Composition for preventing heart disease caused by pulmonary arterial hypertension and treating heart, and functional preparation containing same

Abstract

The invention provides a composition for preventing and treating heart diseases caused by pulmonary arterial hypertension and a functional preparation containing the composition. The composition comprises pimobendan, enalapril, torasemide and spirolactone, and can effectively prevent and treat animal heart diseases and pulmonary arterial hypertension.

Description

Technical Field

[0001] The present invention relates to a composition for preventing and treating heart disease and a functional preparation containing the composition. More specifically, the present invention relates to a composition for preventing and treating heart disease such as heart failure caused by pulmonary hypertension in animals such as dogs and cats, but not humans, and an animal functional preparation containing the composition. Background Art

[0002] The heart receives blood from the veins and continuously circulates it throughout the body via the arteries. To pump blood, the heart contracts, and this contraction is driven by the myocardium, a muscle. However, when the ventricles are overloaded due to hypertension or heart valve disease, or when the myocardial cells themselves are damaged due to myocardial infarction, myocarditis, or cardiac hypertrophy, the amount of blood pumped to the body's organs may not be sufficient, leading to decreased cardiac output and cardiac hypertrophy. The heart is an embryologically fully differentiated organ, making further cell proliferation impossible. Therefore, when increasing cardiac output is needed, the only solution is to increase the size of existing myocardial cells to increase their contractility, a physiological phenomenon known as hypertrophy. If this hypertrophy persists for a period of time, it can easily lead to heart failure. Summary of the Invention

[0003]

Technical Issues

[0004] One cause of heart failure is pulmonary hypertension. As blood flows from the right side of the heart to the lungs through the pulmonary arteries, carbon dioxide is removed from the blood and oxygen is replenished. When blood pressure in the pulmonary arteries rises to high levels, this condition is called pulmonary hypertension. In this condition, blood flow from the right ventricle to the pulmonary artery may become difficult. Consequently, the right ventricle of the heart thickens and enlarges, potentially leading to right heart failure.

[0005] Aspects of the present invention provide a composition for effectively preventing and treating cardiac diseases such as heart failure, and a functional preparation comprising the composition.

[0006] Aspects of the present invention also provide a composition for effectively preventing and treating heart diseases such as heart failure and pulmonary hypertension that may cause heart diseases, and a functional preparation comprising the composition.

[0007] However, aspects of the present invention are not limited to the aspects set forth herein. The above and other aspects of the present invention will become more apparent to those skilled in the art to which the present invention pertains by referencing the detailed description of the present invention given below.

[0008]

Technical solution

[0009] According to one aspect of the present invention, a composition for preventing and treating heart disease and pulmonary hypertension in animals is provided. The composition comprises: pimobendan; enalapril; torsemide; and spironolactone.

[0010] The composition and functional preparation may comprise 0.5 mg of pimobendan, 1 mg of enalapril, 0.2 mg of torsemide and 2 mg of spironolactone.

[0011] Based on the subject's body weight, a single administration dose of pimobendan may be 0.25 mg / kg, a single administration dose of enalapril may be 0.5 mg / kg, a single administration dose of torsemide may be 0.1 mg / kg, and a single administration dose of spironolactone may be 1 mg / kg, and pimobendan, enalapril, torsemide, and spironolactone may be administered twice daily.

[0012] The target can be a dog or a cat.

[0013] Details of other embodiments are described in the detailed description.

[0014] Beneficial effects

[0015] The composition according to an embodiment of the present invention can effectively prevent and treat animal heart disease and pulmonary hypertension by comprising pimobendan, enalapril, torsemide and spironolactone.

[0016] The composition according to the present invention can be prepared into preparations in various dosage forms regardless of the dosage form, and can also be used as an additive to various preparations.

[0017] The composition according to the embodiment of the present invention is effective for pets such as dogs and cats, and can be made into snacks and food for pets.

