A pharmaceutical composition containing levamisole for use in the prevention and / or treatment of arteriosclerosis

Abstract

The present invention relates to the use of rebamipide in methods for preventing and / or treating arterial stiffness and related diseases such as hypertension, heart failure, myocardial infarction, stroke, peripheral arterial disease, renal failure, and chronic kidney disease. Rebamipide can also be used in methods for increasing the elasticity of arterial walls.

Description

Technical Field

[0001] The present invention relates to levamiside for use in a method for preventing and / or treating arterial wall sclerosis in a person having hypertension, heart failure, myocardial infarction, stroke, peripheral arterial disease, renal insufficiency, or chronic kidney disease, or a person at risk of these diseases.

Background Art

[0002] The walls of thick arteries, particularly the aorta, lose elasticity over time, and along with this, the hardening of the arterial wall progresses. This is at least partially due to the stepwise fragmentation and reduction of elastic fibers in the arterial wall and the accumulation of stiffer collagen fibers, partly as a compensatory mechanism for the reduction of arterial elastin and partly due to fibrosis, which often involves calcium deposition in both elastic and collagen fibers. The loss of elastic properties of the arteries is associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, which are the two leading causes of death in developed countries.

[0003] The stiffer and less elastic the blood vessel wall is, the higher the pulse pressure becomes, and the heart has to increase the amount of work to pump blood into the arteries. As the amount of work of the heart increases to maintain the stroke volume, the load on the heart increases. When the load increases in this way, left ventricular hypertrophy and left ventricular remodeling may occur over time, leading to heart failure. As the hardening of the arterial wall progresses, the pressure fluctuations on the microvessels of the brain and kidneys also increase, increasing the risk of stroke and renal insufficiency.

[0004] The hardening of the arterial wall occurs as a result of biological aging, but may be accelerated by a number of risk factors such as inflammation, mechanical stress, hypertension, and atherosclerosis. At present, there is no drug specific for arterial wall sclerosis. Current treatment strategies are antihypertensive drugs, antihyperlipidemic drugs, and exercise.

[0005] Rebamipide (chemical name: 2-[(4-chlorobenzoyl)amino]-3-(2-oxo-1H-quinolin-4-yl)propanoic acid) is clinically used for the treatment of acute and / or chronic gastritis and gastric ulcers. This molecule has recently been reported to suppress the formation of atherosclerotic plaques by controlling lipid metabolism and inflammation, suggesting its usefulness in the treatment of atherosclerosis and associated cardiovascular diseases in patients with hyperlipidemia (Non-Patent Document 1).

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Summary of the Invention

Problems to be Solved by the Invention

[0007] Surprisingly, it has been found that rebamipide has other beneficial effects on the arterial state, independent of its antihyperlipidemic action. After long-term administration of rebamipide, a decrease in arterial wall stiffness has been observed by measuring the pulse wave velocity. Presumably, the mechanism of action is based on the ability of rebamipide to protect the vascular endothelial barrier and reduce vascular permeability by restoring the binding function between endothelial cells, suppressing inflammation, and promoting the secretion of protective glycoproteins.

[0008] The vascular endothelium is a barrier consisting of a thin layer of squamous epithelial cells that covers the inner surface of the arterial, capillary, and venous vessel walls. The integrity of the barrier and the permeability of the blood vessels depend on the regulation of the junctions between endothelial cells. The glycocalyx that protects the vascular endothelium is a complex surface layer of sialic acid-containing glycoproteins, proteoglycans, and glycosaminoglycans, and together they form a scaffold on the apical membrane side of the vascular endothelial cells. The glycocalyx protects the vessel wall from direct contact with the blood flow, contributes to the vascular permeability barrier, and further prevents coagulation and leukocyte adhesion.

[0009] The glycocalyx is easily disrupted by several mechanisms, and as a result, an inflammatory endothelial response may be induced, leading to unstable cell junctions, thereby disrupting the endothelial barrier and increasing vascular permeability. Then, the transendothelial migration of immune cells into the arterial intima is promoted, and vascular inflammation is induced, resulting in structural changes in the arterial wall due to the degradation of elastin by matrix metalloproteinases, the accumulation of abnormal collagen, the proliferation of smooth muscle cells, and changes in the composition of the extracellular matrix, which leads to a decrease in the elasticity and hardening of the arterial wall.

