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

摘要

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.