[0018] The effects of the present invention are not limited to the aforementioned effects, and various other effects are included in this specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figures 1 to 5 is a graph showing the clinical test results of Example 1;

[0020] Figures 6 to 8 Graph showing the blood index test evaluation results of Example 1;

[0021] Figures 9 to 14 Graph showing the results of serum biochemical index testing and evaluation in Example 1;

[0022] Figures 15 to 18 Graph showing the results of serum electrolyte index evaluation in Example 1;

[0023] Figures 19 to 21 is a graph showing the biomarker test results of Example 1;

[0024] Figures 22 to 24 1 is a diagram showing the chest X-ray film evaluation results of Example 1;

[0025] Figures 25 to 32 1 is a diagram showing the cardiac ultrasound evaluation results of Example 1;

[0026] Figure 33 A diagram showing the International Small Animal Society of Cardiology (ISACHC) stage assessment results of Example 1;

[0027] Figures 34 to 38 is a graph showing the clinical test results of Example 2;

[0028] Figures 39 to 41 Graph showing the chest X-ray evaluation results of Example 2;

[0029] Figures 42 to 45 1 is a diagram showing the cardiac ultrasound evaluation results of Example 2;

[0030] Figure 46 is a graph showing the results of pulmonary hypertension severity assessment in Example 2; and

[0031] Figure 47 Graph showing the ISACHC stage evaluation results of Example 2. DETAILED DESCRIPTION

[0032] The advantages and features of the present invention and the methods for achieving the advantages and features will become apparent from the embodiments described in detail below with reference to the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but can be implemented in various forms. These embodiments are provided only to complete the present invention and enable those skilled in the art to fully appreciate the scope of the present invention. The present invention will be defined by the scope of the claims.

[0033] In addition, "and / or" includes each and all combinations of one or more of the items. A numerical range expressed using "to" indicates a numerical range that includes the values ​​described before and after "to" as the lower limit and the upper limit, respectively. "About" or "approximately" refers to a value or numerical range within 20% of the value or numerical range described after "about" or "approximately".

[0034] Embodiments of the present invention will be described below.

[0035] A composition for preventing and treating heart disease according to an embodiment of the present invention includes pimobendan, enalapril, torsemide, and spironolactone. The composition according to the present invention is effective for preventing and treating heart disease in animals such as dogs and cats, but not humans. In particular, the composition according to the present invention is effective for preventing and treating diseases that cause changes in heart size, such as heart failure, a common cause of heart disease, and pulmonary hypertension, a cause of such diseases.

[0036] As used herein, "heart failure" refers to any contractile disorder or heart disease. Generally, clinical symptoms are changes in the cellular and molecular components of the heart and in the mediators that drive homeostatic control. Generally, heart failure is associated with increased heart size and worsening heart function.

[0037] Pimobendan is a positive inotropic vasodilator compound with calcium sensitization and multiple type III phosphodiesterase inhibitory properties. Calcium sensitizers achieve their positive inotropic effects by sensitizing contractile proteins to cytoplasmic calcium, altering calcium binding to troponin C rather than increasing calcium influx into cardiomyocytes. Achieving positive inotropic effects through calcium sensitization can prevent some of the side effects of cytoplasmic calcium overload. Elevated cytoplasmic calcium levels are associated with an increased tendency for arrhythmias and sudden death. Clinical trials of dogs with heart failure using long-term oral administration of pimobendan have shown improved exercise tolerance and quality of life, with no significant adverse effects on survival.

[0038] Pimobendan is a positive inotropic vasodilator with positive myocardial strength and vasodilation effects. This action, in addition to its PDEi-3 effects, also produces a cardiotonic effect by increasing the sensitivity of the myocardial contractile apparatus to calcium, leading to its term as a calcium sensitizer. Because pimobendan exhibits cardiotonic effects without increasing myocardial oxygen demand, it is a drug that does not exacerbate ischemic changes in heart failure, increases myocardial contractility, and carries little risk of arrhythmias, as seen with digitalis. Pimobendan is indicated for the chronic treatment of all dogs with heart failure due to chronic mitral regurgitation (CMVI) or dilated cardiomyopathy (DCM). Pimobendan has been shown to be highly beneficial in treating dogs with clinical signs of heart failure, with significant improvements in clinical symptoms and prolonged survival (PITCH 2000 and QUEST 2008). Pimobendan's therapeutic effects have been shown to be particularly effective in dogs with CMVI and DCM. The EPIC study (2018) investigated whether pimobendan improved clinical / radiological findings and differed in disease progression when administered to dogs with subclinical (asymptomatic) CMVI. The study demonstrated a decrease in LVIDd and LA / Ao as measured by radiographic imaging at day 35 in the pimobendan group compared to the placebo group.

