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Methods and compositions to lower plasma cholesterol levels

A technology of cholesterol and plasma, applied in drug combination, biological test, pharmaceutical formulation, etc., can solve problems such as HDL reduction

Inactive Publication Date: 2002-01-23
埃瑟若詹尼克斯公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Probucol typically lowers LDL cholesterol by 10% to 20%, but also lowers HDL by 20% to 30%

Method used

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  • Methods and compositions to lower plasma cholesterol levels
  • Methods and compositions to lower plasma cholesterol levels
  • Methods and compositions to lower plasma cholesterol levels

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0055] (i) A method of assessing whether a compound is an LDL clearance enhancing agent comprising admixing the drug with cholesterol-containing lipoproteins in vivo or in vitro; isolating the complex, and determining whether binding of the compound to the complex results in enhanced lipoprotein Changes in the three-dimensional structure of apoB-100 in lipoproteins of binding affinity to the LDL receptor;

[0056] (ii) A method of lowering plasma cholesterol in a host, the method comprising, administering to the host a compound capable of forming a complex with cholesterol-containing lipoproteins such as LDL or VLDL, and then determining whether the newly formed complex causes the lipoprotein to react to the LDL receptor Structural alteration of apoB-100 with increased binding affinity;

[0057] (iii) A method of altering the structure of a cholesterol-containing lipoprotein comprising mixing the cholesterol-containing lipoprotein with a compound in vivo or in vitro and determ...

Embodiment 1

[0083] The present invention includes (i) assays for determining whether binding of potential LDL-scavenging drugs to LDL or VLDL can cause structural changes in apoB-100 that affect LDL-receptor binding; and (ii) assays for potential LDL-scavenging enhancing drugs A method for determining whether complexes of LDL or VLDL alter the electrophoretic mobility pattern, and, if so, whether the interaction alters the structure of apoB-100 on LDL or VLDL. Example 1 Monosuccinate of probucol binds to VLDL and LDL in vivo and in vitro

[0084] To test whether probucol monosuccinate can be separated from plasma circulating lipoproteins, rabbits were fed a high fat diet for 6 weeks and the compound was orally administered at a dose of 150 mg / Kg / day. Animals were bled at 6 weeks and plasma lipoproteins were separated by ultracentrifugation at high speed.

[0085] All plasma was separated by fast liquid chromatography (FPLC) with a Superose 6HR 10 / 30 column. with 0.01% EDTA and 0.02% NaN...

Embodiment 2

[0089] To confirm the in vitro binding of probucol monosuccinate to purified human LDL, agarose electrophoresis was performed. Agarose electrophoresis is a technique used to separate and study lipoproteins. Probucol monosuccinate was added to purified human LDL and the mixture was subjected to agarose electrophoresis. Addition of probucol derivatives to LDL altered the mobility of LDL, suggesting that the monosuccinate ester of probucol interacts with LDL, most likely through physical association of the compound with lipoproteins. In contrast, probucol did not alter the mobility of LDL. Example 3 Monosuccinate of probucol binds to LDL and changes the epitope expression of LDL-apoB-100

[0090] To determine whether the binding of monosuccinate to VLDL and LDL can cause changes in the structure of apoB-100, an immunoreactivity assay was designed. This is a sandwich ELISA assay that measures the expression of specific antigenic epitopes on apoB-100. The sandwich ELISA essenti...

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Abstract

A method is disclosed for determining whether a compound binds to a lipoprotein such as LDL or VLDL in a manner which will lower plasma cholesterol is provided that includes assessing the ability of the compound to form a complex with the lipoprotein, e.g., LDL or VLDL, and then determining whether the newly formed complex causes a change in the structure of apoB-100 that results in increased binding affinity to the LDL receptor. Also disclosed is a method for lowering cholesterol in a host in need thereof, including a human, is provided that includes the administration fo an effective amount of a compound which binds to cholesterol-carrying lipoprotein (e.g. LDL or VLDL) in a manner that alters the three dimensional configuration of the lipoprotein and increases the binding affinity of the apoB-100 protein to the LDL receptor, including those on the surface of a hepatic cell.

Description

[0001] The present invention relates to methods and compositions for lowering plasma cholesterol levels by lowering circulating low density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels. Background of the invention [0002] Coronary heart disease (CHD) remains the leading cause of death in industrialized countries. The main cause of CHD is atherosclerosis, a disease characterized by the deposition of lipids, including cholesterol, on the walls of arteries, leading to narrowing of the vascular channels and ultimately hardening of the vascular system. [0003] It is now generally believed that atherosclerosis may begin with local injury of the arterial endothelium, followed by the proliferation of arterial smooth muscle cells from the media to the intimal layer, accompanied by lipid deposition and accumulation of foam cells at the injury site. As the atherosclerotic plaque grows, it progressively closes more and more damaged blood vessels and can eventually le...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00A61K31/10A61K31/12A61K31/165A61K31/166A61K31/18A61K31/192A61K31/20A61K31/222A61K31/225A61K31/455A61K31/7028A61K31/785A61K45/06A61P3/06A61P9/10G01N27/447G01N33/15G01N33/50G01N33/53G01N33/566G01N33/92
CPCG01N33/92A61K31/00G01N2800/044A61P3/06A61P9/10
Inventor 拉塞尔·M·梅德福乌黛·萨克塞纳
Owner 埃瑟若詹尼克斯公司
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