KR101579656B1 - A pharmaceutical composition comprising pravastatin and valsartan - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising pravastatin or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to a pharmaceutical composition comprising a) a first composition comprising pravastatin or a pharmaceutically acceptable salt thereof as an active ingredient and b) a second composition comprising valsartan or a pharmaceutically acceptable salt thereof as an active ingredient, Comprising administering to a subject a composition for treating cardiovascular disease and a composition comprising pravastatin and valsartan as an effective ingredient, or a composition comprising pravastatin and a composition comprising valsartan at the same time, Prevent side effects and provide a method for treating cardiovascular disease.

Description

[0001] A pharmaceutical composition comprising pravastatin and valsartan,

The present invention relates to a pharmaceutical composition comprising pravastatin and valsartan, and more particularly, to a pharmaceutical composition containing pravastatin and valsartan as an effective ingredient for the treatment of cardiovascular diseases without adverse side effects of diabetes.

Generally, hyperlipemia refers to a condition in which lipids such as cholesterol and triglycerides are abnormally increased in plasma. Hypercholesterolemia, especially hypercholesterolemia, induces arterial thrombosis and causes arteriosclerosis which accumulates thick lipids along the blood vessels, which causes blood flow to be reduced and causes cerebral vascular diseases such as ischemic heart disease, angina, myocardial infarction and cerebral infarction. It becomes an important issue. Thus, hyperlipidemia and atherosclerosis are closely related to each other, and by treating hyperlipidemia, arteriosclerosis can be prevented and cardiovascular diseases can be prevented.

Specific examples of hyperlipidemia include hypercholesterolemia, familial beta-lipoproteinemia, diabetic dyslipidemia, nephrotic dyslipidemia, and familial hyperlipidemia. Hypercholesterolemia results in elevation of serum total cholesterol and low density lipoprotein - cholesterol. Low-density lipoproteins carry cholesterol in the blood. In addition, familial beta-lipoprotein, also known as type III hyperlipemia, is characterized by the accumulation of very low density lipoprotein (VLDL), called ultra-low density lipoprotein cholesterol particles, in the serum. In addition, this symptom is associated with the replacement of normal apolipoprotein E3 by the heterologous apolipoprotein E2. Diabetic dyslipidemia leads to a number of lipoprotein abnormalities such as overproduction of VLDL-cholesterol, abnormal lipolysis of VLDL triglyceride, decreased LDL-cholesterol receptor activity, and Type III hyperlipemia that often occurs. Nephrotic dyslipidemia is difficult to treat, and the most common cases are hypercholesterolemia and hypertriglyceridemia. Familial complex hyperlipidemia is divided into multiple phenotypic hyperlipidemia, Type IIa, IIb, IV, V, or Apo beta-lipoproteinemia.

HMG-CoA reductase inhibitors have been used for decades to treat such hyperlipemia. These HMG-CoA reductase inhibitors are known to reduce total cholesterol and LDL-cholesterol in the human body, and to increase HDL-cholesterol levels in some individuals. The step of converting HMG-CoA to mevalonate is an early step in the process of biosynthesis of cholesterol, and the inhibition of HMG-CoA reductase, which inhibits formation of mevalonate, suggests that the HMG-CoA reductase inhibitor has a lowered total cholesterol (Grundi SM, N Engl J Med, 319 (1): 24-32, 25-26, 31 (1998)).

Examples of HMG-CoA reductase inhibitors include mevastatin (US Patent No. 3,983,140), lovastatin (also US Patent No. 4,231,938), also called mebinolin, pravastatin (US Patent No. 4,346,227 and 4,410,629), lactone of pravastatin 4,448,979), belostatin and simvastatin (US Pat. Nos. 4,448,784 and 4,450,171), mivinolin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin.

On the other hand, angiotensin-II-receptor blockers have been rapidly commercialized as hypertension treatment drugs for the past several years. In addition to hypertension, angiotensin-II not only has strong vasoconstriction but also oxidative substances and inflammatory substances and thrombogenesis, as well as aggravation of cardiovascular diseases such as arteriosclerosis, heart failure, angina pectoris, myocardial infarction, renal failure and stroke, And so on. Thus, angiotensin-II-receptor blockers cause blood vessel dilation by blocking activation of the angiotensin-II AT1 receptor, reducing vasopressin secretion, and reducing aldosterone production and secretion.