[0039] Enalapril is a medication used to treat high blood pressure, diabetic kidney disease, and heart failure. For heart disease, enalapril is often used with a diuretic such as furosemide. Enalapril can be taken orally or intravenously. When taken orally, its effects typically begin within an hour and last for a day. Enalapril belongs to a class of drugs called angiotensin-converting enzyme (ACE) inhibitors, and common side effects may include headache, fatigue, and cough.

[0040] Angiotensin-converting enzyme inhibitors (ACEi), such as enalapril, cause vasodilation by inhibiting the formation of angiotensin II, a vasoconstrictor produced by the action of renin, which is secreted by the kidneys. Clinically, ACEi are primarily used to treat heart failure, hypertension secondary to renal disease, and proteinuria. The efficacy of various ACEi (enalapril, benazepril, imidapril, and captopril) has been evaluated in dogs with clinical symptoms (COVE study, 1995; Live study, 1998; and BENCH trial, 1999). These studies have shown that administering ACEi to dogs with heart failure due to diabetic melanoma (DCM) and CMVI can slow the progression of heart failure, improve clinical symptoms, and prolong survival.

[0041] Torsemide is a diuretic used to treat fluid overload caused by heart failure, kidney disease, liver disease, and hypertension. Torsemide itself is not generally preferred for the treatment of hypertension. It is a loop diuretic like the sulfonamide class, which inhibits sodium reabsorption by the kidneys. Common side effects of torsemide may include headache, increased urine output, diarrhea, cough, and dizziness. Other side effects of torsemide may include hearing loss and hypokalemia.

[0042] Diuretics are the most commonly used and effective drugs for the treatment of heart failure. Diuretics reduce circulating blood volume to reduce venous return, ultimately reducing the amount of blood flowing into the ventricles (full capacity). The main diuretics used in small animal clinical practice include: (1) loop diuretics, (2) thiazide diuretics, and (3) potassium-sparing diuretics. Among them, the diuretics with the strongest diuretic effect are loop diuretics, such as torsemide. Furosemide has traditionally been the most widely used drug in veterinary medicine, but it exhibits a ceiling effect (the phenomenon of halving the efficacy after a predetermined period of time) when taken orally and has lower bioavailability than torsemide. In a study investigating the pharmacokinetic characteristics of torsemide in dogs, torsemide showed almost no ceiling effect and showed sustained efficacy even after long-term administration. In addition, in a recent randomized controlled trial comparing the two drugs in a French study, torsemide showed excellent efficacy. Torsemide is often used in dogs refractory to furosemide, but because torsemide has high bioavailability, a long blood half-life, and virtually no ceiling effect, it offers advantages over furosemide in treating dogs with heart failure without increasing the diuretic dose.

[0043] Spironolactone is an anti-aldosterone agent, potassium-sparing diuretic, and spirocyclic compound. It exerts its potassium-sparing diuretic effect by inhibiting the binding of aldosterone to its receptors in the body. Spironolactone is primarily used to treat heart failure, ascites due to liver cirrhosis, and hypertension. It can also be used as an adjunctive treatment for hypokalemia.

[0044] Potassium-sparing diuretics (such as spironolactone) do not directly affect sodium transport and, unlike other diuretics, antagonize the effects of aldosterone in the collecting duct. Consequently, sodium (water) reabsorption is blocked, leading to diuresis. However, since potassium and hydrogen ion excretion does not occur in this region, there is no change in blood potassium or hydrogen concentrations. Therefore, these diuretics are called potassium-sparing diuretics. However, because sodium absorption in this region accounts for a very low proportion of total sodium reabsorption, the diuretic effect is low (approximately 10% of the efficacy of loop diuretics). Therefore, spironolactone should not be used alone and is often combined with a thiazide or loop diuretic to prevent hypokalemia. A study investigating whether spironolactone could delay heart failure in dogs with subclinical myxomatous mitral valve disease (MMVD) was conducted, but the effect was not clearly demonstrated. However, the increases in heart size and cardiac biomarker concentrations on echocardiography were much smaller in the spironolactone group than in the placebo group.

