Synergistic effect of amlodipine and atorvastatin on cholesterol crystal formation inhibition and aortic endothelial cell nitric oxide release

Abstract

The combination of the antihypertensive calcium channel blocker amlodipine and lipid-lowering agent atorvastatin inhibits free cholesterol crystallization in atherosclerotic-like membranes. In addition, treatment with a combination of amlodipine and atorvastatin results in a synergistic effect on the release of NO from aorta endothelial cells.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. patent application Ser. No. 09 / 921,479, filed Aug. 3, 2001 which claims the benefit of and priority to U.S. Provisional Patent Application No. 60 / 223,214, filed Aug. 4, 2000.FIELD OF THE INVENTION [0002] This invention relates to the effect of amlodipine and atorvastatin, alone and in combination, on cholesterol crystal formation and the release of nitric oxide (NO) from endothelial cells. BACKGROUND OF THE INVENTION [0003] Coronary artery disease (CAD) is the leading cause of mortality in the developed world, and is associated with substantial morbidity as well. Typically, the patient with CAD has several concomitant conditions, including hypertension, diabetes, and dyslipidemia, increasing overall risk for poor outcomes and complicating treatment. A therapeutic goal for the treatment of CAD is the development of drugs that can simultaneously target multiple underlying disease...

AI Technical Summary

Benefits of technology

[0012] Hypolipidemic therapy has also been demonstrated to be very useful in reducing morbidity and mortality associated with CAD. Among HMG-CoA reductase inhibitors, atorvastatin calcium (AT) has been shown to be very effective as hypolipdemic therapy. In a recent clinical study involving patients with stable and advanced CAD, aggressive lipid-lowering therapy with AT significantly delayed the time to a first ischemic event and reduced, by 36%, the overall incidence of cardiovascular events, as compared to angioplasty with usual medical care.

[0014] In addition, NO production from endothelial cells in rabbit aorta was systematically measured in the absence and presence of amlodipine, atorvastatin, and the combination of the two compounds. The results of these experiments demonstrated a dramatic synergistic effect of these compounds on NO stimulation. These findings indicate that these agents may effectively stabilize, in a synergistic fashion, NO in the cell by interfering with oxidative destruction.

Problems solved by technology

Lipophilic agents that influence the organization of lipids may interfere with the early formation of cholesterol domains within the membrane, thereby disrupting crystal formation.

The results of this study demonstrated that these compounds interfered with the aggregation of cholesterol into separate intrabilayer domains in an unexpected and highly synergistic fashion.

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