HMG-CoA reductase inhibitors reduce vascular monocyte chemotactic protein-1 expression in early lesions from hypercholesterolemic swine independently of their effect on plasma cholesterol levels

2001 ◽  
Vol 159 (1) ◽  
pp. 27-33 ◽  
Author(s):  
José Martı́nez-González ◽  
José Alfón ◽  
Marı́a Berrozpe ◽  
Lina Badimon
Keyword(s):  
Plasma Cholesterol ◽  
Hmg Coa Reductase ◽  
Early Lesions ◽  
Monocyte Chemotactic Protein ◽  
Reductase Inhibitors ◽  
Cholesterol Levels ◽  
Chemotactic Protein ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase

COMPUTER-AIDED MOLECULAR DESIGN OF NOVEL HMG-CoA REDUCTASE INHIBITORS FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA

2007 ◽  
Vol 06 (04) ◽  
pp. 811-821 ◽  
Author(s):  
VINICIUS B. DA SILVA ◽  
WILLIAN JONIS ANDRIOLI ◽  
IVONE CARVALHO ◽  
CARLTON A. TAFT ◽  
CARLOS H. T. P. SILVA
Keyword(s):  
Density Functional ◽  
Molecular Design ◽  
Competitive Inhibition ◽  
High Serum ◽  
Hmg Coa Reductase ◽  
Reductase Inhibitors ◽  
Cholesterol Levels ◽  
Computer Aided ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase

Elevated cholesterol levels are a primary risk factor for the development of coronary artery disease. Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of stroke and overall mortality. HMG- CoA reductase is an important molecular target of hypolipemic drugs, known as statins, which are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in-liver by competitive inhibition regarding the substrate HMG- CoA . In this paper, we have focused on computer-aided molecular design using density functional theory, flexible docking, molecular dynamics as well as ADME, and synthetic accessibility analyses in order to propose novel potential HMG- CoA reductase inhibitors, designed by bioisosteric modifications which are promising for the treatment of hypercholesterolemia.

scholarly journals Subcutaneous administration of HMG-CoA reductase inhibitors in hyperlipidaemic and normal rats

1992 ◽  
Vol 26 (4) ◽  
pp. 269-280 ◽  
Author(s):  
Jaap Joles ◽  
Nel Willekes-Koolschijn ◽  
Hein Koomans ◽  
Arie van Tol ◽  
Tini Geelhoed-Mieras ◽  
...  
Keyword(s):  
Reductase Inhibitor ◽  
Plasma Lipids ◽  
Reductase Activity ◽  
Plasma Cholesterol ◽  
Subcutaneous Administration ◽  
Hmg Coa Reductase ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitor ◽  
Coa Reductase

Recent reports demonstrate a hypocholesterolaemic effect of daily subcutaneous injections of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in different rat models of hyperlipidaemia. However, this effect is not seen after oral administration of HMG-CoA reductase inhibitors in rats. We found that oral administration of the HMG-CoA reductase inhibitor Simvastatin also had no effect on plasma cholesterol in severely hyperlipidaemic Nagase analbuminaemic rats (NAR). Simvastatin (an apolar compound dissolved in propylene glycol) was infused continuously for 28 days into the subcutis of control Sprague-Dawley rats (SDR) and NAR using an implanted osmotic pump. All doses which were effective in reducing cholesterol in the NAR (reductions up to -60%), reduced apolipoprotein AI but not apolipoprotein B and caused a severe inflammatory reaction in the dermis. Similar toxicity was observed in the SDR. Subcutaneous administration of the vehicle (propylene glycol) did not cause this reaction and did not affect plasma lipids. Administration of Lovastatin in osmotic pumps resulted in a similar inflammatory reaction. Incorporation of Simvastatin into liposomes did not diminish the toxic effect. On the other hand, infusion of Pravastatin (a polar HMG-CoA reductase inhibitor dissolved in isotonic saline) caused no changes in the dermis and had no effect on plasma lipids in NAR or SDR. Liver microsomes prepared from the Pravastatin-treated rats demonstrated a 3- to 4-fold increase in HMG-CoA reductase activity as compared to untreated rats, confirming uptake of the drug. We conclude that continuous subcutaneous administration of the HMG-CoA reductase inhibitors Simvastatin, Lovastatin and Pravastatin for 28 days may not reduce plasma cholesterol in rats by a mechanism which is related to inhibition of HMG-CoA reductase activity in the liver. The decrease of plasma cholesterol effected by subcutaneous infusion of Simvastatin or Lovastatin in NAR coincides with, and may be related to inflammatory changes caused by administering these compounds into the dermis.

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