[0045] According to one embodiment, the composition according to the present invention can include the pimobendan of 5 weight portions, the enalapril of 10 weight portions, the torsemide of 2 weight portions and the spironolactone of 20 weight portions. According to the composition of the present invention, the pimobendan, enalapril, torsemide and the spironolactone of the amount of effective prevention and treatment of heart disease can be respectively included, and in view of the body weight of the target group (such as, target objects such as dogs or cats) of the composition according to the present invention, the corresponding components of the required amount of single administration can be included. According to one embodiment, the composition can include the pimobendan of 0.5mg, the enalapril of 1mg, the torsemide of 0.2mg and the spironolactone of 2mg. The tablet of tableting and being made by this composition can include the pimobendan of 0.5mg, the enalapril of 1mg, the torsemide of 0.2mg and the spironolactone of 2mg. The gross weight range of each tablet is unrestricted, and can be set according to the type of dog, the ability to take medicine, the absorption rate of tablet component etc. For example, tablets prepared by compressing the composition may weigh 100 mg per tablet and contain 0.5 mg of pimobendan, 1 mg of enalapril, 0.2 mg of torsemide, and 2 mg of spironolactone. For detailed description, please refer to the experimental examples described below.

[0046] The composition for preventing and treating heart disease according to the embodiment of the present invention can be prepared into various oral or parenteral dosage forms. When preparing the composition, commonly used fillers, extenders, binders, wetting agents,

[0047] Oral solid preparations include tablets, pills, powders, granules, capsules, and the like, and are prepared by mixing one or more excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, and the like with one or more compounds. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, oral solutions, emulsions, syrups, and the like. In addition to commonly used simple diluents such as water or liquid paraffin, they may also include several excipients such as wetting agents, sweeteners, flavorings, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized solutions, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, polyethylene glycol, Tween 61, cocoa butter, glyceryl laurate, and glycerol gelatin.

[0048] According to one embodiment, a composition for preventing and treating heart disease can be formulated by adding excipients. For example, the composition for preventing and treating heart disease can be prepared into a tablet by adding fat, such as chicken fat, and tocopheryl acetate. Since the fat and tocopheryl acetate are coated on the surface of the tablet, the fat is not absorbed into the interior of the tablet, thereby preventing the tablet from breaking or becoming wet.

[0049] The composition for preventing and treating heart disease according to embodiments of the present invention can be prepared into various functional foods. For example, the composition for preventing and treating heart disease according to embodiments of the present invention can be prepared into various foods, such as chewing gum, caramel products, candies, ice cream and sweets, beverages such as soft drinks, mineral water, and alcoholic beverages, and health functional foods such as vitamins or minerals. Furthermore, the composition for preventing and treating heart disease according to embodiments of the present invention can be formulated into oral preparations for pets, specifically, tablets, capsules, liquids, gels, pastes, oral sprays, oral tablets, powders, and chewable tablets, or animal feed, but is not limited thereto.

[0050] The composition for preventing and treating heart disease according to an embodiment of the present invention can be directly prepared as a food or used together with other food ingredients, and can be appropriately used according to conventional methods. The amount of the mixed active ingredients can be appropriately determined according to the purpose of use.

[0051] Functional foods according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients. These natural carbohydrates include monosaccharides such as glucose and fructose, or sugar alcohols such as sorbitol and erythritol. Sweeteners such as natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame, may be used. The proportion of natural carbohydrates is preferably selected within the range of 0.01 to 0.04 parts by weight, preferably approximately 0.02 to 0.03 parts by weight, per 100 parts by weight of the health functional food according to the present invention.

[0052] Functional food according to the present invention, in addition to the above-mentioned ingredients, can also comprise the carbonating agent used in various nutrients, vitamins, electrolytes, correctives, coloring agents, pectin acid and its salt, alginic acid and its salt, organic acid, protective colloid thickener, pH adjusting agent, stabilizer, preservative, glycerine, alcohol, carbonated beverage etc. In addition, functional food according to the present invention can also comprise pulp for the preparation of natural fruit juice, fruit juice beverage and vegetable beverage. These compositions can be used alone or in combination. The ratio of this type of additive is not important, but generally in the functional food according to the present invention 100 weight parts, is selected in the scope of 0.01 to 0.1 weight part.

[0053] The present invention will be described in more detail below by way of examples. These examples are provided only to illustrate the present invention, and the scope of the present invention is not limited by these examples.

[0054] <Example 1> Preparation of a composition for preventing and treating heart disease

[0055] The preparation for treatment is prepared by mixing the components in Table 1 with each other. heart disease The unit in Table 1 is mg. The composition having the following composition was compressed to prepare tablets each containing 100 mg.

