1. Field of the Invention
The present invention relates to a lipoprotein (a) lowering agent and a cholesterol lowering agent, each containing a proanthocyanidin as an effective ingredient; and also to medicaments comprising these lowering agents as effective ingredients, respectively. The medicaments according to the present invention are useful for the prevention and treatment of ischemic heart diseases, arteriosclerosis, cerebrovascular dementia, diabetes, angiopathic Parkinson's diseases and the like; and for the reduction of the total blood cholesterol level without affecting HDL-cholesterol.
2. Description of the Related Art
Serum lipoprotein (a) [hereinafter abbreviated as "Lp(a)"] is rich in cholesterol, is prone to aggregation in the presence of calcium, and also tends to bond to a connective tissue such as glycosaminoglycan. The possibility of induction of lipid deposition on the arterial wall is therefore indicated in "Arteriosclerosis", 17, 639-658(1989). Further, Lp(a) bonded to glycosaminoglycan or the like is more ingestible by a macrophage and may hence be considered to act for the promotion of conversion into foam cells.
In addition, the apo (a) of an apoprotein inherent to Lp (a) is known to have high homology with plasminogen [Biochem. Biophys. Acta., 960, 91-97(1988)] and thus to inhibit the fibrinolysis system ["Biochemistry", 28, 2370-2374, 1988; Nature, 339, 303-305 (1989)].
In view of these, Lp(a) is considered to play a role in the onset and deterioration of arteriosclerosis. For ischemic heart diseases, cerebral infarction, carotid sclerosis, cerebrovascular dementia, diabetes and angiopathic Parkinson's diseases, Lp(a) is, in fact, considered to be a detrimental factor different from low-density lipoprotein cholesterol and platelet aggregates which have heretofore been considered to be dangerous ["Arteriosclerosis", 17, 639-658 (1989)].
Conventional remedial agents for hyperlipemia were developed while paying attention to their effects in lowering especially the levels of low-density lipoprotein cholesterol and triglyceride among plasma lipids, so that their effects on Lp(a) were hardly taken into account. There are even some instances where the LP(a) level tends to be increased instead of being lowered. Probucol ["Atherosclerosis, 79, 267-269(1989)], clofibrat ["Metabolism", 24, 1047-1054 (1975)], cholestyramine ["Atherosclerosis", 73, 135-141(1988)] and the like can be mentioned as examples of such agents although they are known as remedial agents for hyperlipemia. Only nicotinic acid and derivatives thereof have been recognized to have lowering effects for serum Lp(a) ["Atherosclerosis, 57, 293-301(1985); "Current Therapeutic Res. 54, 550-552(1993)].
In addition, stanozolol, asteroid, ["Biochem. Biophys. Acta., 795, 293-296(1984)] and neomycin, an antibiotic, ["Atherosclerosis, 57, 293-301(1985)] have also been recognized to have lowering effects for serum Lp(a) but involve problems in side effects and the like.
Concerning foods, there is only one report that both palm oil and fish liver oil lowered the serum Lp(a) level ["Clin. Res., 38, 250A(1990)]. It has however been reported that fish liver oil has no lowering effects for Lp(a) ["Thrombosis Res., 58, 667-668 (1990)]. This is contradictory with the results in the former report.
Moreover, there is the potential danger that use of fish liver oil or palm oil in a greater dose to enhance its effectiveness may lead to overcalorie due to fats and fatty acids contained therein. In the case of fish liver oil, there is an additional potential danger of overintake of vitamins A and D. Fish liver oil also involves the problem that the onset rates of side effects such as nausea, vomiting, diarrhea and abdominal pain are high ["Lancet", 8658, 177-181(1989)].
On the other hand, the state of a high blood cholesterol level, that is, so-called "hypercholesterolemia" is regarded to be a factor dangerous for cardiovascular diseases. As a result of epidemiological studies, it has been proved that populations who intake saturated fatty acids and cholesterol in large amounts have, with few exceptions, a relatively high serum cholesterol level and a high mortality due to coronary heart diseases.
Examples of cholesterol lowering agents conventionally employed to lower the blood cholesterol level include exocholesterol absorption inhibitors, cholesterol excretion promoters relying upon diassimilation of cholesterol into bile acid, and cholesterol biosynthesis inhibitors.
As such pharmaceuticals, a variety of agents are known. Under the circumstances, however, many of them are not fully satisfactory because their effects are not sufficient or they are chemically-synthesized products so that their safety in long-term administration cannot be guaranteed.
There is a demand for a safer cholesterol lowering agent of natural origin, particularly when used in a form incorporated in food, drink or the like.
As has been described above, the agents and food which are conventionally known to lower the serum Lp(a) level or the blood cholesterol level involve problems in safety and also in side effects when taken in a large amount.
The development of an Lp(a) lowering agent and a cholesterol lowering agent, each of which has sufficiently strong effects and without any problem in the safety for the human body still remains as an unachieved theme.
Although a close correlation has been formed between a fat intake and an onset rate of heart diseases, the onset rate of heart diseases in France is, however, low in spite of high fat intake. This is called the "French paradox". Red wine is a brewage, which has been tasted widely for many years mainly in Europe and has been consumed much particularly in France. In recent years, the relation between the "French paradox" and red wine has drawn attention ["Lancet, 339, 1523-1526 ( 1992 ) ]
USPTO Backgrounds
USPTO Backgrounds