KR20140008049A - Pharmaceutical composition for prevention and treatment of heart failure and combined formulation including the same - Google Patents

Abstract

The present invention provides a pharmaceutical composition and a combined formulation for preventing or treating heart failure, comprising fimasartan, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. The composition of the present invention increases the ejection fraction of the left ventricle to smoothen the blood circulation and thus can be used as an agent for treating heart failure, thereby preventing, alleviating, and treating circulatory dysfunction including heart failure.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing, alleviating, and treating heart failure, and a combination preparation comprising the same,

The present invention relates to a pharmaceutical composition for preventing, alleviating or treating heart failure and a combination preparation containing the same.

The heart is a pump made up of muscles, circulating blood throughout the body to supply oxygen and nutrients, and collecting the carbon dioxide and waste generated in the body, which plays an important role in maintaining life. The human heart is divided into the left heart, which is responsible for the systemic circulation, and the right heart, which is responsible for the pulmonary circulation. These are divided into an atrium that receives blood and a ventricle that releases blood.

Heart failure is a condition in which the function of the heart fails to meet the cardiac output required by the body. The term "heart failure" refers to a condition in which the cardiac output falls below 50 to 60%. When the heart does not shrink - relax well, the blood circulation is not good and more blood is collected in each room and lung of the heart than normal. When a heart failure occurs, the heart will try to adapt to it by first increasing the heart and sending more blood to the tissue or organ. When this condition is long, adaptive action reaches its limit and causes more problems.

Heart failure is caused by various causes such as excessive postloading and full load, impaired blood flow into the ventricles, cardiac insufficiency due to myocardial ischemia, and primary myocardial disease. Cardiomyopathy is usually caused by an abnormality in the heart muscle, and cardiomyopathy, which is different from other cardiovascular diseases, occurs in the heart muscle. The cardiomyopathy is one of the major causes of heart failure.

Thus, cardiomyopathy and heart failure due to various causes are serious diseases that are life-threatening, but they are not easily detected or easily left to be diagnosed. However, as a result, the patient may suffer sudden death from a heart attack. Therefore, if a suspected outbreak is suspected, he or she must be treated, and in the worst case, a heart transplant is required.

Heart failure is caused by various causes, especially cardiac insufficiency caused by cardiomyopathy, which is different from cardiovascular disease.

Therefore, there is a desperate need for the development of medicines that can effectively prevent, alleviate, and cure heart failure based on various causes, particularly heart failure caused by cardiomyopathy apart from cardiovascular diseases.

Disclosure of Invention Technical Problem [8] The present invention provides a pharmaceutical composition containing, as an active ingredient, Pimassartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient to inhibit progression of heart failure and improve myocardial function To provide.

The present invention provides a pharmaceutical composition for preventing, alleviating or treating heart failure comprising the compound represented by the following formula (1), fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

[Formula 1]

2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3 [[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -pyrimidine-4 (3H Fimasaltan represented by Formula 1, which is a) -one, is a substance registered in Korean Patent Nos. 0354654, 0617953, and US Patent No. 6294542.

Heart failure refers to a symptom in which the cardiac output is decreased, specifically, a symptom in which the cardiac output falls to 50 to 60% or less. Heart failure is caused by cardiac muscle abnormalities caused by various causes, and may be caused by cardiovascular disease or by cardiomyopathy irrespective of cardiovascular disease. In case of cardiac insufficiency due to cardiac insufficiency, particularly, dilated cardiomyopathy, the left ventricle is enlarged due to the damage of the myocardial tissue, and the thickness of the myocardium becomes thinner, and thus the heart exhibits symptoms of loss of normal pump function.

The pharmaceutical composition comprising as an active ingredient the Pimacartan of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, increases the cardiac output to a level exceeding 60% or more, and is useful for alleviation, prevention and treatment of heart failure And exhibits excellent effects. In particular, heart failure, which is different from cardiovascular diseases such as cardiomyopathy, can be effectively prevented, alleviated and treated.

The pharmaceutical composition comprising the said palmasaltan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present invention can effectively treat heart failure caused by dilated cardiomyopathy.

Specifically, the pharmaceutical composition of the present invention has an effect of normalizing the decrease in left ventricular ejection fraction due to dilated cardiomyopathy. In addition, the pharmaceutical composition of the present invention has an effect of normalizing the increase in the size of the left ventricular lumen caused by dilated cardiomyopathy.