[0056]

Table 1

[0057] Element Content (100mg) Pimobendan 0.5mg Enalapril 1mg Torsemide 0.2mg Spironolactone 2mg preservative appropriate amount Other additives appropriate amount

[0058] <Experimental Example 1> Confirmation of the Effect of Prevention and Treatment of Heart Disease

[0059] In order to confirm the preventive and therapeutic effects of the composition of Example 1 on heart disease, the following experiment was conducted.

[0060] <Experimental Methods>

[0061] A test group administered with the composition of Example 1 and a placebo group administered with a placebo were selected and experiments were conducted to evaluate the efficacy and stability of the administration. Thirty experimental dogs diagnosed with International Small Animal Society of Cardiology (ISACHC) stage III or higher heart failure were selected as the test group and placebo group. The 30 experimental animals selected were all small dogs of the same sex, including 15 females and 15 males.

[0062] Heart failure status in the selected experimental animals was classified by veterinary cardiologists based on clinical examination, chest X-ray, and direct examination of the heart using echocardiography, and the ACVIM guidelines for pulmonary hypertension. Dogs with other organ diseases during clinical examination were excluded.

[0063] As a test drug administration method, the tablets prepared in Example 1 were orally administered to experimental animals twice daily, with 1 / 2 tablet administered per kg of the experimental animal's body weight. The tablets were administered at the same time interval of 12 hours each morning and evening, regardless of whether meals were taken, for a 56-day administration period.

[0064] This study tested the drug in dogs with heart failure caused by various factors, including valvular disease. ISACHC III heart failure is a severe form of heart failure, and dogs with this condition exhibit clear clinical signs of heart disease, such as pulmonary edema or syncope. Among these dogs, pulmonary hypertension, a complication of heart disease, was separately assessed for indicators of pulmonary hypertension, and the effects of drug administration were observed.

[0065] The drug administration test intervals were one day before administration (Day 0), 7 days after administration (Day 7), 14 days after administration (Day 14), 28 days after administration (Day 28), and 56 days after administration (Day 56).

[0066] The specific observation items and test methods are as follows.

[0067] Observation Project

[0068] 1) CBC: Hematology indicators (RBC indicators and WBC indicators)

[0069] 2) Serum biochemistry test: kidney indicators (BUN and creatinine), liver indicators (ALT and ALP), total protein (TP, albumin), electrolyte indicators (Na, K, Cl, P, etc.)

[0070] 3) X-ray assessment of heart and lung fields: VHS, VLAS, and lung field morphology

[0071] 4) Echocardiography: LA / Ao, LVIDdn, MVE, E / E', TR velocity, PR velocity, RVOT ET / AT, RVOT AT measurement

[0072] 5) Blood symmetric dimethylarginine (SDMA) concentration: Evaluation of kidney improvement

[0073] 6) Blood N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration: Evaluation of cardiac function improvement

[0074] 7) Blood canine pancreatic lipase immunoreactivity (cPL) concentration: Evaluation of pancreatic numerical improvement

[0075] 8) As clinical test items, exercise intolerance (1 to 4; 1 is the best and 4 is the worst), appetite (1 to 4), labored breathing (1 to 4), coughing (1 to 4) and fainting (1 to 4) are checked with different numerical values.

[0076] The observation test method involves testing clinical test items one day before administration (Day 0), 7 days after administration (Day 7), 14 days after administration (Day 14), 28 days after administration (Day 28), and 56 days after administration (Day 56), with the test results recorded by a veterinarian and a guardian. X-rays, cardiac ultrasounds, and biomarker tests for the observation items are performed at a designated hospital, and the test results are recorded.

[0077] The effect evaluation criteria based on the test results of each clinical test item are as follows.

[0078] 1) Effect evaluation criteria

[0079] - Whether clinical symptoms have improved: increased energy, decreased coughing, increased appetite, decreased labored breathing, decreased fainting

[0080] - Improvement in CBC and serum biochemistry

[0081] - Improvement in heart size and lung infiltrates on chest X-ray

[0082] - Improved cardiac test parameters on echocardiography

[0083] - Improved cardiac biomarker test results

[0084] 2) Effect evaluation method

[0085] -Is clinical symptoms improved?: Evaluated through guardian records and veterinary examination records

[0086] - Improved CBC and serum biochemistry: Assessment of liver, kidney, pancreas, electrolytes, etc.