These angiotensin-II-receptor blockers are effective for the prevention and treatment of cerebral vascular diseases, additional heart failure associated with various symptoms of diabetes, cardiomyopathy, angina pectoris, myocardial infarction, renal failure and stroke, antiplatelet activity, It is known that it has the effect of inhibiting the harmful action of aldosterone and preventing the chain deterioration of the circulatory system disease.

Examples of angiotensin-II-receptor blockers include losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan and the like.

About 60% of patients with hypertension are hyperlipidemic. Hypertension and hyperlipidemia are closely related to each other. Cardiovascular disease patients are treated with hypertension treatment and hyperlipidemia treatment. Heart failure, angina, myocardial infarction, heart failure, It is known to reduce the incidence and mortality of complications.

However, in the case of the combination therapy of hypertension treatment with hyperlipidemia treatment, there is a problem that the drug efficacy is lowered due to interaction between drugs, and statins for treating hyperlipidemia have recently been reported to have a side effect of diabetes Therefore, it is known that there is a high risk of side effects of diabetes even in combination therapy of hypertension treatment with statin drugs.

Therefore, the inventors of the present invention have conducted extensive studies on medicines for the treatment of cardiovascular diseases. As a result, when treating pravastatin, a treatment for hyperlipidemia, and valsartan, a treatment for hypertension, there is no problem of lowering the drug efficacy, The inventors of the present invention have confirmed that cardiovascular diseases can be effectively treated when pravastatin or valsartan alone is used alone and that side effects of diabetes can be effectively prevented. It was also confirmed that no side effects due to the two drug interactions were observed.

It is an object of the present invention to provide a pharmaceutical composition for treating cardiovascular diseases comprising pravastatin and valsartan as an active ingredient.

More specifically, it is an object of the present invention to provide a pharmaceutical composition for treating cardiovascular diseases, which comprises pravastatin or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof as an active ingredient and is capable of preventing side effects of diabetes will be.

Another object of the present invention is to provide a pharmaceutical composition comprising a) a first composition comprising pravastatin or a pharmaceutically acceptable salt thereof as an active ingredient and b) a second composition comprising valsartan or a pharmaceutically acceptable salt thereof as an active ingredient And to provide a kit for treating cardiovascular diseases that can prevent side effects of diabetes.

Another object of the present invention is to provide a pharmaceutical composition comprising pravastatin or a pharmacologically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof as an active ingredient to a subject or a pharmaceutical composition comprising pravastatin or a pharmacologically acceptable salt thereof A method of preventing cardiovascular disease and preventing diabetic side effects, comprising administering to a subject simultaneously or sequentially or in reverse order a composition comprising a salt and a composition comprising valsartan or a pharmaceutically acceptable salt thereof, .

In one aspect of the present invention, there is provided a pharmaceutical composition comprising pravastatin or a pharmacologically acceptable salt thereof (hereinafter referred to as pravastatin unless otherwise specified) and valsartan, or a pharmaceutically acceptable salt thereof (hereinafter, (Hereinafter referred to as valsartan unless otherwise specified) as an active ingredient, and to prevent side effects of diabetes mellitus.

It has been known that the combination of HMG-CoA reductase inhibitor and angiotensin-II receptor blocker, which is a therapeutic agent for hypertension, before the present invention can provide a therapeutic effect of cardiovascular disease and kidney disease, Techniques have been disclosed (WO 99/11260) for reducing blood pressure and lipid levels by administering a medication comprising atorvastatin and valsartan, a hypertension remedy, and for treating angina and atherosclerosis in mammals.

However, when such an HMG-CoA reductase inhibitor and an angiotensin-II receptor blocker are administered in combination, it is known that competitive inhibition occurs between the drugs, thereby decreasing the efficacy of the drug and increasing the risk of side effects. In addition, insulin resistance by the HMG-CoA reductase inhibitor is known to counteract the insulin resistance-inhibiting effect of the angiotensin-II receptor blocker.

Accordingly, the present inventors have developed a combination of an HMG-CoA reductase inhibitor and an angiotensin-II receptor blocker that can not only provide excellent therapeutic effects of cardiovascular diseases but also prevent side effects of diabetes The combination therapy of valsartan, one of the HMG-CoA reductase inhibitors, pravastatin and angiotensin-II receptor blockers, not only can effectively treat cardiovascular disease, but also prevents diabetes It was confirmed that not only the side effects but also diabetes could be prevented.

