Method of forcing the reverse transport of cholesterol from a body part to the liver while avoiding harmful disruptions of hepatic cholesterol homeostasis and pharmaceutical compositions and kit related thereto

Abstract

The present invention provides various methods, systems and compositions for forcing the reverse transport of cholesterol from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations, and other significant components of living biological systems. The method comprises the step of parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period whereby said liposomes pick-up said cholesterol during said treatment period. The method optionally includes the step of periodically assaying plasma LDL concentrations with an assay during said treatment period to asess said plasma LDL concentrations and obtain an LDL profile, and adjusting said parenteral administration in response to said LDL profile. Exemplary assays are selected from the group consisting of an assay of plasma esterified cholesterol, an assay of plasma apolipoprotein-B, a gel filtration assay of plasma, an ultracentrifugal assay of plasma, a precipitation assay of plasma, and a immuno turbidometric assay of plasma. Generally the compositions described herein include large liposomes of a size and shape larger than fenestrations of an endothelial layer lining hepatic sinusoids in said liver, whereby said liposomes are too large to readily penetrate said fenestrations. Therapeutically effective amounts of said compositions include in the range of 10 mg to 1600 mg phospholipid per kg body weight per dose. The large liposomes are selected from the group consisting of uni-lamellar liposomes and multi-lamellar liposomes. In variants, the liposomes have diameters larger than about 50 nm, diameters larger than about 80 nm, and diameters larger than about 100 nm. The methods optionally include the step of enhancing tissue penetration of a cholesterol acceptor by co-administration of an effective amount of a compound, said compound selected from the group consisting of a small acceptor of cholesterol and a drug that increases endogenous small acceptors of cholesterol. The small acceptor is selected from the group consisting of a high-density lipoprotein, a phospholipid protein complex having a group selected from the group consisting of apoA-I, apoA-II, apoA-IV, apoE, synthetic fragments thereof, natural fragments thereof, an amphipathic protein, and an amphipathic peptide, said protein substantially free of phospholipid, small phospholipid liposomes, and a small cholesterol acceptor. The includes an agent that raises physiologic HDL concentrations, said agent selected from the group consisting of nicotinic acid, ethanol, a fibric acid, a cholesterol synthesis inhibitor, a drug that increases HDL concentrations, and derivatives thereof. The invention further provides a method of, and composition for regulating hepatic parenchymal cell cholesterol content and gene expression by the steps described herein. Other systems, and compositions for treating, and improving various medical techniques are also described.

1 . A method of forcing the reverse transport of cholesterol from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations comprising the step of: 
 parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period    whereby said liposomes pick-up said cholesterol during said treatment period.    
     
     
         2 . The method in accordance with  claim 1  further comprising the step of periodically assaying plasma LDL concentrations with an assay during said treatment period to assess said plasma LDL concentrations and obtain an LDL profile, and adjusting said parenteral administration in response to said LDL profile.  
     
     
         3 . The method in accordance with  claim 2  in which said assay is selected from the group consisting of an assay of plasma esterified cholesterol, an assay of plasma apolipoprotein-B, a gel filtration assay of plasma, an ultracentrifugal assay of plasma, a precipitation assay of plasma, and a immuno turbidometric assay of plasma.  
     
     
         4 . The method in accordance with  claim 1  in which the large liposomes are of a size and shape larger than fenestrations of an endothelial layer lining hepatic sinusoids in said liver, 
 whereby said liposomes are too large to readily penetrate said fenestrations.  
 
     
     
         5 . The method in accordance with  claim 1  in which the therapeutically effective amount is in the range of 10 mg to 1600 mg phospholipid per kg body weight per dose.  
     
     
         6 . The method in accordance with  claim 1  in which the liposomes are given periodically during said treatment period.  
     
     
         7 . The method in accordance with  claim 1  in which the large liposomes are selected from the group consisting of uni-lamellar liposomes and multi-lamellar liposomes.  
     
     
         8 . The method in accordance with  claim 1  in which the liposomes have diameters larger than about 50 nm.  
     
     
         9 . The method in accordance with  claim 1  in which the liposomes have diameters larger than about 80 nm.  
     
     
         10 . The method in accordance with  claim 1  in which the liposomes have diameters larger than about 100 nm.  
     
     
         11 . The method in accordance with  claim 1  in which parenteral administration is selected from the group of intravenous administration, intra-arterially administration, intramuscular administration, subcutaneous administration, transdermal administration, and intraperitoneal administration.  
     