[0010] Considerable research has shown that levamisole exhibits anti-inflammatory properties in numerous unrelated diseases. It has also been reported to improve cell junctions (Non-Patent Document 2). Furthermore, it increases mucin and mucin-like secretions in various tissues such as the stomach (Non-Patent Document 3), eyes (Non-Patent Document 4), and intestinal tract (Non-Patent Document 5). Since the vascular glycocalyx has many similarities with mucin, levamisole is thought to promote secretion by a similar mechanism. When the glycocalyx, which is the main protective barrier of the vessel wall, is restored, vascular permeability decreases, thereby suppressing inflammation, and as a result, the decrease in the elasticity of the vessel wall is suppressed or prevented.

Means for Solving the Problems

[0011] Accordingly, the present invention provides levamiside or a pharmaceutical composition thereof for use in a method for preventing and / or treating arterial wall sclerosis. Since this condition is a serious risk factor for the occurrence and progression of other diseases and conditions, the method may further include preventing and / or treating hypertension, heart failure, myocardial infarction, stroke, peripheral arterial disease, renal insufficiency, and / or chronic kidney disease.

[0012] It is a great advantage that the activity of levamiside does not stop at plaque removal in arteriosclerotic patients as previously thought, but rather the molecule targets multiple different mechanisms that lead to an increase in arterial elasticity and an improvement in the health of the arteries. This expands the potential for use even in people with normal blood lipids, that is, those who do not suffer from either arteriosclerosis or hyperlipidemia. Accordingly, in a preferred embodiment, levamiside is used in people with normal blood lipid values.

[0013] As used herein, "levamiside" shall include all forms of this active ingredient, such as the anhydrous form, the hydrate form, or the solvate form (e.g., the hemihydrate form), the crystalline form, etc., and pharmaceutically acceptable salts thereof.

[0014] "Prevention" or "preventive use" is understood herein to mean preventing or delaying an increase in arterial wall sclerosis and / or related diseases such as hypertension, heart failure, myocardial infarction, stroke, peripheral arterial disease, renal insufficiency, and chronic kidney disease.

[0015] "Treatment" is understood herein to mean a therapy that can suppress, arrest, delay, or reverse the progression of arterial wall sclerosis and / or related diseases.

[0016] Furthermore, the present invention provides levamiside for use in a method for preventing and / or treating hypertension, heart failure, myocardial infarction, stroke, peripheral arterial disease, renal insufficiency, and / or chronic kidney disease by reducing arterial wall sclerosis.

[0017] Furthermore, the present invention provides a method for preventing and / or treating arteriosclerosis by administering a pharmaceutically effective amount of levamiside or a pharmaceutical composition thereof to a subject in need of such treatment. The subject is preferably a human subject, specifically a person having hypertension, heart failure, myocardial infarction, stroke, peripheral arterial disease, renal insufficiency, or chronic kidney disease or a person at risk thereof.

[0018] Furthermore, the present invention provides the use of levamiside for the manufacture of a medicament for preventing and / or treating arteriosclerosis in a person having hypertension, heart failure, myocardial infarction, stroke, peripheral arterial disease, renal insufficiency, or chronic kidney disease or a person at risk thereof.

[0019] Furthermore, the present invention provides levamiside for use in a method of increasing the elasticity of the arterial wall. The method comprises administering levamiside or a pharmaceutical composition thereof to a subject in need of such treatment. The subject is preferably a human subject, specifically a person having hypertension, heart failure, myocardial infarction, stroke, peripheral arterial disease, renal insufficiency, or chronic kidney disease or a person at risk thereof.

[0020] In the therapeutic indications described in the present invention, levamiside can be used in oral dosage forms such as tablets, capsules, dragees, granules, microparticles (sachets), orally dispersible tablets or films, sublingual tablets, crushed tablets, oral solutions, oral suspensions, syrups, gargles, oral rinses; or rectal dosage forms such as suppositories and enemas; or dosage forms for parenteral administration such as injections or infusions. Preferably, oral dosage forms such as tablets, capsules, dragees, and granules can be in enteric release forms such as enteric-coated sustained release or enteric-coated controlled release.