As described above, the pharmaceutical composition of the present invention is effective in relieving, preventing, and treating heart failure by inhibiting the decrease of the left ventricular ejection fraction and the increase of the size of the left ventricular lumen inducing heart failure, thereby effectively treating and alleviating heart failure caused by various causes And prophylactic agents.

In addition, the pharmaceutical composition of the present invention can effectively prevent, alleviate and cure cardiac insufficiency due to dilated cardiomyopathies induced by anticancer agents.

Administration of anticancer drugs can lead to heart failure due to cardiomyopathy. In conclusion, continuous administration of anticancer agents may cause symptoms of heart failure, such as decreased left ventricular ejection fraction and decreased left ventricular luminal size. The pharmaceutical composition comprising the palmasalazine of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof inhibits the decrease of left ventricular ejection fraction leading to heart failure and the increase of the size of left ventricular lumen, Can be treated.

The anticancer agent may be an anthracycline-based substance. For example, the anticancer agent may be at least one selected from the group consisting of doxorubicin, dirubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, Aminobutyric acid, valine, valine, valivin, actinomycin, or a mixture of two or more thereof.

The pharmaceutically acceptable salt of Pimacartan according to the present invention may be a pharmaceutically acceptable salt. The pharmaceutically acceptable salt means a salt commonly used in the medical industry. Examples of the salt include inorganic ion salts such as calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galactaric acid, tartaric acid and tartaric acid. Organic acids such as lactic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, mandelic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, succinic acid, Sulfonic acid salts prepared by acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or naphthalenesulfonic acid, glycine, , Lysine and the like, and amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like. However, the types of salts defined in the present invention are not limited by the listed salts , Preferably potassium palate potassium.

The hydrate of Pimasartan according to the present invention may be a monohydrate, an dihydrate, a trihydrate, a dihydrate, a pentahydrate or the like, preferably a trihydrate.

The pharmaceutical composition comprising the present invention as an active ingredient may be one for use in combination with an anticancer agent. Concomitant administration of an anticancer drug may cause heart failure. When the anticancer drug and the pharmacological treatment of the present invention are administered in combination, heart failure induced by the anticancer drug can be prevented, and side effects caused by the anticancer drug can be prevented.

The anticancer drug administered in combination with the pharmaceutical composition of the present invention may be an anthracycline-based substance.

The anthracycline substance may be selected from the group consisting of doxorubicin, dirubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrabicin, aclarubicin, , Valvivin, actinomycin, and may be a mixture of two or more, preferably doxorubicin.

The pharmaceutical composition comprising as an active ingredient the palmasaltan of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof, may be used in combination with any one or two selected from the group consisting of a cardiovascular agent, a vasodilator, an antithrombotic agent, It can be used in combination with more than two kinds of preparations. In such a case, it is possible to treat the disease together with heart failure which may accompany the disease.

The pharmaceutical composition comprising the palmasalactan, the pharmaceutically acceptable salt thereof, or the hydrate or solvate thereof of the present invention as an active ingredient may further contain one or more active ingredients having pharmacological activity.

The active ingredient having the above pharmacological activity may be a component exhibiting a similar or similar function to that of the pirasalactan.

In addition, the active ingredient having pharmacological activity may be a component that causes heart failure by taking the active ingredient, and the ingredient that causes heart failure by taking the active ingredient may be an anti-cancer drug.

In addition, the active ingredient having pharmacological activity may be a component having therapeutic activity against cardiovascular diseases that causes heart failure, and a component having therapeutic activity against cardiovascular diseases that causes heart failure may be a cardiac agent, a vasodilator, Thrombotic agents and hypertension treatments.

The present invention provides a combination preparation comprising Pimacartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and an anticancer agent.

The anticancer agent may be an anthracycline-based substance.

The anthracycline substance may be selected from the group consisting of doxorubicin, dirubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrabicin, aclarubicin, , Valvivin, actinomycin, or a mixture of two or more thereof. The combination preparation can prevent heart failure that can be induced by the anticancer drug, thereby preventing side effects caused by the anticancer drug and improving the compliance of the patient with the medicament.

The present invention provides a combination preparation comprising Pimassa tincture represented by the above formula (1), a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and doxorubicin.

The present invention relates to a pharmaceutical composition comprising one or more agents selected from the group consisting of Pimalacetan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a therapeutic agent for cardiac arrest, vasodilator, antithrombotic agent and hypertension The formulation is provided.