In the present invention, "pravastatin" is (3 R, 5 R) -3,5- dihydroxy -7 - ((1 R, 2 S, 6 S, 8 R, 8a R) -6- hydroxy- 2-methyl -8 - {[(2 S) -2- methyl-butanoyl] oxy} -1,2,6,7,8,8a- hexahydro-1-yl) - the acid of the formula and to HMG-CoA reductase inhibitor having the structural formula I and is mainly used for the treatment of hyperlipidemia such as dyslipidemia.

[Structural formula I]

In the present invention, " valsartan " refers to a mixture of N- (1-oxopentyl) -N - [[2 '- (lH-tetrazol-5-yl) Refers to an angiotensin-II-receptor blocker having the following formula (II): (a) an anti-hypertensive agent that relaxes blood vessels by blocking the action of angiotensin II, which causes blood pressure increase and oxidative substances, But is used for the treatment of cardiovascular diseases such as heart failure, ischemic heart disease and stroke, and kidney diseases.

[Structural Formula II]

For the purposes of the present invention, "pharmaceutically acceptable salts" means salts prepared according to methods conventional in the art, and such methods of preparation are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic and organic acids and bases which are pharmacologically or physiologically acceptable. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include alkali metals, such as sodium, or potassium, alkaline earth metals, such as magnesium.

In the pharmaceutical composition of the present invention, pravastatin and valsartan may be contained in a ratio of about 1: 1 to 1:10 by weight, preferably 1: 2 to 1: 5, May be included in a ratio of 1: 3 to 1: 4.

The content of pravastatin and valsartan contained in the pharmaceutical composition of the present invention is not particularly limited, but may be in the range of 0.0001 to 90% by weight, more preferably 0.01 to 50% by weight, based on the total weight of the final composition.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" means a carrier or diluent that does not interfere with the biological activity and properties of the compound being administered, without stimulating the organism.

The type of the carrier that can be used in the present invention is not particularly limited, and any carrier conventionally used in the art and pharmaceutically acceptable may be used. Non-limiting examples of the carrier include saline, sterilized water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and the like. These may be used alone or in combination of two or more.

In addition, if necessary, other conventional additives such as an antioxidant, a buffer and / or a bacteriostatic agent can be added to the composition, and a diluent, a dispersant, a surfactant, a binder and / or a lubricant may be additionally added thereto to form an aqueous solution, a suspension, Capsules, granules, tablets or the like. The pharmaceutical composition of the present invention can be manufactured into various formulations depending on whether the intended administration mode is oral administration or parenteral administration.

Non-limiting examples of formulations for oral administration include troches, lozenges, tablets, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, .

Such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose, or gelatin, for formulation into oral dosage forms such as tablets, capsules and the like. Binder; Excipients such as dicalcium phosphate and the like; Disintegrating agents such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol wax, and the like. Furthermore, in the case of a capsule formulation, in addition to the above-mentioned substances, a liquid carrier such as a fatty oil may be further contained.

Formulations for parenteral administration include, for example, injectable forms such as subcutaneous, intravenous, or intramuscular injections; Suppository injection system; Or an aerosol formulation that allows for inhalation through the respiratory tract, but is not limited thereto. In order to formulate the injectable preparation, the composition of the present invention may be mixed with a stabilizer or a buffer in water to prepare a solution or suspension, which may be formulated for unit administration of an ampoule or a vial. When formulated for spraying with an aerosol or the like, a propellant or the like may be blended with the additive such that the water-dispersed concentrate or the wet powder is dispersed.

The pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount " of the present invention means a therapeutic or prophylactic treatment of a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention And the effective dose level refers to the level of the disease to be treated, the severity of the disease, the activity of the drug, the age, body weight, health, sex, sensitivity of the patient to the drug, Duration, duration of administration, factors involved in combination with or contemporaneously with the composition of the present invention, and other factors well known in the medical arts. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered singly or multiply. It is important to take into account all of the above factors and administer an amount that will achieve the maximum effect in the least amount without side effects.