     
         12 . The method in accordance with  claim 1  further comprising the step of enhancing tissue penetration of a cholesterol acceptor by co-administration of an effective amount of a compound, said compound selected from the group consisting of a small acceptor of cholesterol and a drug that increases endogenous small acceptors of cholesterol.  
     
     
         13 . The method in accordance with  claim 12  in which said small acceptor is selected from the group consisting of a high-density lipoprotein, a phospholipid protein complex having a group selected from the group consisting of apoA-I, apoA-II, apoA-IV, apoE, synthetic fragments thereof, natural fragments thereof, an amphipathic protein, and an amphipathic peptide, said protein substantially free of phospholipid, small phospholipid liposomes, and a small cholesterol acceptor; said drug including an agent that raises physiologic HDL concentrations, said agent selected from the group consisting of nicotinic acid, ethanol, a fibric acid, a cholesterol synthesis inhibitor, a drug that increases HDL concentrations, and derivatives thereof.  
     
     
         14 . The method in accordance with  claim 12  in which said co-administration of said compound is simultaneous with said parenteral administration of said large liposomes.  
     
     
         15 . The method in accordance with  claim 14  in which said co-administration of said compound is separated in time from said parenteral administration of said therapeutically effective amount of a multiplicity of said large liposomes by an effective time period.  
     
     
         16 . The method in accordance with  claim 13  in which said effective time period is in the range of 1 minute to two weeks.  
     
     
         17 . A method of regulating hepatic parenchymal cell cholesterol content, said cell having at least one gene selected from the group consisting of a gene for an LDL receptor, a gene for HMG-CoA reductase, a gene for cholesterol 7-alphahydroxylase, and a gene regulating a function involved in cholesterol homeostasis; and, homeostasis thereof, comprising the step of: 
 parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol during a treatment period.    
     
     
         18 . The method in accordance with  claim 17  further comprising the steps of periodically assaying plasma LDL concentrations with an assay during said treatment period to assess said plasma LDL and to obtain an LDL profile, and adjusting said parenteral administration in response to said LDL profile.  
     
     
         19 . The method in accordance with  claim 18  in which said assay is selected from the group consisting of an assay of plasma esterified cholesterol, an assay of plasma apolipoprotein-B, a gel filtration assay of plasma, an ultracentrifugal assay of plasma, a precipitation assay of plasma, and a immuno turbidometric assay of plasma.  
     
     
         20 . The method in accordance with  claim 17  further comprising the step of enhancing tissue penetration of a cholesterol acceptor with co-administration of an effective amount of a compound, said compound selected from the group consisting of a small acceptor of cholesterol and a drug that increases endogenous small acceptors of cholesterol.  
     
     
         21 . The method in accordance with  claim 20  in which said small acceptor is selected from the group consisting of a high-density lipoprotein, a phospholipid protein complex having a group selected from the group consisting of apoA-I, apoA-II, apoA-IV, apoE, synthetic fragments thereof, natural fragments thereof, an amphipathic protein, and an amphipathic peptide, said protein substantially free of phospholipid, small phospholipid liposomes, and a small cholesterol acceptor; said drug including an agent that raises physiologic HDL concentrations, said agent selected from the group consisting of nicotinic acid, ethanol, a fibric acid, a cholesterol synthesis inhibitor, a drug that increases HDL concentrations, and derivatives thereof.  
     
     
         22 . The method in accordance with  claim 20  in which said co-administration of said compound is simultaneous with said administration of said large liposomes.  
     
     
         23 . The method in accordance with  claim 20  in which said co-administration of said compound is separated in time from said parenteral administration of said therapeutically effective amount of a multiplicity of said large liposomes by an effective time period.  
     
     
         24 . The method in accordance with  claim 26  in which said effective time period is in the range of 1 minute to two weeks.  
     
     
         25 . The method in accordance with  claim 17  in which the therapeutically effective amount is in the range of 10 to 1600 mg/kg/dose.  
     
     
         26 . The method in accordance with  claim 17  in which the liposomes are given in repeated doses.  
     
     
         27 . The method in accordance with  claim 17  further comprising the step of controlling the expression of said genes by said parenteral administration of a multiplicity of said large liposomes.  
     
     
         28 . The method in accordance with  claim 17  in which said parenchymal cell functions in a system having hepatic sinusiods, an endothelial layer lining said hepatic sinusoids, and fenestrations; and, in which the large liposomes are of a size and shape larger than said fenestrations of said endothelial layer lining said hepatic sinusoids, 
 whereby said large liposomes are too large to readily penetrate said fenestrations.  
 
