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.

Description

[0001] This application claims priority to U.S. Provisional Application Serial Number 60 / 381,512, filed May 17, 2002, incorporated herein by reference in its entirety.1. TECHNICAL FIELD[0002] The invention provides methods of treating or preventing a disease, condition or disorder associated with dyslipidemia with apolipoprotein-sphingomyelin complexes or pharmaceutical compositions thereof. The invention further provides compositions for treating or preventing a disease, condition or disorder associated with dyslipidemia and methods for the production of the compositions.2. BACKGROUND OF THE INVENTION[0003] Circulating cholesterol is carried by plasma lipoproteins--complex particles of lipid and protein composition that transport lipids in the blood. Four major classes of lipoprotein particles circulate in plasma and are involved in the fat-transport system: chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). Chylomic...

AI Technical Summary

Benefits of technology

[0040] Quite surprisingly, it has been discovered that when apolipoproteins such as ApoA-I are administered in the form of apolipoprotein-sphingomyelin ("Apo-SM") complexes, far less apolipoprotein is required to achieve the same or better cholesterol mobilization and, hence, therapeutic benefit, than that provided by other apolipoprotein-lipid complexes. For example, whereas soybean phosphatidylcholine ("soybeanPC") treatment regimens require administration of from 20-50 mg / kg (or 1-4 g / person) apolipoprotein every 2-5 days (i.v.), treatment regimens according to the invention require the administration of only 0.05 to 25 mg / kg (40 mg to 2 g per person) of apolipoprotein every 2-10 days (i.v.). Thus, the methods of the invention reduce by 2- to 25-fold the amount of apolipoprotein required for therapeutic benefit, thereby reducing substantially the cost of treatment, making the treatment regimen more convenient for the patient and perhaps reducing possible adverse effects associated with administration of the drug.

[0041] It has further been discovered that the mobilization of cholesterol (elevation of HDL-cholesterol above a baseline level before administration, wherein the baseline level is an initial level of HDL-cholesterol, or is a level known to one of skill in the art as a level that the patient in question would have, or an individual of the size and gender of the would have, prior to administration of a drug) is significantly sustained for a longer period of time for proApoA-I-SM complexes, i.e., longer than that of conventional apolipoprotein-phosphol-ipid complexes. Thus, treatments according to the invention may be less frequent than current treatment protocols, typically about every 2 to 10 days, as compared with about every 2 to 5 days, without loss of therapeutic benefit. Furthermore, a decreased dose may be administered with the same frequency. In many embodiments, administration is about every 5 to 10 days, significantly reducing the number of clinic or hospital visits required by the patient.

[0043] Use of the ApoA-I-SM complexes according to the invention is also advantageous because lower anticipated doses of the volume of ApoA-I-SM complexes infused or injected leads to faster and easier administration and improved patient comfort.

[0044] Use of the ApoA-I-SM complexes according to the invention is further advantageous because SM is a much more chemically stable lipid than soybean phosphatidylcholine (soybean PC), hence there is greater stability of ApoA-I complexes and longer product shelf-life compared to convention complexes.

Problems solved by technology

Indeed, high serum levels of HDLs are regarded as a negative risk factor.

However, each has its own drawbacks and limitations in terms of efficacy, side-effects and qualifying patient population.

The use of such resins at best, however, only lowers serum cholesterol levels by about 20%, and is associated with gastrointestinal side-effects, including constipation and certain vitamin deficiencies.

Moreover, since the resins bind other drugs, other oral medications must be taken at least one hour before or four to six hours subsequent to ingestion of the resin; thus, complicating heart patient's drug regimens.

However, serum HDL cholesterol levels are only moderately increased.

Niacin can increase HDL when used at adequate doses, however, its usefulness is limited by serious side effects when used at such high doses.

Although serum cholesterol may be reduced in certain patient subpopulations, the biochemical response to the drug is variable, and is not always possible to predict which patients will obtain favorable results.

Atromid-S.RTM. has not been shown to be effective for prevention of coronary heart disease.

However, the lipid response is heterogeneous, especially among different patient populations.

Indeed, no efficacy was observed in patients with established coronary heart disease.

Serious side-effects are associated with the use of fibrates including toxicity such as malignancy, (especially gastrointestinal cancer), gallbladder disease and an increased incidence in non-coronary mortality.

Estrogen treatment is, of course, limited to a specific patient population (postmenopausal women) and is associated with serious side effects including induction of malignant neoplasms, gall bladder disease, thromboembolic disease, hepatic adenoma, elevated blood pressure, glucose intolerance, and hypercalcemia.

The therapeutic use of ApoA-I, ApoA-I.sub.Milano, ApoA-I.sub.Paris and other variants, as well as reconstituted HDL, is presently limited, however, by the large amount of apolipoprotein required for therapeutic administration and by the cost of protein production, considering the low overall yield of production.

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