The preferred daily dose of the pharmaceutical composition comprising pravastatin and valsartan of the present invention may be 0.5 mg / kg / day to 50 mg / kg / day, more preferably 1 mg / kg / day to 20 mg / kg / Day. The preferred dosage frequency of the pharmaceutical compositions of the present invention may be, but is not limited to, once daily.

In the present invention, cardiovascular disease refers to diseases that occur in the heart and major arteries. Examples of cardiovascular diseases include hypertension, heart failure, cardiomyopathy, ischemic heart disease (coronary artery disease) angina, myocardial infarction, arrhythmia, atherosclerosis ), Cerebral vascular disease (stroke), and the like.

Hypertension is the blood pressure that is applied to the blood vessel wall, which is the blood pressure of the blood pressure measured more than once in the blood pressure more than 140mmHg or the diastolic blood pressure is more than 90mmHg.

Ischemic heart disease refers to a disease in which the myocardium does not function properly due to a lack of oxygen supplied to the heart muscle as needed for the heart muscle due to various causes. The most common cause is a heart artery supplying blood to the heart ) Is narrowed or clogged.

Coronary artery disease is a disease caused by abnormalities in the coronary arteries (coronary arteries), which are blood vessels that supply oxygen and nutrients to the heart muscle. Comprehensive coronary artery disease is the most common cause of coronary artery disease.

Angina pectoris is a disease in which the inner diameter of the coronary artery is narrowed due to arteriosclerosis, and the heart muscle is not supplied with the necessary amount of blood. Usually, when the heart needs much nutrients and oxygen as in exercise, Failure to supply the heart muscle results in cardiac dysfunction.

Myocardial infarction is a myocardial necrosis of the coronary artery (heart artery) that supplies blood to the heart. It is a disease of the heart that is piled up on the wall of the coronary artery narrowed by arteriosclerosis, Thrombosis completely blocks the flow of blood, causing heart muscle necrosis (decaying) and chest pain.

Atherosclerosis (atherosclerosis) refers to a disease in which blood vessels become greasy and the blood vessel wall becomes hard, and cholesterol deposits on the innermost membrane of the blood vessels, and cell proliferation occurs to form a bloody atheroma. The inner surface of these blood vessels becomes tangled and the wall thickens, narrowing the diameter of the blood flowing inside, and obstructing blood circulation. When the fibrous membrane surrounding the bacillus is exploded, a blood clot forms in the blood vessel. In addition, hemorrhage occurs in the aneurysm, and the diameter of the blood vessels is rapidly narrowed or clogged.

Cerebrovascular disease (stroke) can be divided into ischemic stroke and hemorrhagic stroke. Ischemic stroke is a cerebral blood vessel that supplies blood to the brain is blocked by arteriosclerosis or thrombosis, resulting in ischemic stroke. And blood supply is blocked by the bleeding is hemorrhagic stroke.

According to one embodiment of the present invention, patients with hypercholesterolemia were divided into three groups: group 1 received pravastatin alone, group 2 received valsartan alone, group 3 received pravastatin and valsartan In the combination therapy group, the plasma hsCRP levels were significantly reduced and the flow-mediated dilation (FMD) was significantly increased as compared with the single treatment group, indicating that the endothelial function was improved. In addition, plasma insulin levels were significantly reduced compared to the single treatment group, and the Insulin-Sensitivity Check Index (QUICKI) was increased compared to the single treatment group, and plasma adiponectin levels were significantly increased compared to the single treatment group. In addition, the combination therapy group showed significantly reduced blood pressure and cholesterol levels compared to baseline (Table 1). These results demonstrate that the combination therapy of pravastatin and valsartan can prevent not only the side effects of diabetes, but also the effect of treating cardiovascular diseases through endothelial function strengthening, blood pressure lowering and cholesterol lowering.

In another aspect of the present invention, the present invention provides a method of treating cardiovascular diseases which can prevent side effects of diabetes, comprising a) a first composition comprising pravastatin as an active ingredient and b) a second composition comprising valsartan as an active ingredient For example.

The first composition and the second composition may be respectively a pharmaceutical composition containing pravastatin as an active ingredient and a pharmaceutical composition containing valsartan as an active ingredient. These pharmaceutical compositions may be prepared by adding a pharmaceutically acceptable carrier As shown in FIG.

The content of pravastatin and valsartan contained in the first composition and the second composition of the present invention is not particularly limited but is preferably 0.0001 to 90% by weight, more preferably 0.01 to 50% by weight based on the total weight of the final composition ≪ / RTI >

The kind of the kit of the present invention is not particularly limited, and a kit of a type commonly used in the art can be used.

The kit of the present invention may be packaged in the form that the first composition and the second composition are each contained in a separate container or contained in one container divided into one or more compartments and the first composition and the second composition May be packaged in the form of a unit dose of one dose each.

The first composition and the second composition in the kit may be separately administered at appropriate times depending on the health condition of the subject to be administered.

The weight ratio of pavastatin of the first composition and valsartan of the second composition contained in the kit of the present invention may be about 1: 1 to 1:10, preferably 1: 2 to 1: 5, Preferably 1: 3 to 1: 4.

A preferred daily dosage of the first composition of the invention is 0.1 mg / kg / day to 10 < RTI ID = 0.0 >

mg / kg / day, more preferably 0.5 mg / kg / day to 5 mg / kg / day. The preferred dosage frequency of the first composition of the present invention may be once per day.

A preferred daily dosage of the second composition of the invention is 0.5 mg / kg / day to 50

mg / kg / day, more preferably 2 mg / kg / day to 20 mg / kg / day. The preferred dosage frequency of the second composition of the present invention may be once per day.

In another embodiment of the present invention, the present invention provides a method of treating a subject, comprising administering to the subject a pharmaceutical composition comprising pravastatin and valsartan, or administering a first composition comprising pravastatin and a second composition comprising valsartan simultaneously, And a method for preventing or treating a cardiovascular disease.

As used herein, the term "individual" refers to all animals, including humans who are at risk of developing cardiovascular disease or who are suffering from cardiovascular disease.

The term "treatment" as used in the present invention means all the acts of administering the composition of the present invention to an individual so as to improve or improve symptoms of cardiovascular disease.

As used herein, the term "prevention" means any act that inhibits or delays the onset of cardiovascular disease by administering the composition of the present invention to an individual.

The term "administering " of the present invention means introducing the pharmaceutical composition of the present invention to a subject by any appropriate method, and the administration route can be administered through various routes of oral or parenteral administration as long as it can reach the target tissues.

The preventive or therapeutic method of the present invention specifically includes a step of administering to a subject suffering from cardiovascular disease or suffering from cardiovascular disease a pharmaceutical composition comprising pravastatin and valsartan in a pharmaceutically effective amount, Administering a first composition and a second composition comprising valsartan, each in a pharmaceutically effective amount. The appropriate once and / or daily total usage of the composition can be suitably determined by those skilled in the art within the scope of sound medical judgment.

In the treatment method of the present invention, the first composition and the second composition are used in a weight ratio of pravastatin to valsartan of 1: 1 to 1:10, preferably 1: 2 to 1: 5, more preferably 1: 1: 4 ratio.

The specific pharmaceutically effective amount of the composition for a particular subject will vary depending on factors such as the type and severity of the response desired to be achieved, the age, weight, general health status, sex or diet of the subject, The route of administration, the rate of the route and composition, the duration of the treatment, etc., and may be varied depending on factors such as the concurrent or contemporaneously used drugs and other components of the composition, etc., and similar factors well known in the medical field, Preferred dosages of the compositions are as described above.

When the pharmaceutical composition or the first composition and the second composition of the present invention are administered at the above-mentioned frequency and dose, synergistic action between pravastatin and valsartan can exert an excellent cardiovascular disease therapeutic effect and prevent side effects of diabetes And can effectively treat cardiovascular disease.

The route of administration and the mode of administration of the pharmaceutical composition, the first composition and the second composition of the present invention are not particularly limited and may be any route of administration and administration mode as long as the composition can reach the desired site . The pharmaceutical composition, the first composition and the second composition of the present invention can be administered orally or parenterally.

Examples of the parenteral administration method include, but are not limited to, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, or local administration.

The kit comprising the pharmaceutical composition comprising pravastatin and valsartan as an active ingredient of the present invention and a second composition comprising pravastatin and a second composition comprising valsartan is characterized by a synergistic action of pravastatin and valsartan to produce a blood pressure lowering effect and a hyperlipemia treatment Effects simultaneously, it can provide an excellent therapeutic effect on cardiovascular diseases as compared with the single component, and can prevent side effects of diabetes and can be effectively used for treating cardiovascular diseases.

Figure 1 shows the percent change in the rate of change in high-sensitivity CRP (hsCRP) (right) and blood flow-mediated vasodilation response (FMD) after pravastatin alone, concomitant administration of pravastatin and valsartan, Left). The mean (left) or median (right) is presented along with the SEM.
FIG. 2 is a graph showing the rate of change (A) of adiponectin level, the rate of change of insulin level (B), and the rate of change of QUICKI (C) after administration of pravastatin alone, concomitant administration of pravastatin and valsartan, and administration of valsartan alone, Graph. The mean value is presented along with the median (A, B) or SEM.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example 1. Experimental object and design .

Fifty-one patients with hypercholesterolemia (LDL cholesterol level> = 130 mg / dL) participated in the study. Patients were excluded for liver disease, chronic kidney disease, neglected diabetes (HbA1c> 9% or 75 mmol / mol), severe hypertension or alcoholics. At the end of treatment, drug compliance was assessed by counting the number of drugs. In order to minimize acute side effects of valsartan, the drug used in the experiment was titrated with increasing doses from 80 mg to 160 mg over 2 weeks.

Two patients had hypotension and one had a dry cough. Therefore, data of 48 patients were analyzed. Patients were randomly assigned to one of three treatments. : 40 mg of pravastatin, placebo, 40 mg of pravastatin, 160 mg of valsartan, 160 mg of valsartan and placebo were given daily for 2 months in each treatment group.

This experiment was designed as a randomized, simple, blinded, placebo-controlled trial with three treatment groups (each 2 months) and interchange (two 2-month washout periods). Secret allocation was done through a collaboration with statisticians. Of the 48 patients, 23 had metabolic syndrome. This experiment was approved by the Gil Hospital Commission and all participants agreed

Example  2. Laboratory analysis and results

2-1. Laboratory analysis

Blood samples for analysis were collected at 8 am after overnight fasting on the day before the end of each 2-month treatment period. Lipid, glucose, and plasma adiponectin were analyzed twice by ELISA analysis (R & D Systems, Inc., Minneapolis, MN, USA). HsCRP levels were measured by latex agglutination (CRP-Latex (II) ® Denka-Seiken, Tokyo, Japan), plasma insulin levels were measured by immunosorbent assay (INSULIN-RIABEAD® II, SRL, (Koh KK, Quon MJ, Han SH, et al. Diabetes Care 2008; 31: 776-782, Koh, K., KK, Quon MJ, Han SH, et al J Am Coll Cardiol 2010; 55: 1209-1216, Koh KK, Quon MJ, Han SH, et al., Atherosclerosis 2009; 204: 483-4907-9). The deviation between analysis and analysis is less than 6%. (QUICKI) was calculated (Katz, Nambi SS, Mather K, et al. J Clin Endocrinol Metab 2000; 85: 2402-2410, Chen H, Sullivan G, 1914-1925). Image analysis of the right superior rectus artery was performed with an ATL HDI 3000 ultrasonic machine (ATL Philips, Bothell, WA, USA) equipped with a 10 MHz linear-array transducer. (Koh KK, Quon MJ, Han SH, et al. Diabetes Care 2008 : 31: 776-782, Koh KK, Quon MJ, Han SH, et al J Am Coll Cardiol 2010; 55: 1209-1216, Koh KK, Quon MJ, Han SH, et al., Atherosclerosis 2009; 204: 483- 4907-9) The error within the measurement for repeated measurements of the maximum diameter was 0.01 ± 0.06 mm and the error within the measurement for repeated measurements of flow-mediated expansion (FMD) percent was 0.13 ± 1.33%.

Data were expressed as mean ± SEM or mean value (25-75%). Normalized test As shown in Tables 1 and 2, Student's paired t or Wilcoxon signed-rank test was used to compare changes in values before and after each treatment with changes in treatment. The effects of the three treatments were analyzed by one-way repeated-measures ANOVA or Friedman repeated ANOVA. Post hoc comparisons, Pearson, or Spearman correlations were used. Based on the results of previous experiments (Koh KK, Quan MJ, Han SH, et al. Atherosclerosis 2009; 204: 483-4909), we found that 40 patients had FMD between baseline and pravastatin treatment groups It was calculated to provide 80% power to detect an absolute increase of 1.7% or more. The comparison of endothelium-dependent expansions between the three treatments was the primary endpoint of the study. All other comparisons were considered secondary. P <0.05 was considered statistically significant.