[0087] -Resolution of pulmonary hypertension on chest radiograph: determined by assessment of VHS (heart dimensions), VLAS (left atrial dimensions), and lung field morphology (lung field infiltrate findings)

[0088] - Improvement in cardiac test parameters assessed by echocardiography: determined by assessing LA / Ao (aorta to left atrial diameter ratio), LVIDdn (left ventricular end-diastolic diameter), MVE (mitral valve filling velocity), E / E' (mitral valve filling velocity to tissue Doppler velocity ratio), TR velocity (tricuspid regurgitation velocity), PR velocity (pulmonary regurgitation velocity), RVOT ET / AT (right ventricular outflow tract ejection time / acceleration time), and RVOT AT (right ventricular outflow tract acceleration time)

[0089] - Improved cardiac biomarker testing results: SDMA concentration, which reflects renal perfusion status, was used to assess the degree of improvement in renal circulation and inhibition of renal remodeling, and NT-proBNP concentration was used to assess whether right heart pressure decreased due to pulmonary hypertension.

[0090] 3) Statistical interpretation methods

[0091] - Each test indicator was tested for normal distribution by Kolmogorov-Smirnov test.

[0092] - The differences in test indicators among the groups were compared by Mann-Whitney U test, and the differences before and after administration were compared by Wilcoxson signed-rank test.

[0093] -P<0.05 was assessed as statistically significant.

[0094] <Experimental Results 1>

[0095] 1. Clinical testing

[0096] As a result of the clinical test of Example 1, the evaluation results of exercise intolerance, appetite, syncope, labored breathing and cough are shown in Tables 2 and Figures 1 to 5 middle.

[0097]

Table 2

[0098] Test indicators / test time points Day 0 Day 7 Day 14 Day 28 Day 56 Exercise intolerance (1 to 4) 3.07 1.87 1.47 1.33 1.13 Appetite (1 to 4) 2.87 1.67 1.27 1.00 1.07 Fainting (1 to 4) 3.33 1.73 1.33 1.07 1.00 Labored breathing (1 to 4) 2.67 1.80 1.47 1.33 1.20 Cough (1 to 4) 1.87 1.13 1.07 1.00 1.00

[0099] In Table 1, numerical values ​​1 to 4 of the clinical evaluation results were evaluated to represent the following situations, respectively.

[0100] - Exercise intolerance: 1. Not at all, 2. Feeling tired after long periods of walking, 3. Having trouble walking when walking, 4. Refusing to walk

[0101] - Appetite: 1 Very good, 2 Good, 3 Picky eater (will only eat delicious food), 4 Refuse to eat

[0102] - Breathing effort: 1 Not at all, 2 Hyperventilation after play, 3 Hyperventilation within 30 minutes even when resting, 4 Hyperventilation even during sleep

[0103] - Fainting: 1 Not at all, 2 Faint once or less a day after exercise or excitement, 3 Faint once or less a day regardless of exercise or excitement, 4 Faint once or more a day regardless of exercise or excitement - Coughing: 1 Not at all, 2 Cough when excited or drinking water, 3 Cough less than 10 times a day regardless of excitement or drinking water, 4 Cannot sleep due to coughing

[0104] Figures 1 to 5 It is a graph showing the clinical test results of Example 1. Figures 1 to 5 Evaluation results of exercise intolerance, appetite, syncope, labored breathing, and cough of the test group and the placebo group are shown separately as clinical test results.

[0105] Reference Figures 1 to 5 In terms of exercise intolerance assessment, the dogs' exercise intolerance improved significantly after one week of administration (day 7), and as a result, these dogs did not feel particularly tired in their daily lives. Since the 14th day of administration (day 14), most of the dogs did not experience exercise intolerance symptoms in their daily lives.

[0106] In terms of appetite assessment, the appetite of the sick dogs was significantly improved after one week of administration (day 7), so these dogs did not particularly refuse food in daily life. Since the 14th day of administration (day 14), most of the sick dogs showed a healthy appetite in daily life.

[0107] In terms of respiratory effort assessment, the respiratory effort symptoms of the sick dogs were significantly improved from one week after administration (day 7), so these dogs did not have major problems in their daily lives. From the 14th day of administration (day 14), most of the sick dogs did not have any special respiratory effort symptoms in their daily lives.

[0108] In terms of cough assessment, the cough symptoms of the sick dogs improved significantly after one week of administration (day 7), so these dogs did not have major problems in their daily lives. Since the 14th day of administration (day 14), most of the sick dogs did not have cough symptoms unless they were stimulated in their daily lives.