     
     
         29 . The method in accordance with  claim 17  in which the large liposomes are selected from the group consisting of uni-lamellar liposomes and multi-lamellar liposomes.  
     
     
         30 . The method in accordance with  claim 17  in which the liposomes have diameters larger than about 50 nm.  
     
     
         31 . The method in accordance with  claim 17  in which the liposomes have diameters larger than about 80 nm.  
     
     
         32 . The method in accordance with  claim 17  in which the liposomes have diameters larger than about 100 nm.  
     
     
         33 . The method in accordance with  claim 17  in which parenteral administration is selected from the group of intravenous administration, intra-arterial administration, intramuscular administration, subcutaneous administration, transdermal administration, and intraperitoneal administration.  
     
     
         34 . A method of suppressing hepatic expression of a cholesterol ester transfer protein gene in vivo comprising the step of: 
 parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids, said phospholipids selected from the group of phospholipids substantially free of sterol and phospholipids containing sterol, for an effective period of time,    whereby plasma LDL and HDL are controlled as a result of said administration.    
     
     
         35 . The method in accordance with  claim 34  further comprising the step of periodically assaying plasma LDL concentrations with an assay during said treatment period to assess said plasma LDL.  
     
     
         36 . The method in accordance with  claim 35  in which said assay is selected from the group consisting of an assay of plasma esterified cholesterol, an assay of plasma apolipoprotein-B, a gel filtration assay of plasma, an ultracentrifugal assay of plasma, a precipitation assay of plasma, and a immuno turbidometric assay of plasma.  
     
     
         37 . The method in accordance with  claim 34  in which the liposomes are given periodically.  
     
     
         38 . The method in accordance with  claim 34  in which the therapeutically effective amount is in the range of 10 mg/kg/dose to 1600 mg/kg/dose.  
     
     
         39 . The method in accordance with  claim 34  further comprising the step of enhancing tissue penetration of a cholesterol acceptor with co-administration of an effective amount of a compound, said compound selected from the group consisting of a small acceptor of cholesterol and a drug that increases endogenous small acceptors of cholesterol.  
     
     
         40 . The method in accordance with  claim 39  in which said small acceptor is selected from the group consisting of a high-density lipoprotein, a phospholipid protein complex having a group selected from the group consisting of apoA-I, apoA-II, apoA-IV, apoE, synthetic fragments thereof, natural fragments thereof, an amphipathic protein, and an amphipathic peptide, said protein substantially free of phospholipid, small phospholipid liposomes, and a small cholesterol acceptor, said drug including an agent that raises physiologic HDL concentrations, said agent selected from the group consisting of nicotinic acid, ethanol, a fibric acid, a cholesterol synthesis inhibitor, a drug that increases HDL concentrations, and derivatives thereof.  
     
     
         41 . The method in accordance with  claim 39  further comprising the step of periodically assaying plasma LDL concentrations with an assay during said treatment period to assess said plasma LDL.  
     
     
         42 . The method in accordance with  claim 41  in which said assay is selected from the group consisting of an assay of plasma esterified cholesterol, an assay of plasma apolipoprotein-B, a gel filtration assay of plasma, an ultracentrifugal assay of plasma, a precipitation assay of plasma, and a immuno turbidometric assay of plasma.  
     
     
         43 . The method in accordance with  claim 39  in which said co-administration of said compound with the administration of said large liposomes is simultaneous.  
     
     
         44 . The method in accordance with  claim 39  in which said co-administration of said compound is separated in time from said parenteral administration of said therapeutically effective amount of a multiplicity of said large liposomes by an effective time period.  
     
     
         45 . The method in accordance with  claim 44  in which said separation in time is in the range of 1 minute to two weeks.  
     
     
         46 . The method in accordance with  claim 34  in which the large liposomes are of a size and shape larger than fenestrations of an endothelial layer lining hepatic sinusoids, 
 whereby said large liposomes are too large to readily penetrate said fenestrations.  
 
     
     
         47 . The method in accordance with  claim 34  in which the large liposomes are selected from the group consisting of uni-lamellar liposomes and multi-lamellar liposomes.  
     
     
         48 . The method in accordance with  claim 34  in which the liposomes have diameters larger than about 50 nm.  
     
     
         49 . The method in accordance with  claim 34  in which the liposomes have diameters larger than about 80 nm.  
     
     
         50 . The method in accordance with  claim 34  in which the liposomes have diameters larger than about 100 nm.  
     
     
         51 . A method of suppressing the rise in plasma LDL concentrations after administration of an agent having small acceptors of cholesterol comprising the step of: 
 co-administering an effective amount of a multiplicity of an agent having large liposomes comprised of phospholipids substantially free of sterol with said administration of said agent having said small acceptors.    
     
     
         52 . The method in accordance with  claim 51  in which said agent having small acceptors consists essentially of small acceptors and in which said agent having large liposomes consists essentially of large liposomes.  
     
     
         53 . The method in accordance with  claim 51  in which said co-administration of said agent having large liposomes is simultaneous with said administration of said agent having small acceptors.  
     
     
         54 . The method in accordance with  claim 51  in which said co-administration of said agent having large liposomes is separated in time from said administration of said agent having small acceptors by an effective time period.  
     
     
         55 . The method in accordance with  claim 54  in which said effective time period is in the range of 1 minute to two weeks.  
     
     
         56 . A method of diagnosing a side-effect of reverse transport of cholesterol from peripheral tissues to the liver in vivo accompanying parenteral administration of a multiplicity of large liposomes and small liposomes during a treatment period, comprising the step of: 
 periodically assaying plasma LDL concentrations with an assay to obtain an assayed LDL concentration, said assay selected from the group consisting of an assay of plasma esterified cholesterol, an assay of plasma apolipoprotein-B, a gel filtration assay of plasma, an ultracentrifugal assay of plasma, and a precipitation assay having a component, said component selected from the group consisting of polyanions, divalent cations, and antibodies, an assay of triglyceride in plasma, and an immunoturbidometric assay or plasma, to determine the level of a therapeutically effective amount of each of said liposomes,    whereby a side effect of administration of said liposomes is diagnosed and effectively regulated.    
     
     
         57 . A method of diagnosing and treating a side-effect of reverse transport of cholesterol from peripheral tissues to the liver in vivo accompanying parenteral administration of a multiplicity of large liposomes and small liposomes during a treatment period, comprising the steps of: 
 periodically assaying plasma LDL concentrations with an assay to obtain an assayed LDL concentration, said assay selected from the group consisting of an assay of plasma esterified cholesterol, an assay of plasma apolipoprotein-B, a gel filtration assay of plasma, an ultracentrifugal assay of plasma, and a precipitation assay having a component, said component selected from the group consisting of polyanions, divalent cations, and antibodies, an assay of triglyceride in plasma, and an immunoturbidometric assay or plasma, to determine the level of a therapeutically effective amount of each of said liposomes; and,    adjusting said therapeutically effective amount of each of said small and large liposomes in response to said assayed LDL concentration during said treatment period.    
     
     
         58 . The method in accordance with  claim 57  further comprising the steps of co-administering a pharmaceutical agent to lower said LDL concentration with said liposome administration, and adjusting the administration of said agent responsive to said assayed LDL concentration.  
     
     
         59 . An improved method of dialysis treatment of a patient in which said improvement comprises the step of: 
 administering a therapeutically effective amount of an agent, said agent selected from the group consisting of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol and small acceptors, during treatment of said patient.    
     
     
         60 . The method in accordance with  claim 59  in which said dialysis treatment is selected from the group consisting of hemodialysis, peritoneal dialysis, and rectal dialysis.  
     
     
         61 . The method in accordance with  claim 59  in which said agent is added directly to blood or blood plasma of said patient.  
     
     
         62 . The method in accordance with  claim 59  in which said administration of said agent is selected from the group consisting of extracorporeal administration and intracorporal administration.  
     
     
         63 . The method in accordance with  claim 59  in which said agent is added directly to dialysate of said patient.  
     
     
         64 . The method in accordance with  claim 59  in which plasma component concentrations are periodically assayed, said components selected from the group consisting of LDL, HDL, unesterified cholesterol, phospholipid, and liposome acceptors.  
     
     
         65 . The method in accordance with  claim 59  in which said patient has cells, and further comprising the steps of treating said patient's cells, together or after separation into erythrocytes, leukocytes, and platelets, extracorporeally with liposomes, and periodically assaying a component, said component selected from the group consisting of cellular cholesterol, phospholipid, fluidity, fragility, and cell function.  
     
     
         66 . The method in accordance with  claim 63  in which said dialysate is assayed for cholesterol, the determine the effectiveness of said treatment.  
     
     
         67 . An improved method of angioplasty in which said improvement comprises the step of: 
 administering a therapeutically effective amount of an agent, said agent selected from the group consisting of a large liposome comprised of phospholipids substantially free of sterol and small acceptors, during the treatment of said patient.    
     
     
         68 . The method in accordance with  claim 67  in which said administration of said agent occurs at an effective period of time.  
     
     
         69 . The method in accordance with  claim 67  in which said administration of said agent occurs simultaneously with said angioplasty.  
     
     
         70 . The method in accordance with  claim 68  in which said effective period of time is in the range of 1 minute to two years from the time of said angioplasty.  
     
     
         71 . An improved method of reducing the lipid content of arterial lesions comprising the steps of: 
 inducing the reverse transport of cholesterol from peripheral tissues to the liver in vivo by administering a therapeutically effective amount of an agent to a subject, said agent selected from the group consisting of large liposomes comprised of phospholipids substantially free of sterol and small acceptors;    periodically monitoring plasma LDL concentrations of said subject to obtain an LDL concentration profile;    adjusting said therapeutically effective amount of said agent responsive to said LDL concentration profile; and,    administering a pharmaceutical agent to said subject, said agent selected from the group consisting of compounds to lower LDL concentrations, small acceptors, and compounds to raise HDL concentrations, responsive to said LDL concentration profile,    whereby said reduction in lipid content of said arterial lesions is effectively treated and monitored over a treatment period.    
     
     
         72 . The method in accordance with  claim 71  in which said arterial lesions comprise lipid rich, rupture prone type IV and type V arterial lesions, 
 whereby plaque rupture, thrombosis, and tissue infarction are greatly reduced.  
 
     
     
         73 . An improved method of assessing the efficiency of a treatment for reducing the lipid content of arterial lesions, said lesions coming into contact with plasma and a component thereof comprising the steps of: 
 inducing the reverse transport of cholesterol from peripheral tissues to the liver in vivo by administering a therapeutically effective amount of an agent to a subject, said agent selected from the group consisting of large liposomes comprised of phospholipids substantially free of sterol and small acceptors; and,    periodically monitoring said plasma component with an assay, said assay selected from the group consisting of an assay for plasma unesterified cholesterol and phospholipid, an assay of plasma cholesterol ester transfer protein activity, an assay of bile acids and cholesterol in stool an assay of bile acids and cholesterol in bile, an assay of hepatic gene expression in a liver biopsy, an assay of gene expression in a peripheral blood leukocytes, said gene comprising a gene involved in cholesterol metabolism, an assay of plasma LDL concentration, and a vascular imaging technique.    
     
     
         74 . The method in accordance with  claim 73  in which said vascular imaging technique is selected from the group consisting of cardiac catherization, magnetic resonance imaging, ultrasound, and ultrafast CT.  
     
     
         75 . A method of beneficially altering arterial function and controlling plasma LDL concentrations and hepatic cholesterol homeostasis in vivo comprising the step of: 
 parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period.    
     
     
         76 . The method in accordance with  claim 75  further comprising the step of taking a measurement of arterial function, said measurement selected from the group consisting of a measurement of endothelial-derived relaxing factor, a measurement of intracellular calcium concentration in arterial cells, a measurement of arterial cell proliferation, an assay of arterial enzymes, an assay in the presence of calcium channel blockers, an assay of arterial uptake of liposomes, an assay of arterial accumulation of liposomes, and an assay of arterial retention of liposomes.  
     
     
         77 . The method in accordance with  claim 76  in which the measurement of endothelial-derived relaxing factor is selected from the group consisting of a functional determination of endothelial-dependant arterial relaxation and chemical determination of production of said endothelial relaxing factor.  
     
     
         78 . A method of beneficially altering blood platelet function while controlling plasma LDL concentrations, arterial function, hepatic cholesterol homeostasis and said platelet function in vivo comprising the step of: 
 parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period.    
     
     
         79 . The method in accordance with  claim 78  further comprising the step of taking a measurement of platelet function, said measurement selected from the group consisting of a measurement of a ratio of cholesterol to phospholipid in said platelets, a measurement of platelet reactivity, a measurement of platelet metabolic markers, a measurement of platelet calcium fluxes, a measurement of intracellular calcium, a measurement of platelet aggregability, and a measurement of platelet granule release.  
     
     
         80 . The method in accordance with  claim 78  further comprising the step of taking a measurement of said arterial function, said measurement selected from the group consisting of a measurement of endothelial-derived relaxing factor, a measurement of intracellular calcium concentration in arterial cells, a measurement of arterial cell proliferation, and an assay of arterial enzymes.  
     
     
         81 . The method in accordance with  claim 80  in which the measurement of endothelial relaxing factor is selected from the group consisting of a functional determination of endothelial-dependant arterial relaxation and chemical determination of production of said endothelial relaxing factor.  
     
     
         82 . A method of forcing the reverse transport of cholesterol from peripheral tissues to the liver in vivo and delivering said cholesterol to said liver while controlling plasma LDL concentrations, comprising the step of: 
 delivering the cholesterol to the liver at a sufficiently slow rate so that hepatic cholesterol homeostasis is free of substantial disruption by administration of an agent, said agent selected from the group consisting of large liposomes and small acceptors to a subject, said large liposomes being substantially incapable of penetrating endothelial fenestrae of said liver and substantially incapable of interacting with hepatic parenchymal cells.    
     
     
         83 . The method in accordance with  claim 82  in which the large liposomes are chemical compositions of liposomes of a size so that said liposomes are cleared slowly by the liver.  
     
     
         84 . The method in accordance with  claim 82  in which the step of delivering comprises slowly infusing said liposomes.  
     
     
         85 . The method in accordance with  claim 82  in which the step of delivering comprises administering small doses of said liposomes, separated in time, to avoid increasing said LDL concentration.  
     
     
         86 . The method in accordance with  claim 82  further comprising the step of periodically assaying said plasma LDL concentrations with an assay to obtain an assayed LDL concentration, said assay selected from the group consisting of an assay of plasma esterified cholesterol, an assay of plasma apolipoprotein-B, a gel filtration assay of plasma, an ultracentrifugal assay of plasma, and a precipitation assay having a component, said component selected from the group consisting of polyanions, divalent cations, and antibodies, an ultracentrifugal assay of plasma, a precipitation assay of plasma, and a immuno turbidometric assay of plasma, to determine the level of a therapeutically effective amount of each of said liposomes.  
     
     
         87 . A method of forcing the reverse transport of cholesterol from peripheral tissues to the liver in vivo and delivering said cholesterol to primarily to hepatic Kupffer cells rather than hepatic parenchymal cells so that hepatic cholesterol homeostasis is not harmfully disrupted and controlling said homeostasis and effecting a plasma component, comprising the step of: 
 administering an effective amount of liposomes, said liposomes selected from the group of liposomes being substantially incapable of penetrating endothelial fenestrae of said liver and incapable of subsally interacting with hepatic parenchymal cells and said liposomes being of a size, composition or shape so that are directed away from said hepatic parenchymal cells.    
     
     
         88 . The method in accordance with  claim 87  further comprising the step of periodically monitoring said plasma component with an assay, said assay selected from the group consisting of an assay for plasma unesterified cholesterol and phospholipid, an assay of plasma cholesterol ester transfer protein activity, an assay of bile acids and cholesterol in stool, an assay of bile acids and cholesterol in bile, an assay of hepatic gene expression in a liver biopsy, an assay of hepatic gene expression in a peripheral blood leukocytes, said gene comprising a gene involved in cholesterol metabolism, an assay of plasma LDL concentration, and a vascular imaging technique.  
     
     
         89 . A method of catabolizing cholesterol with macrophages in vivo and also affecting a plasma component or structural aspects of an artery, comprising the step of: 
 administering an effective amount of liposomes to a subject substantially free of cholesterol and being of a size and composition such that said liposomes are capable of being taken up by said marcrophages and capable of being catabolized by said macrophages,    whereby said cholesterol is mobilized by said liposomes resulting in said liposomes being taken up by said macrophages and catabolized.    
     
     
         90 . The method in accordance with  claim 89  further comprising the step of periodically monitoring said plasma component with an assay, said assay selected from the group consisting of an assay for plasma unesterified cholesterol and phospholipid, an assay of plasma cholesterol ester transfer protein activity, an assay of bile acids and cholesterol in stool, an assay of bile acids and cholesterol in stool, an assay of hepatic gene expression in a liver biopsy, an assay of gene expression in a peripheral blood leukocytes, said gene comprising a gene involved in cholesterol metabolism, an assay of plasma LDL concentration, and a vascular imaging technique.  
     
     
         91 . A method of forcing the reverse transport of cholesterol from a body part, said body part selected from the group of peripheral tissues, cells, and platelets, in vivo comprising the step of: 
 administering for a treatment period a therapeutically effective amount of a multiplicity of non-liposomal particles for cholesterol depletion of peripheral tissues while avoiding harmful disruptions of hepatic cholesterol homeostasis, said particles being selected from the group of a particle substantially free of cholesterol and particles free of cholesterol.    
     
     
         92 . The method in accordance with  claim 91  in which said non-liposomal particles are selected from the group consisting of triglyceride-phospholipid emulsions, said emulsions selected from the group of emulsions that are not taken up rapidly by hepatic parenchymal cells, emulsions that are not taken up to a large extent by parenchymal cells, and triglyceride-phospholipid-protein emulsions.  
     
     
         93 . A method of delivering a drug in vivo and avoiding harmful disruptions of hepatic cholesterol homeostasis, comprising the steps of: 
 entrapping said drug with an agent, said agent selected from the group consisting of a cholesterol poor liposome, a cholesterol free liposome, an emulsion, a liposome primarily taken up slowly by hepatic parenchymal cells, an emulsion primarily taken up slowly by hepatic parenchymal cells, said agent selected from the group consisting of an agent with a protein and an agent without protein to obtain an entrapped drug; and, administering a therapeutically effective amount of said entrapped drug for a treatment period.    
     
     
         94 . The method in accordance with  claim 93  in which the step of administering comprises the step of slowly infusing said entrapped drug.  
     
     
         95 . The method in accordance with  claim 93  in which the step of administering comprises the step of administering small doses of said agent, appropriately separated in time, to avoid harmfull disruptions in hepatic cholesterol homeostasis.  
     
     
         96 . The method in accordance with  claim 93  in which the step of administering includes using low doses of said agent, 
 whereby disrupting hepatic cholesterol homeostasis is avoided.  
 
     
     
         97 . A method of controlling plasma LDL levels in vivo and lowering blood viscosity, comprising the step of: 
 parenteral administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period, said effective amount administered in a dosage, said dosage selected from a single dose and repeated doses.    
     
     
         98 . The method in accordance with  claim 97  further comprising the steps of taking a measurement, said measurement selected from the group consisting of a measurement of blood flow in a carotid artery, measurement of blood flow in a coronary artery, a measurement of blood flow in a lower limb, an ultrasound measurement of blood flow in other vessels, an MRI measurement of blood flow, a radioisotope tracer measurement of blood flow, and a measurement of blood viscosity.  
     
     
         99 . A method of controlling plasma LDL levels in vivo and reducing the sphingomyelin to phosphatidylcholine ratio in a cell membrane and cell aging, comprising the step of: 
 parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period, said effective amount administered in a dosage, said dosage selected from a single dose and repeated doses.    
     
     
         100 . The method in accordance with  claim 99  further comprising the step of periodically assaying said cells with an assay, said assay selected from the group consisting of an assay of sphingomyelin, an assay of phosphatidylcholine, an assay of membrane function, and an assay of cellular function.  
     
     
         101 . A method of controlling hepatic secretion of apolipoprotein-B while forcing the reverse transport of cholesterol from peripheral tissues to the liver, comprising the step of: 
 parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period, said effective amount administered in a dosage, said dosage selected from a single dose and repeated doses.    
     
     
         102 . A method of controlling hepatic expression of 7-alpha hydroxylase while forcing the reverse transport of cholesterol from peripheral tissues to the liver, comprising the step of: 
 parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period, said effective amount administered in a dosage, said dosage selected from a single dose and repeated doses.    
     
     
         103 . A method of controlling plasma LDL levels, hepatic cholesterol homeostasis, arterial enzymes, platelet function, and hepatic gene expression, comprising the step of: 
 parenterally administering a therapeutically effective amount of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol for a treatment period, said effective amount administered in a dosage, said dosage selected from a single dose and repeated doses.    
     
     
         104 . The method in accordance with claim  103  further comprising the step of diagnosing the efficacy of said administration by taking a measurement of enzyme activity, said measurement selected from the group consisting of a measurement of an arterial lipase activity, a measurement of arterial triglyceride lipase activity, a cholesterol esterase activity, a measurement of lysophospholipase activity, a cholesterol synthesis inhibitor, a drug that increases HDL concentrations, and derivatives thereof.  
     