2-2. Analysis

There was no significant difference between the default values for any of the measured parameters (Tables 1 and 2). There was no effect transferred from one treatment period to the next treatment period.

One) Effect of treatment on blood pressure and lipid

The combination therapy of valsartan alone or valsartan and pravastatin showed significant reductions in blood pressure during cardiac contraction and expansion when compared to baseline after two months of treatment. This reduction was significantly greater than that observed with pravastatin alone (P <0.05 by ANOVA) (Table 1)

Pravastatin alone or in combination with valsartan and pravastatin showed significant reductions in total cholesterol (P <0.001), triglyceride (P <0.05), LDL cholesterol (P <0.001) and apolipoprotein B levels when compared to baseline . This decrease was significantly greater than that observed in valsartan alone (P <0.05 by ANOVA) (Table 1)

2) Effect of treatment on vascular motor function and inflammation markers

(P <0.001) in the combination of pravastatin, valvastatin, valsartan, and valsartan increased by 37 ± 2%, 47 ± 3% and 32 ± 2%, respectively (P < 0.001 by ANOVA; Figure 1 and Table 1)

In addition, the plasma hsCRP levels were decreased from 0.85 to 0.60 (P <0.001), from 1.00 to 0.65 (P <0.001), from 1.10 to 0.80 mg / L (P = 0.158). However, combination therapy significantly reduced plasma hsCRP levels significantly more than monotherapy (P = 0.019 by ANOVA; Figure 1 and Table 1)

These results show that endothelial function and inflammation are greatly improved by the combination therapy of pravastatin and valsartan.

3) The effect of treatment on adiponectin and insulin resistance

(P = 0.007), 2.81 to 3.73 (P <0.001), and 2.96 to 3.45 ㎍ / mL (P = 0.002) in patients treated with pravastatin, pravastatin and valsartan ). Interestingly, a significant increase was also observed in the combination therapy over monotherapy values (P = 0.003 by ANOVA; Figure 2A and Table 1)

In addition, the plasma insulin levels were decreased from 10.90 to 9.35 (P = 0.012), from 10.16 to 7.78 (P <0.001), from 9.62 to 8.67 uU / mL (P = 0.103). However, combination therapy significantly reduced plasma insulin levels compared to monotherapy (P = 0.049 by ANOVA; Figure 2B and Table 1)

(P = 0.020), 6 ± 1% (P <0.001), and 2 ± 1% (P = 0.053, respectively) compared with the baseline values in the basal torsion group ). Interestingly, concomitant therapy significantly increased the QUICKI value compared to single treatment (r = 0.521, P <0.001 after treatment with pravastatin, r = 0.437, P = 0.002 after combination treatment, r = 0.297 after treatment with valsartan, 0.040)

These results show that the combination of pravastatin and valsartan can prevent the development of diabetes.

There was a correlation between the adiponectin level and the percentage change in QUICKI (r = 0.521, P <0.001 after treatment with pravastatin, r = 0.437, P = 0.002 after combination treatment, r = 0.297 after treatment with valsartan, (R = -0.284, P = 0.050 after treatment with pravastatin, r = -0.373, P = 0.009 after combination treatment, r = -0.258 after treatment with valsartan, P = 0.077)

On the other hand, the inventors investigated whether the rate of pravastatin or valsartan-induced change in FMD percent, serologic markers of inflammation and insulin resistance was mediated by changes in lipid protein or blood pressure levels, but there was no significant correlation. Notably, after concomitant therapy, FMD improvement correlated with changes in QUICKI (r = 0.397; P = 0.005) and insulin level changes (r = -0.292; P = 0.040).

[Table 1] Effects of pravastatin, concomitant use and valsartan in 48 patients with hypercholesterolemia

Data are expressed as mean ± SEM or median.