[0021] The normal daily dose of levamiside can range from 1 to 5000 mg, more preferably from 50 to 2500 mg, even more preferably from 100 to 1000 mg, and most preferably from 600 to 900 mg in an average human (weighing 70 kg). When administering an immediate-release formulation of levamiside, the daily dose is usually divided into multiple doses and administered separately. The daily dose can be divided into 2 to 6 doses and administered 2, 3, 4, 5, or 6 times a day. In a preferred embodiment, the daily dose is divided into 3 doses and administered 3 times a day, for example, a 200 mg dose is administered 3 times a day. Alternatively, the entire daily dose can be administered once, especially in the form of a sustained-release formulation, for example, a 600 mg dose is administered once a day.

Mode for Carrying Out the Invention

[0022] Hereinafter, the present invention will be described more specifically with reference to examples. However, the following examples are provided for illustrative purposes only, and thus the present invention is not limited thereto.

Examples

[0023] As the cardiovascular system ages, the cushioning function of arteries deteriorates, thereby increasing the pulse pressure (the amplitude between systolic and diastolic phases). The pulse wave velocity (PWV), that is, the speed at which the blood pressure pulse propagates through the circulatory system, is the gold standard for a method of quantifying arterial wall sclerosis. PWV can be easily measured non-invasively in humans, has high reproducibility, and further predicts future cardiovascular events and total mortality independent of conventional cardiovascular risk factors.

[0024] The speed of the pulse wave propagating along the artery changes according to the elasticity of the arterial wall, and the lower the elasticity of the arterial wall, the faster the propagation speed of the pulse wave. PWV is calculated as the value obtained by measuring the propagation time of the pressure wave at a known distance and dividing the distance between two positions of the pulse transducer by the time delay measured during the pressure rise process at each position.

[0025] To examine the effect of levamiside on arteries, a small-scale trial was conducted in patients with arterial wall sclerosis. Patients with no signs of arteriosclerosis or hyperlipidemia and a PWV higher than the normal value for the corresponding age group (see Non-Patent Document 6) were randomly divided into two groups, and either 200 mg of levamiside (two 100-mg tablets) or a placebo was administered three times a day for 12 months. The PWV (cfPWV) between the carotid artery and the femoral artery was measured in both groups at 0, 3, 6, 9, and 12 months.

[0026] From the evaluation conducted after the end of the trial, the sclerosis of the arterial wall gradually decreased in the levamiside administration group, while no change was observed during the test period in the placebo group. The difference between the two groups reached statistical significance. The results obtained from the test indicate that the administration of levamiside helps arterial regeneration, thereby reducing arterial wall sclerosis and preventing hypertension, cardiovascular diseases, and related diseases.

Claims

1. A pharmaceutical composition comprising levamiside and used for the prevention and / or treatment of arteriosclerosis.

2. A pharmaceutical composition having only levamiside as an active ingredient and used for the prevention and / or treatment of hypertension, heart failure, myocardial infarction, stroke, peripheral arterial disease, renal insufficiency, and chronic kidney disease caused by arteriosclerosis.

3. A pharmaceutical composition comprising levamiside and used for a method of increasing the elasticity of the arterial wall.

4. Using levamiside in a person with normal blood lipid levels The pharmaceutical composition according to any one of Claims 1 to 3.

5. Administering levamiside in an oral dosage form selected from tablets, capsules, dragees, granules, microparticles (sachets), orally disintegrating tablets or films, sublingual tablets, crushed tablets, oral solutions, oral suspensions, syrups, gargles, oral rinses; or a rectal dosage form selected from suppositories and enemas; or by parenteral administration by injection or infusion The pharmaceutical composition according to any one of Claims 1 to 4.

6. The oral dosage form is in the form of enteric release, enteric sustained release or enteric controlled release The pharmaceutical composition according to Claim 5.

7. Administering levamiside in a daily dose of 1 to 5000 mg The pharmaceutical composition according to any one of Claims 1 to 6.