The pharmaceutical composition comprising the Pimacartan represented by Formula 1, the pharmaceutically acceptable salt thereof, or the hydrate or solvate thereof of the present invention can be administered to a subject including human to prevent, ameliorate or treat heart failure. The pharmaceutical composition of the present invention can be administered to patients taking anticancer drugs to effectively prevent, alleviate or treat heart failure.

Pimersartan of the present invention represented by the above formula (1), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof provides use for preventing, alleviating or treating heart failure.

The composition of the present invention may be prepared by incorporating at least one pharmaceutically acceptable carrier in addition to the above-mentioned components for administration. The pharmaceutically acceptable carrier may be a mixture of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components. If necessary, an antioxidant, , And other conventional additives such as a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Thus, the composition of the present invention can be a patch, a liquid, a pill, a capsule, a granule, a tablet, a suppository, etc., and can be preferably formulated into a tablet. These formulations may be prepared by conventional methods used in the art for formulation or by methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA, and may be formulated into a variety of formulations, .

The pharmaceutical compositions of the present invention can be administered via any conventional route of administration so long as they can reach the target tissue.

The composition of the present invention may be administered orally, intraperitoneally, intravenously, intramuscularly, subcutaneously, intraperitoneally, intranasally, intrapulmonary, rectally, intrathecally, It is not limited and preferably can be orally administered.

The dosage of the pharmaceutical composition according to the present invention varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of disease. The daily dose or the dose of the active ingredient of the pharmaceutical composition of the present invention is 0.1 to 1000 mg / kg, preferably 50 to 500 mg / kg, and can be administered once or several times a day.

The composition of the present invention can be used as a pharmaceutical composition, a combined administration preparation and a therapeutic agent having an application for heart failure by increasing the heart rate, so that it is possible to prevent, alleviate and cure circulatory dysfunction including heart failure.

FIG. 1 is a graph showing the heart rate of the experimental group and the control group from 2 to 10 weeks.
FIG. 2 is a graph showing changes in heart rate and systolic luminal diameter for 8 weeks in the experimental group and the control group.
Fig. 3 shows the body mass of rats following administration of fimasartan and / or doxorubicin.
Figure 4 shows the survival rate of rats following administration of fimasartan and / or doxorubicin.
FIG. 5 is a photograph of the abdominal state of a rat administered with Pimalsartan and / or doxorubicin.
FIG. 6 shows LVEF (left ventricular heart rate) and LVID (left ventricular endometrial cavity) of rats receiving pigsartan and / or doxorubicin.
Figure 7 is the cardiac pressure-volume curve of rats to which Pimalsartan and / or doxorubicin was administered.
FIG. 8 is a graph showing lung and heart volume index of rats administered fimasartan and / or doxorubicin.

Hereinafter, the present invention will be described by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Manufacturing example . Doxorubicin  Induction of heart failure due to induced dilated cardiomyopathy Confirm

In order to prepare an animal model of heart failure to be administered with the pharmaceutical composition of the present invention, specifically, to confirm the induction of dilated cardiomyopathy by doxorubicin, the following experiment was conducted.

Male SD (Sprague Dawley) rats (body weight 300-350 g) were divided into experimental group 1 (6 animals), experimental group 2 (6 animals) and control group (5 animals). In the experimental group, 2.5 mg / kg (experimental group 1) or 3.0 mg / kg (experimental group 2) of doxorubicin (Doxorubicin, Adriamycin, Sigma, 44583) and 0.9% physiological saline Respectively.

Doxorubicin administration was performed by echocardiography (Sequoia, Siemens, 12MHz probe) at week 2 to week 10 to determine whether the cardiac cardiomyopathy was induced by measuring the ejection fraction of rats. The rats were also observed for 12 weeks.

FIG. 1 is a graph showing the induction effect of doxorubicin on doxorubicin according to the present invention, and is a graph showing the heart rate of the experimental group 1, the experimental group 2, and the control group at intervals of 2 weeks from week 2 to week 10. As can be seen from FIG. 1, in the experimental group 1 and the experimental group 2, the cardiac output was significantly decreased from the 4th week of the experiment. From the 6th week of the experiment, the heart rate declined to 60%, indicating that the administration of doxorubicin induced heart failure.

In addition, it was confirmed that 25% of the rats died at 8 weeks and 100% died at 12 weeks as a result of the experiment.