* P <0.05, + P <0.01, ‡ P <0.001 for comparison with each reference value

BMI: body mass index, hsCRP: sensitive sensitive C-reactive protein, ADP: adiponectin, HbA1c: glycated hemoglobin

Quantitative insulin-sensitive check index (QUICKI) = 1 / [log (insulin) + log (glucose)]

P / C = pravastatin vs combination, C / V = combination, valsartan, P / V = pravastatin etc.

NS = Not significant

4) Effect of treatment in patients with metabolic syndrome

 As shown in Table 2, the present inventors analyzed 23 patients with metabolic syndrome.

Overall, similar results were observed in 23 patients with metabolic syndrome compared with the effect of each treatment method in 48 patients with hypercholesterolemia. In comparison with baseline, the endothelial dysfunction measured by FMD was improved in the three treatment groups, and FMD was significantly improved in combination with pravastatin and valsartan (P = 0.008 by ANOVA). Combination therapy was also compared with valsartan therapy (P = 0.003 by ANOVA), and concomitant therapy increased plasma adiponectin levels, decreased fasting plasma insulin levels, increased insulin sensitivity, and improved metabolic phenotypes (R = 0.499; P = 0.015) and insulin level change (r = -0.480; P = 0.001, P = 0.065, P = 0.070 by ANOVA) = 0.021), respectively.

[Table 2] Effects of pravastatin, concomitant use and valsartan in 23 hypercholesterolemic patients with metabolic syndrome

Data are expressed as mean ± SEM or median.

* P <0.05, + P <0.01, ‡ P <0.001 for comparison with each reference value

BMI: body mass index, hsCRP: sensitive sensitive C-reactive protein, ADP: adiponectin, HbA1c: glycated hemoglobin

Quantitative insulin-sensitive check index (QUICKI) = 1 / [log (insulin) + log (glucose)]

P / C = pravastatin vs combination, C / V = combination, valsartan, P / V = pravastatin etc.

NS = Not significant

These results show that the combination of pravastatin and valsartan lowers cholesterol and lowers blood pressure in patients with hypercholesterolemia, as well as enhances endothelial cell function and insulin sensitivity synergistically compared with monotherapy. It is a combination of pravastatin and valsartan Administration can not only prevent side effects of diabetes but also provide a therapeutic effect of cardiovascular diseases.

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. More variations are possible within a range that does not. Accordingly, the present invention may be embodied in other ways than those specifically described and illustrated herein, and will be understood by those skilled in the art.

Claims (16)

A pharmaceutical composition for the prevention of diabetic side effects and for the treatment of cardiovascular diseases, which comprises pravastatin or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises pravastatin and valsartan in a weight ratio of 1: 1 to 1:10. The pharmaceutical composition according to claim 1, which comprises pravastatin and valsartan in a weight ratio of 1: 2 to 1: 5. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 1, wherein the cardiovascular disease is selected from the group consisting of hypertension, heart failure, cardiomyopathy, angina pectoris, myocardial infarction, atherosclerosis, cerebrovascular disease, stroke. A kit for the prevention of diabetic side effects and a cardiovascular disease treatment comprising pravastatin or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof as an active ingredient. 7. The kit according to claim 6, wherein the weight ratio of pravastatin to valsartan is from 1: 1 to 1:10. 7. The kit of claim 6, wherein the weight ratio of pravastatin to valsartan is from 1: 2 to 1: 5. The kit according to claim 6, wherein the cardiovascular disease is selected from the group consisting of hypertension, heart failure, cardiomyopathy, angina pectoris, myocardial infarction, atherosclerosis, cerebrovascular disease, stroke. delete A method for the prevention of diabetic side effects and a method for treating cardiovascular diseases, comprising the step of administering a composition containing pravastatin and valsartan as an active ingredient to an individual other than a human. delete delete 12. The method according to claim 11, wherein the composition comprising pravastatin and valsartan as an active ingredient comprises pravastatin and valsartan in a weight ratio of 1: 1 to 1:10. 12. The method according to claim 11, wherein the composition comprising pravastatin and valsartan as an active ingredient comprises pravastatin and valsartan in a weight ratio of 1: 2 to 1: 5. 12. The method of claim 11, wherein the cardiovascular disease is selected from the group consisting of hypertension, heart failure, cardiomyopathy, angina pectoris, myocardial infarction, atherosclerosis, cerebrovascular disease, stroke.

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