Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Reexamination Certificate
2000-06-07
2002-04-02
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
C424S774000
Reexamination Certificate
active
06365411
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to plant extracts and the use of plant extracts for medicinal purposes. More specifically, the present invention relates to Justicia plant extracts and their use for lowering cellular cholesterol and cholesteryl ester concentration. This invention relates to the preparation by thin-layer chromatographic fractionation of an ethanolic extract from the leaves of the plant Justicia and preferably from the species
Justicia wynaadensis
(“WJ”) which possesses biological activity, and the use of such extracts for the treatment of hypercholesterolemia and atherosclerosis.
DESCRIPTION OF THE RELATED ART
Hypercholesterolemia is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol carrying lipoproteins by inhibiting cholesterol synthesis, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels which place an individual at increased risk for the development or exacerbation of atherosclerosis.
The liver has a central role in the storage, synthesis, and metabolic transformations of lipids. One major function of the liver is to package triglycerides and cholesterol, which are insoluble in plasma, into particles called lipoproteins which can be carried in the bloodstream. The liver both secretes lipoproteins and also reabsorbs them after they have exchanged their lipid loads with peripheral tissues.
Four major classes of lipoproteins are known. All have an “oildrop” core of neutral lipid (triglycerides and/or cholesteryl esters) surrounded by an amphiphilic surface layer of phospholipids, cholesterol, and apolipoproteins. The larger the “oildrop” core, the less dense is the lipoprotein particle. In decreasing order of size, the four classes are: (a) chylomicrons, which are secreted by the small intestine rather than the liver, and consist mostly of triglycerides absorbed from dietary fat; (b) very low density lipoproteins (VLDLs), which are secreted by the liver and contain mostly triglycerides; (c) low density lipoproteins (LDLs), which are generated in the liver from VLDL remnants, and contain mostly cholesteryl esters rather than triglycerides; and (d) high density lipoproteins (HDLs), which are secreted by the liver as phospholipid-rich discoidal particles, but which develop a lipid core by scavenging cholesterol from peripheral tissues.
Atherosclerosis weakens the arterial wall and narrows the flow path of blood within the vessels. Atherosclerotic lesions frequently appear in particular in the coronary arteries, producing coronary heart disease. As the plaque increases in size, the coronary arteries may become completely blocked; when that occurs, the heart muscles are deprived of oxygen from the blood and the victim suffers a “heart attack”, or myocardial infarction.
The risk of coronary heart disease increases dramatically as the plasma concentration of LDL cholesterol increases. Consequently, development of methods for lowering LDL cholesterol levels has become a major focus of medical research. The straightforward approach of reducing dietary cholesterol intake suffers from two limitations. The first is that cholesterol is present in all animal fats, and many Americans are unwilling to sacrifice their preferred diet. The second is that the liver and other tissues synthesize cholesterol de novo if the dietary supply is inadequate.
Cholesterol is an essential component of cellular membranes as well as a necessary precursor of metabolically important compounds such as bile acids and steroids. Cells obtain their necessary complement of cholesterol by taking up LDL particles through a specialized LDL receptor. The activity of the LDL receptors varies according to the cell's need for more cholesterol. Both peripheral cells and liver cells take up LDL through the receptor mechanism. However, unlike other cells, liver cells can both secrete and metabolically transform cholesterol, thereby removing it from the body. Thus when LDL receptor activity is low, the plasma LDL cholesterol level may be expected to rise, because LDL particles are not being removed from circulation as quickly as they are produced from VLDL remnants. This effect is accentuated by the fact that the liver removes VLDL remnants from circulation via the same LDL receptor; when LDL receptor activity is low, a smaller fraction of VLDL remnants is degraded, and consequently more remnants are converted into LDL particles instead. LDL receptor down-regulation thus decreases LDL clearance at the same time that the rate of LDL particle generation is increased. The result of this dual mechanism is that cholesterol levels climb markedly when LDL receptor activity decreases. It is thus believed that the ability to lower cellular cholesterol and cholesteryl esterase levels would be of great benefit in reducing the adverse effects of hypercholesterolemia. This is especially important in blood cells (monocytes) and in cells that line the blood vessels.
A number of patents in the literature disclose compounds which are useful as anti-atherosclerotic agents in general. For example, U.S. Pat. No. 4,623,662, issued De Vries on Nov. 18, 1986, discloses ureas and thioureas as ACAT inhibitors useful for reducing the cholesterol ester content of an arterial wall, inhibiting atherosclerotic lesion development, and/or treatment of mammalian hyperlipidemia. U.S. Pat. No. 4,722,927, issued to Holmes on Feb. 2, 1988, discloses disubstituted pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for inhibiting intestinal absorption of cholesterol.
In the rain forest region of Karnataka State, India, a scandent herb Justicia Wynaadensis (“JW”) known as “medicine plant” is widely consumed by the local population by incorporating its extract into desserts. This seasonal plant is believed by the local tribes to possess healing properties. The extracts of the leaves are consumed for the treatment of a variety of diseases. This is especially common in the months of June through August because of the belief that the medicinal properties reach their peak during this season. This plant is now considered to be distributed exclusively in this region of the South Indian rain forest.
However, nothing is known regarding the pharmacology or biochemistry of this plant, except that upon ingestion a purple-colored urine is noticed. In addition, there are no known literature references disclosing the extracts of this plant or their use to lower cholesterol or in the treatment of atherosclerosis.
The plant extracts of the present invention lower cellular cholesterol and cholesteryl ester concentration. In view of its rich color (bluish purple), pleasant aroma, and years of consumption by the local population its potential as a food supplement with cellular cholesterol lowering properties deserves attention.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to a method of producing a new active compound for lowering cellular cholesterol levels.
It is another object of the present invention to provide an industrially feasible method of producing aforementioned extract.
The above objects are achieved by the present invention which was completed on the basis of the discovery by the present inventor that the Justicia extract is capable of lowering cellular cholesterol. Specifically, the present invention relates to a method for preparing a composition capable of lowering cellular cholesterol and cholesteryl ester concentration comprising the steps of: preparing an aqueous extract of dried and powdered leaves of the plant Justicia by adding about 10 parts by weight of said leaves to about 90 parts by weight of about 95% water-miscible alcohol at room temperature for a time sufficient to complete dissolution, centrifuging and filtering the solution; subjecting
Norman Eric J.
Subbiah M. T. Ravi
Frost Brown Todd LLC
Lilling Herbert J.
University of Cincinnati
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