Method of treating dyslipidemic disorders

Abstract

The invention provides methods of treating or preventing a condition or disorder associated with dyslipidemia with compositions comprising apolipoprotein-sphingomyelin complexes. The methods of the invention permit reduction, by 4- to 20-fold, of the amount of apolipoprotein required for therapeutic administration to bring about an ameliorative effect.

What is claimed is:  
     
         1 . A method of treating dyslipidemia or a disease associated with dyslipidemia, comprising administering to a subject an apolipoprotein-sphingomyelin complex comprising apolipoprotein and sphingomyelin in an amount effective to achieve a serum level of free or complexed apolipoprotein in the range of 10 mg/dL to 300 mg/dL above a baseline level before administration.  
     
     
         2 . The method of  claim 1  in which the disease associated with dyslipidemia is selected from the group consisting of coronary heart disease; coronary artery disease; cardiovascular disease, hypertension, restenosis, vascular or perivascular diseases; dyslipidemic disorders; dyslipoproteinemia; high levels of low density lipoprotein cholesterol; high levels of very low density lipoprotein cholesterol; low levels of high density lipoproteins; high levels of lipoprotein Lp(a) cholesterol; high levels of apolipoprotein B; atherosclerosis (including treatment and prevention of atherosclerosis); hyperlipidemia; hypercholesterolemia; familial hypercholesterolemia (FH); familial combined hyperlipidemia (FCH); lipoprotein lipase deficiencies, such as hypertriglyceridemia, hypoalphalipoproteinemia, and hypercholesterolemialipoprotein.  
     
     
         3 . The method of  claim 1  in which the apolipoprotein is selected from the group consisting of preproapoliprotein, preproApoA-I, proApoA-I, ApoA-I, preproApoA-II, proApoA-II, ApoA-II, preproApoA-IV, proApoA-IV, ApoA-IV, ApoA-V, preproApoE, proApoE, ApoE, preproApoA-I Milano , proApoA-I Milano , ApoA-I Milano , preproApoA-I Paris , proApoA-I Paris , and ApoA-I Paris .  
     
     
         4 . The method of  claim 3  in which the apolipoprotein is a homodimer.  
     
     
         5 . The method of  claim 3  in which the apolipoprotein is a heterodimer.  
     
     
         6 . The method of  claim 1  in which the ratio of SM:apolipoprotein of the complex is in the range of 1:1 to 200:1 (mole/mole).  
     
     
         7 . The method of  claim 1  in which the ratio of SM:apolipoprotein of the complex is in the range of 1:2 to 200:1 (mole/mole).  
     
     
         8 . The method of  claim 1  in which the ratio of SM:apolipoprotein of the complex is about 2:1 (wt/wt).  
     
     
         9 . The method of  claim 1  in which the complex-comprises apolipoprotein and sphingomyelin.  
     
     
         10 . The method of  claim 9  in which the complex further includes phosphatidylcholine.  
     
     
         11 . The method of  claim 10  in which the phosphatidylcholine is soybean phosphatidylcholine.  
     
     
         12 . The method of  claim 1  wherein from 50% to70% of the lipid content of the complex is sphingomyelin.  
     
     
         13 . The method of  claim 1  wherein from 30-50% of the lipid content of the complex is phosphatidylcholine.  
     
     
         14 . The method of  claim 1  wherein the range of 10 mg/dL to 300 mg/dL is achieved between 5 minutes and 1 day after administration.  
     
     
         15 . The method of  claim 1  in which the apolipoprotein-sphingomyelin complex is administered at a periodic interval in an amount of about 40 mg to 2 g per person per administration.  
     
     
         16 . The method of  claim 15  in which administration is intravenous administration.  
     
     
         17 . The method of  claim 15  in which the periodic interval is about every 3 to 15 days.  
     
     
         18 . The method of  claim 15  in which the periodic interval is about every 5 to 10 days.  
     
     
         19 . The method of  claim 15  in which the periodic interval is about every 10 days.  
     
     
         20 . The method of  claim 15  in which the periodic interval is several times per day, wherein the dose does not reach a daily toxic dose.  
     
     
         21 . The method of  claim 15  in which administration is by slow infusion with a duration of more than one hour.  
     
     
         22 . The method of  claim 15  in which administration is by rapid infusion of one hour or less.  
     
     
         23 . The method of  claim 15  in which administration is by a single bolus injection.  
     
     
         24 . The method of  claim 1  in which the complex is co-administered with bile-acid resins, niacin, statins or fibrates.  
     
     
         25 . A method of treating a disease associated with dyslipidemia, comprising administering to a subject an apolipoprotein-sphingomyelin complex in an amount effective to achieve a circulating plasma concentrations of a HDL-cholesterol fraction between 10% and 1000% of the initial HDL-cholesterol fraction concentration before administration.  
     