[0109] In terms of syncope evaluation, the sick dogs showed almost no syncope symptoms since one week of administration (day 7), and syncope symptoms were hardly observed in the sick dogs during other administration periods.

[0110] 2. Blood index test

[0111] As the blood index test of Example 1, anemia or polycythemia (secondary to cyanosis) was evaluated by red blood cell count (RBC) and hematocrit (PCV) during administration. In addition, the occurrence of inflammation was evaluated by evaluating white blood cell count (WBC). The evaluation results of the blood index test are shown in Tables 3 and Figures 6 to 8 shown.

[0112]

Table 3

[0113] Test indicators / test time points Day 0 Day 7 Day 14 Day 28 Day 56 RBC 6.34 6.52 6.44 6.72 6.46 PCV 39.76 40.08 41.66 43.90 40.99 WBC 14.05 13.64 12.74 12.36 12.36

[0114] Figures 6 to 8 Graphs showing the evaluation results of the blood index test in Example 1. Figures 6 to 8 Evaluation results of red blood cell count (RBC), hematocrit (PCV), and white blood cell count (WBC) during the administration period are shown, respectively.

[0115] Refer to Table 3 and Figures 6 to 8 , no significant changes in the blood cell ratio were observed before and after administration.

[0116] 3. Serum biochemical index test

[0117] As the serum biochemical index test of Example 1, the renal function biochemical indexes (BUN, creatinine), liver function biochemical indexes (ALT, ALP) and serum protein indexes (TP, albumin) during the administration period were evaluated. The results of the serum biochemical index test evaluation are shown in Table 4 and Figures 9 to 14 shown.

[0118]

Table 4

[0119]

[0120] Figures 9 to 14 Graphs showing the evaluation results of the serum biochemical index test in Example 1. Figures 9 to 14 Evaluation results of BUN, creatinine, ALP, ALT, TP, and albumin (Alb) are shown, respectively.

[0121] Refer to Table 4 and Figures 9 to 14 , it has been reported that when an overdose of cardiac drugs (e.g., diuretics) is administered, an increase in renal parameters is often observed, but Figure 9 The BUN assessment results shown and Figure 10 As shown in the results of creatinine evaluation, no significant changes in renal indices were observed before and after administration of Example 1 comprising the composition according to the present invention.

[0122] Elevated liver enzyme levels have been widely reported in dogs with right heart failure (pulmonary hypertension). These elevated liver enzyme levels have been reported to decrease as symptoms of heart failure improve. Figure 11 The ALP evaluation results shown and Figure 12 As shown in the ALT evaluation results, in this experiment, a gradual improvement (decrease) in liver enzyme test indicators was also observed before and after administration.

[0123] Total protein and albumin tend to increase with excessive use of diuretics included in cardiac medications (when dehydration is severe), but tend to decrease when symptoms of heart failure such as decreased liver function or fluid retention are severe. Figure 13 The evaluation results of TP and Figure 14 In this study, the serum protein levels of Alb were evaluated. These serum protein indicators showed a gradual upward trend after administration. However, no significant increase indicating dehydration was observed, only a gradual upward trend due to the suppression of fluid retention and liver treatment was observed.

[0124] 4. Serum electrolyte index test

[0125] As a serum electrolyte index test of Example 1, changes in the concentrations of electrolytes Na, K, Cl, and P in the serum during administration were evaluated. The results are shown in Tables 5 and Figures 15 to 18 middle.

[0126]

Table 5

[0127]

[0128] Figures 15 to 18 Graphs showing the evaluation results of serum electrolyte indices in Example 1. Figures 15 to 18 Changes in the concentrations of Na, Cl, K, and P as serum electrolytes in the blood are shown respectively.

[0129] Due to the nature of cardiac medications, electrolyte imbalances are a common side effect. Torsemide, an ingredient in this test drug, acts on the loop of Henle in the kidneys to remove sodium and exert its pharmacological effects, resulting in hyponatremia, hypokalemia, and hypochloremia. On the other hand, drugs such as spironolactone and enalapril act on the collecting ducts, retaining potassium and potentially causing hyperkalemia or hypernatremia. Therefore, when these drugs are properly mixed, they can prevent these electrolyte imbalances.

[0130] Refer to Table 5 and Figures 15 to 18 In this study, no statistically significant changes in sodium, potassium, and chloride levels were observed before and after administration. