The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are considered first-line therapeutic agents for the prevention of coronary heart disease and atherosclerotic disorders related to hypercholesterolemia. Statins inhibit lipid deposition in the aortic endothelium. Although it has been accepted that the statins are potent inhibitors of cholesterol biosynthesis in the liver and that they lower circulating cholesterol levels, several cholesterol-independent (pleiotropic) effects have been reported. The cholesterol-independent effects of statins involve normalization of the nitric oxide (NO)-NO synthase system, anti-inflammatory effects through the inhibition of cytokine/chemokine production, inhibition of vascular smooth muscle cell proliferation and migration, and inhibition of platelet thrombus formation/reduction of the thrombotic response. Some pleiotropic effects of statins may depend on the inhibition of the biosynthesis of farnesyl- and geranylgeranyl-nonsterol compounds from mevalonate in the cells. The Rho/Rho kinase pathway and the phospatidylinositol-3 kinase/Akt pathway mediate the pleiotropic effects of statins. As variations occur in absorption, metabolism, and excretion mechanisms due to the characteristics of specific statins including their hydrophilicity and lipophilicity, there are differences in the transfer mechanisms of statins into tissues. However, the pleiotropic effects occur regardless of statin hydrophilicity and lipophilicity. This review summarizes the pleiotropic effects of statins on lipid deposition in blood vessels.
The efficacy of KRN8601 for neutropenia associated with HIV infection was evaluated in 24 patients. KRN8601 was infused intravenously at a dosage of 200 micrograms/m2 for 14 consecutive days. Neutrophil counts recovered in 19 (90.5%) out of 21 evaluable patients by KRN8601 treatment. The concomitant myelosuppressive agents for the treatment of HIV infection and complications could be continued without dose reduction in 15 (88.2%) out of 17 patients. The clinical improvement was observed in 66.7% (12/18) of patients who were treated with anti-microbial agents for opportunistic infections which indicates that KRN8601 shows an additive effect on infections when it was given with anti-microbial agents. Adverse events and abnormal laboratory findings were observed in 3 and 7 patients, respectively, and they were reversible and tolerable. This study demonstrated that KRN8601 improved neutropenia with HIV infection, made possible to continue the full dose of myelosuppressive treatments and have additive effect on the treatment of secondary infections.
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