     
         125 . An improved dialysis apparatus for the treatment of a patient in which said improvement comprises: 
 means for administering a therapeutically effective amount of an agent, said agent selected from the group consisting of a multiplicity of large liposomes comprised of phospholipids substantially free of sterol and small acceptors, during treatment of said patient.    
     
     
         126 . The apparatus of claim  125  in which said means for administering said agent is selected from the group consisting of means for extracorporeal administration and means for intracorporal administration.  
     
     
         127 . An improved angioplasty apparatus in which said improvement comprises: 
 means for administering a therapeutically effective amount of an agent, said agent selected from the group consisting of a large liposome comprised of phospholipids substantially free of sterol and small acceptors, during the treatment of said patient.    
     
     
         128 . A pharmaceutical composition for reducing the size of arterial lesions that enters the liver of a subject consisting essentially of a multiplicity of non-liposomal particles for cholesterol depletion of peripheral tissues while avoiding harmful disruptions of hepatic cholesterol homeostasis, said particles being selected from the group of particles substantially free of cholesterol and particles free of cholesterol for a treatment period.  
     
     
         129 . The pharmaceutical composition of claim  128  in which said non-liposomal particles are selected from the group consisting of triglyceride-phospholipid emulsions, said emulsions selected from the group of emulsions that are not taken up rapidly by hepatic parenchymal cells, emulsions that are not taken up to a large extent by parenchymal cells, and triglyceride-phospholipid-protein emulsions.  
     
     
         130 . A pharmaceutical composition for reducing the size of arterial lesions that enters the liver of a subject consisting essentially of a drug entrapped within an agent, said agent selected from the group consisting of a cholesterol poor liposome, a cholesterol free liposome, an emulsion, a liposome primarily taken up slowly by hepatic parenchymal cells, an emulsion primarily taken up slowly by hepatic parenchymal cells, said agent selected from the group consisting of an agent with a protein and an agent without protein.  
     
     
         131 . A pharmaceutical composition for increasing plasma HDL concentrations, while controlling plasma LDL levels, hepatic cholesterol homeostasis, and hepatic gene expression, comprising a first agent, said first agent comprising a multiplicity 
 of small liposomes to raise HDL concentrations, and a second agent, said second agent comprising large liposomes comprised of phospholipids substantially free of sterol.    
     
     
         132 . An improved pharmaceutical composition for reducing the size of arterial lesions that enters the liver of a subject, said composition consisting essentially of liposomes, in which said improvement comprises an anti-oxidant and derivatives thereof.  
     
     
         133 . The pharmaceutical composition of claim  132  in which said anti-oxidant is selected from the group consisting of vitamin E, ascorbate, probucol, carotenoids, derivates thereof, and a material resistant to oxidation.  
     
     
         134 . An improved pharmaceutical composition for reducing the size of arterial lesions that enters the liver of a subject, said improvement comprising palmitoyl-oleyl-phosphatidyl choline.  
     
     
         135 . An improved pharmaceutical composition for reducing the size of arterial lesions that enters the liver of a subject, said improvement comprising a double bond in a second fatty acyl chain of components of said composition, 
 whereby said composition is more fluid and more readily accepts cholesterol transfer from said arterial lesions.    
     
     
         136 . An improved pharmaceutical composition for reducing the size of arterial lesions that enters the liver of a subject, said improvement comprising PEG-liposomes.  
     
     
         137 . A method of treating atherosclerosis in a subject comprising the step of administering a liposome composition to said subject, said liposome composition selected from the group consisting of unilamellar liposomes and multilamellar liposomes, said liposomes having an average diameter of about 50-150 nanometers, in which LDL levels in said subject do not increase.  
     
     
         138 . A method of controlling cholesterol metabolism in hepatic parenchymal cells in a subject in vivo through cell-cell communication from Kupffer cells to said parenchymal cells, comprising the step of administering a liposome composition to said subject, said liposome composition selected from the group consisting of large unilamellar liposomes and large multilamellar liposomes, said liposomes having an average diameter of about 50-150 nanometers, in which LDL levels in said subject do not increase.  
     
     
         139 . A method in accordance with claim  138  further comprising the steps of diagnosing the efficacy of said control of said cholesterol metabolism by assaying an indicator in said subject, said indicator selected from the group consisting of plasma LDL concentrations of said subject, hepatic gene expression of said subject, plasma CETP levels of said subject, sterol excretion of controlling cholesterol metabolism in hepatic parenchymal cells in said subject, and sterol excretion in bile of said subject; and adjusting said administration in response to said assay.