Example  One. Pima Saltan  Identification of inhibition of heart failure 1

1) Preparation of experimental animals and administration of test substances

Male SD rats (body weight 300-350 g) were newly taken and classified into experimental group (19 rats) and control group (8 rats). Experimental group and control group received 2.5 mg / kg doxorubicin (Doxorubicin, Adriamycin, Sigma, 44583) every week by intravenous injection of the tail. In the experimental group, 10 mg / kg of phimacartan dissolved at 1 mg / ml in 0.5% carboxymethyl cellulose (hereinafter, referred to as 'CMC') was orally administered daily from the time of administration of doxorubicin, CMC alone was administered at the same dose as the experimental group.

Since doxorubicin was administered, the mortality rate of rats was 25% at 8 weeks and 100% at 12 weeks.

2) Echocardiography  Measure

The effect of inhibition of heart failure was assessed by echocardiography (Sequoia, Siemens, 12 MHz probe) with ejection fraction and end-systolic diameter of the experimental group and the control group, respectively, at intervals of 2 weeks from 0 to 8 weeks of doxorubicin administration The results are shown in FIG.

FIG. 2 is a graph showing changes in the ejection fraction and the end-systolic diameter of the experimental group administered with CMC and the 10 mg / kg Pimacartan for 8 weeks in total.

2, while the heart rate of the control group was reduced to less than 60%, it was confirmed that the heart rate was maintained at about 75% in the experimental group. In the systolic lumen diameter, it was confirmed that the experimental group remained constant around 0.4mm while the control group was increased to more than 0.5mm. From these results, it was found that the heart failure, which causes the obstruction of the normal functioning of the heart, was alleviated by the pigsartan and the function was improved.

Example  2. Pima Saltan  Identification of inhibition of heart failure 2

1) Preparation of experimental animals and administration of test substances

Seventy male Sprague Dawley rats (300-350 g body weight) were newly taken and were divided into three groups: Doxorubicin only, 22 rats, Fimasartan 5 mg / kg, 22 rats, Fimasartan 10 mg / kg, , 19) and Group 4 (No doxorubicin, 8). In the first, second and third groups except the fourth group, 3.0 mg / kg doxorubicin was administered once a week by the tail vein from week 0 to week 8. In the fourth group, the tail vein was administered once a week instead of doxorubicin. 0.9% physiological saline was administered by the same dose. In group 2, pigsartan dissolved at 1 mg / ml in 0.5% CMC daily at 0 mg / kg to 8 mg / day was administered at 5 mg / kg in group 3, and in group 3, Was administered at 10 mg / kg. Group 1 received the same oral dose of 0.5% CMC daily.

2) Body mass  And survival rate change observation

The body masses of the first, second, third, and fourth group rats were measured weekly from week 0 to week 8. The survival rates of all of the groups were recorded daily from day 41 (6th week) to 9th day (10th week) at the beginning of death.

In addition, a first group of doxorubicin monotherapy and a third group of 10 mg / kg of pimacaltan were randomly taken at the 8th week, and anesthetized with 1.0% isoflurane (Iso Flurane, Choongwae Pharma) Respectively.

Figure 3 shows the body mass of the first, second, third and fourth group rats. Figure 4 shows the survival rates of groups 1, 2, 3 and 4. The vertical axis survival rate in FIG. 4 is a value obtained by dividing the number of surviving rats by the number of the first parking lot in the 0-th park, and the horizontal axis represents the number of days. Dox Only in FIG. 3 and FIG. 4 represent the first group, Low Fima in the second group, High Fima in the third group, and Normal control in the fourth group.

FIG. 5 is a photograph of the abdominal state of each group 1 rat administered doxorubicin alone at week 8 and group 3 rats administered 10 mg / kg fimasartan.

As shown in FIG. 3, the body mass of the group 4 of the normal control was gradually increased, whereas the body mass of the group 1, 2, and 3 of the heart failure was significantly decreased from the 3rd week. However, the decrease in the body mass was remarkably alleviated in the second and third groups in which Pimacartan was administered compared with the first group.

Also, as shown in FIG. 4, while the survival rate of the first group rats not receiving the pigsartan decreased to less than 0.6, the survival rates of the ninth group in the second and third group rats were 20% And 40%, respectively. When the survival rates of the second and third group rats were lowered, they were also delayed by about 9 days and 15 days, respectively, as compared with the first group. From this, it was found that the survival rate reduced by heart failure was treated with the Pimassaran treatment, the survival rate of the rats was increased, and the heart failure was prevented, alleviated or treated by Pimassartan.