     
         26 . The method of  claim 25  in which the disease associated with dyslipidemia is selected from the group consisting of coronary heart disease; coronary artery disease; cardiovascular disease, hypertension, restenosis, vascular or perivascular diseases; dyslipidemic disorders; dyslipoproteinemia; high levels of low density lipoprotein cholesterol; high levels of very low density lipoprotein cholesterol; low levels of high density lipoproteins; high levels of lipoprotein Lp(a) cholesterol; high levels of apolipoprotein B; atherosclerosis (including treatment and prevention of atherosclerosis); hyperlipidemia; hypercholesterolemia; familial hypercholesterolemia (FH); familial combined hyperlipidemia (FCH); lipoprotein lipase deficiencies, such as hypertriglyceridemia, hypoalphalipoproteinemia, and hypercholesterolemialipoprotein.  
     
     
         27 . The method of  claim 25  in which the apolipoprotein is selected from the group consisting of preproapoliprotein, preproApoA-I, proApoA-I, ApoA-I, preproApoA-II, proApoA-II, ApoA-II, preproApoA-IV, proApoA-IV, ApoA-IV, ApoA-V, preproApoE, proApoE, ApoE, preproApoA-I Milano , proApoA-I Milano , ApoA-I Milano , preproApoA-I Paris , proApoA-I Paris , and ApoA-I Paris .  
     
     
         28 . The method of  claim 27  in which the apolipoprotein is a homodimer.  
     
     
         29 . The method of  claim 27  in which the apolipoprotein is a heterodimer.  
     
     
         30 . The method of  claim 25  in which the ratio of SM:apolipoprotein of the complex is in the range of 1:1 to 200:1 (mole/mole).  
     
     
         31 . The method of  claim 25  in which the ratio of SM:apolipoprotein of the complex is in the range of 1:2 to 200:1 (mole/mole).  
     
     
         32 . The method of  claim 25  in which the ratio of SM:apolipoprotein of the complex is about 1:2 (wt/wt).  
     
     
         33 . The method of  claim 25  wherein the circulating plasma concentration of the HDL-cholesterol fraction is achieved between 5 minutes and 1 day after administration.  
     
     
         34 . The method of  claim 25  in which the complex comprises apolipoprotein and sphingomyelin.  
     
     
         35 . The method of  claim 34  in which the complex further includes phosphatidylcholine.  
     
     
         36 . The method of  claim 35  in which the phosphatidylcholine is soybean phosphatidylcholine.  
     
     
         37 . The method of  claim 25  wherein from 50% to70% of the lipid content of the complex is sphingomyelin.  
     
     
         38 . The method of  claim 25  wherein from 30-50% of the lipid content of the complex is phosphatidylcholine.  
     
     
         39 . The method of  claim 25  in which the apolipoprotein-sphingomyelin complex is administered at a periodic interval in an amount of about 40 mg to 2 g per person per administration.  
     
     
         40 . The method of  claim 39  in which administration is intravenous administration.  
     
     
         41 . The method of  claim 39  in which the periodic interval is about every 3 to 15 days.  
     
     
         42 . The method of  claim 39  in which the periodic interval is about every 5 to 10 days.  
     
     
         43 . The method of  claim 39  in which the periodic interval is about every 10 days.  
     
     
         44 . The method of  claim 39  in which the periodic interval is several times per day, wherein the dose does not reach a daily toxic dose.  
     
     
         45 . The method of  claim 39  in which administration is by slow infusion with a duration of more than one hour.  
     
     
         46 . The method of  claim 39  in which administration is by rapid infusion of one hour or less.  
     
     
         47 . The method of  claim 39  in which administration is by a single bolus injection.  
     
     
         48 . The method of  claim 39  in which the complex is co-administered with bile-acid resins, niacin, statins, or fibrates.  
     
     
         49 . A method of treating dyslipidemia or a disease associated with dyslipidemia, comprising administering to a subject an apolipoprotein-sphingomyelin complex in an amount effective to achieve a circulating plasma concentration of a HDL-cholesterol fraction between 30 and 300 mg/dL.  
     
     
         50 . A method of treating dyslipidemia or a disease associated with dyslipidemia, comprising administering to a subject an apolipoprotein-sphingomyelin complex in an amount effective to achieve a circulating plasma concentration of cholesteryl esters between 30 and 300 mg/dL.  
     
     
         51 . The method of  claim 49  wherein the circulating plasma concentration of the HDL-cholesterol fraction is achieved between 5 minutes and 1 day after administration.  
     
     
         52 . The method of  claim 49  wherein the circulating plasma concentration of cholesteryl esters is achieved between 5 minutes and 1 day after administration.