2004 Jun 15;93(12):1487-94.
Ballantyne CM, Blazing MA, King TR, Brady WE, Palmisano J.
Baylor College of Medicine, Houston, Texas, USA.
Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia.
This study compared the efficacy and safety of co-administered ezetimibe + simvastatin with atorvastatin monotherapy in adults with hypercholesterolemia. Seven hundred eighty-eight patients were randomized 1:1:1 to 3 treatment groups; each group was force-titrated over four 6-week treatment periods: (1) 10 mg of atorvastatin as the initial dose was titrated to 20, 40, and 80 mg; (2) co-administration of 10 mg of ezetimibe and 10 mg of simvastatin (10/10 mg) was titrated to 10/20, 10/40, and 10/80 mg of ezetimibe + simvastatin; and (3) co-administration of 10/20 mg of ezetimibe + simvastatin was titrated to 10/40 mg (for 2 treatment periods) and 10/80 mg of ezetimibe + simvastatin. Key efficacy measures included percent changes in low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) from baseline to the ends of (1) treatment periods 1 and 2 (for LDL cholesterol) comparing co-administration of 10/20 mg and 10/10 mg of ezetimibe + simvastatin with 10 mg of atorvastatin and (2) treatment period 4 (for LDL cholesterol and HDL cholesterol) comparing co-administration of 10/80 mg of ezetimibe + simvastatin with 80 mg of atorvastatin. Baseline LDL and HDL cholesterol levels were comparable between treatment groups. At the end of treatment period 1, the mean decrease of LDL cholesterol was significantly.
J Immunol. 2005 Feb 15;174(4):2327-35.
Gegg ME, Harry R, Hankey D, Zambarakji H, Pryce G, Baker D, Adamson P, Calder V, Greenwood J.
Division of Cellular Therapy
Suppression of autoimmune retinal disease by lovastatin does not require th2 cytokine induction.
Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In an acute mouse model of autoimmune retinal disease, we demonstrate that treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage, and leukocytic infiltration into the retina. Efficacy was reversed by coadministration of mevalonolactone, the downstream product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, but not by squalene, which is distal to isoprenoid pyrophosphate metabolites within the cholesterol biosynthetic pathway. Lovastatin treatment (20 mg/kg/day i.p.) over 7 days, which resulted in plasma lovastatin hydroxyacid concentrations of 0.098 +/- 0.03 muM, did not induce splenocyte Th2 cytokine production but did cause a small reduction in Ag-induced T cell proliferation and a decrease in the production of IFN-gamma and IL-10. Thus, it is possible to dissociate the therapeutic effect of statins in experimental autoimmune uveitic mice from their activity on the Th1/Th2 balance. Statins inhibit isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase, a key molecule in the endothelial ICAM-1-mediated pathway that facilitates lymphocyte migration. Consistent with inhibition of leukocyte infiltration in vivo, lovastatin treatment of retinal endothelial cell monolayers in vitro leads to inhibition of lymphocyte transmigration, which may, in part, account for drug efficacy. Unlike lovastatin, atorvastatin treatment showed little efficacy in retinal inflammatory disease despite showing significant clinical benefit in experimental autoimmune encephalomyelitis. These data highlight the potential differential activity of statins in different inflammatory conditions and their possible therapeutic use for the treatment of human posterior uveitis.
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Drug category:Antilipemic agents
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