As shown in FIG. 5, the first group administered with only doxorubicin without administration of Pimacartan was filled with Ascites due to heart failure, whereas the third group administered with Pimacartan showed almost no revenge. From this, it can be seen that Pimassaran significantly reduces ascites, a common symptom of heart failure.

3) Echocardiography  Measure

To confirm the suppressive effect of heart failure, we performed echocardiography (Sequoia, Siemens, 12 MHz probe) at 0, 6 and 8 weeks in groups 1, 2, 3 and 4 respectively. LVIDs (Left Ventricular end diastolic Internal Dimension), LVIDs (Left Ventricular end systolic Internal Dimension), systolic LV lumen (LVIDs), heart rate Size) (mm) were measured.

Table 1 and FIG. 6 show the echocardiogram results of 0, 6, and 8,

6 shows left ventricular ejection fraction (LVEF), left ventricular internal dimension (LVID), and left ventricular internal lumen (LVEF).

[Table 1] Echocardiogram results of 0, 6, and 8

As shown in Table 1, the heart rate and heart rate of the second and third groups were significantly higher than those of the first group. In addition, the systolic left ventricular lumen size of Group 2 and Group 3 was also significantly lower than that of Group 1, and this resulted in the failure of heart failure due to the increase in the lumen of the ventricles by Fimasartan. It was found to be mitigated.

As can be seen from FIG. 6, the heart rate and cardiac output of the second and third groups were significantly higher than those of the first group. In addition, systolic left ventricular luminal size in Group 2 and Group 3 was also significantly lower than that in Group 1, suggesting that the size of the ventricular lumen extended to the heart failure by Pimassartan decreased, Was improved.

4) Hemodynamic Parameter  Measure

The hemodynamic parameters of the 9th week were measured in the same manner as in the 0th, 6th and 8th week.

The measurement showed that the maximum slope (+ dP / dt) of heart rate, LV ESV (left ventricular end systolic volume, end-systolic LV volume), left ventricular end diastolic volume (LV EDV) ), The maximum slope of relaxation pressure (-dP / dt) and τ (weiss, Isovolumic relaxation constant).

Table 2 below is a table showing the hemodynamic parameters of 9th week.

[Table 2] Hemodynamic parameters of ninth week

As shown in Table 2, the heart rate, heart rate, and pressure change rate per hour in group 2 and group 3 were significantly higher than those in group 1. In addition, the systolic LV volumes of the second and third groups were also significantly lower than those of the first group. From these results, the size of the ventricle extended to the heart failure decreased and the ventricular outflow rate increased, And the function of the. Particularly, the rate of pressure change per hour was significantly increased as compared with that of the first group. Thus, it was found that the Pimassartan of the present invention had an excellent effect in restoring the elasticity of the ventricle. In addition, the τ value of the second group and the third group was significantly increased compared to the first group, it was confirmed that the cardiac relaxation function of the Pmasartan-treated group significantly improved.

5) Calculated from the pressure-volume curve of ninth week Hemodynamic Parameter  Measure

Group 1, group 2, group 3, and group 4 rats were each anesthetized by anesthesia in anesthesia vials infused with 3.0% isoflurane (Choongwae Pharma). The rats were then held on a holding plate and maintained at the rectal temperature using a heating pad and a temperature controller. The lungs were opened with the aid of a 16G catheter (Angiocath) to connect the lungs with a ventilator (Harvard) and a respiratory rate of 2.5 cc / Respectively.

For drug administration, the skin on the right side of the rats was cut to expose the jugular vein, and the polyethylene (PE-10) with a 30G needle connected to the external diameter vein was intubated. Then, to maintain the osmotic pressure of the heart, the injection water containing albumin and 0.9% physiological saline (1: 1) was supplied at a rate of 0.15 ml per minute for the first 5 minutes and then 0.04 ml per minute for a total of 20 minutes. When the rats stabilized, the ventilator was stopped for 3 seconds and the baseline of the pressure-volume curve was obtained.

To measure mean arterial pressure, polyethylene (PE-50) was inserted into the left femoral artery. In order to prevent the coagulation of blood in the blood, a 0.9% physiological saline pack was filled with 500 IU / ml heparin (Choongwae Pharmaceutical Co.) and the mean arterial pressure was measured.

