Prevention or treatment of abnormal lipoprotein, atherosclerosis and cholestasis

Abstract

Using an animal model, transgenic animals that do not express functional SR-BI and apoE which develop severe atherosclerosis, by age four weeks in transgenic mice, a class of drugs, PROBUCOL (4,4′-(isopropylidenedithio) bis(2,6-di-tert-butylphenol)) and monoesters of PROBUCOL, and BO 653, 2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butyl-benzofuran, has been discovered which is useful in normalizing abnormal lipoprotein levels and/or characteristics, such as those found in lipoprotein X-associated disease. These animals are good models for screening of drugs useful in the treatment and/or prevention of cardiac fibrosis, myocardial infarction, defects in electrical conductance, atherosclerosis, unstable plaque, and stroke, as well as for lipoprotein disorders such as cholestasis and lipoprotein X associated disorders. Studies demonstrate normalization of lipoprotein levels and structure, as well as significant decreases in atherosclerosis and prevention of heart attack, even when administered after disease onset.

We claim:  
     
         1 . A method for treating or preventing a disorder or disease characterized by abnormal lipoprotein or cholesterol metabolism comprising administering to an individual in need thereof a compound selected from the group consisting of 4,4′-(isopropylidenedithio) bis(2,6-di-tert-butylphenol), monoesters and other derivatives thereof, 2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butyl-benzofuran or a derivative thereof, vitamin E and vitamin C, wherein the compound is administered in an amount effective to decrease lipoprotein levels or normalize lipoprotein structure or reduce abnormal cholesterol metabolism.  
     
     
         2 . The method of  claim 1  wherein the compound is 4,4′-(isopropylidenedithio) bis(2,6-di-tert-butylphenol), monoesters and other derivatives thereof.  
     
     
         3 . The method of  claim 1  wherein the compound is 2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butyl-benzofuran or a derivative thereof.  
     
     
         4 . The method of  claim 1  wherein the compounds are selected from the group consisting of vitamin E and vitamin C.  
     
     
         5 . The method of  claim 1  wherein the compound is administered orally.  
     
     
         6 . The method of  claim 1  wherein the compound is administered to an individual with cholestasis.  
     
     
         7 . The method of  claim 1  wherein the compound is administered to an individual with atherosclerosis.  
     
     
         8 . The method of  claim 1  wherein the compound is administered to an individual with lipoprotein X.  
     
     
         9 . The method of  claim 1  wherein the compound is administered to an individual with a disease due to abnormalities in cholesterol metabolism.  
     
     
         10 . The method of  claim 9  wherein the disease is Niemann-Pick Type C or Tangier diseases.  
     
     
         11 . A formulation for use in any of the methods of claims  1 - 10 .