The diaphragm was cut with electrocautery and the heart was exposed. A 22G needle was punctured at the apex of the left atrium, and a catheter (Millar, SPR-838, 2F, 12cm) was inserted into the left atrium, The left ventricle was placed in a suitable position to draw a curve. A continuous signal of 1,000 times per second was acquired using an ARIA P-V conductance system (Millar Instruments, Houston, TX) connected to the catheter, a PowerLab / 4SP A / D converter (AD Instruments, MountainView, The pressure-volume signals obtained from the catheter were converted in a Millar pressure-volume system and expressed as a pressure-volume curve through a PowerLab (ADInstrument Inc. USA), and analyzed using a PVAN program (Millar Instrument). Place the catheter tip in the left ventricle while viewing the pressure curve and measure the loop of the pressure-volume curve once the animal model is stable.

EES (End Systolic Pressure-Volume Relation, Systolic Pressure-Volume), Slope-EDPVR (End-Diastolic Pressure-Volume Relation), Emax ), Preload recruitable stroke work (PRSW), dP / dt-EDV (end diastolic volume, diastolic volumetric slope) were measured.

FIG. 7 is a pressure-volume curve for each of the first, second, third, and fourth groups that completed all the experiments and remained at 9 weeks, and Table 3 below shows the hemodynamic parameters derived therefrom. Graph.

[Table 3] Hemodynamic parameters of ninth hour, derived from the pressure-volume curve

As shown in Table 3, the PRSWs of the second and third groups were significantly higher than those of the first group. In the third group, dP / dt-EDV is close to that of the fourth control group. It was shown that heart failure was reversed due to the increased blood flow to the heart failure, and the hemodynamic parameters derived from the pressure - volume curve showed that Pimassartan had an excellent effect in preventing, alleviating or treating heart failure.

Also, as shown in FIG. 7, the slope of the pressure-volume curves of the second and third groups was not significantly different from that of the fourth control group, whereas the slope of the pressure- It can be observed that there is a significant difference. This means that the blood transport reduced by heart failure is normalized by the administration of Pimassaran.

6) Lung and heart mass index

After completion of the above experiments, the first, second, third and fourth group rats were taken to measure the mass of ventricles and lungs of each group, and the mass index of the lungs and heart were calculated.

The mass index is calculated according to the following formula.

8 is a formula showing a method for calculating the lung and heart mass index, Figure 9 is a graph comparing the lung and heart volume index for each drug group.

Table 4 below is a table showing lung and heart volume index by autopsy of rats surviving week 9 after completing all the experiments.

[Table 4] Pulmonary and cardiac mass index

As shown in Table 4, it can be seen that the 8-block body mass, ventricular mass, and lung mass index of the second and third groups were significantly lower than those of the first group. As the weight of the lungs per rat weight decreases, the degree of pulmonary congestion in rats of the second and third groups decreases to a significant level as compared to the first group.

Claims (13)

Pharmaceutical composition for preventing, alleviating or treating heart failure, comprising fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The pharmaceutical composition of claim 1, wherein the heart failure is due to dilated cardiomyopathy. The pharmaceutical composition for preventing, alleviating or treating heart failure according to claim 1, wherein the heart failure is induced by an anticancer agent. The pharmaceutical composition of claim 3, wherein the anticancer agent is an anthracycline-based substance. The method of claim 4, wherein the anthracycline-based substance is doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleomycin, daunorubicin, dactinomycin, pyrarubicin, aklarubicin, pef A pharmaceutical composition for preventing, alleviating or treating heart failure, which is at least one selected from the group consisting of romanic acid, daunorubicin, balubicin, and actinomycin. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered in combination with at least one drug selected from the group consisting of cardiovascular agents, vasodilators, antithrombotic agents, and hypertension drugs. The pharmaceutical composition for preventing, alleviating or treating heart failure according to claim 1, wherein the pharmaceutical composition is administered in combination with an anticancer agent. The pharmaceutical composition for preventing, alleviating or treating heart failure according to claim 7, wherein the anticancer agent is an anthracycline-based substance. A pharmaceutical composition for preventing, alleviating or treating heart failure, wherein comasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is administered in combination with doxorubicin. For preventing, alleviating or treating heart failure comprising fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and at least one drug selected from the group consisting of cardiac agents, vasodilators, antithrombotic agents and antihypertensive agents Combinations. A combination preparation for preventing, alleviating or treating heart failure, including fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and an anticancer agent. The combination agent according to claim 11, wherein the anticancer agent is an anthracycline-based substance. A combination preparation for preventing, alleviating or treating heart failure, including fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and doxorubicin.

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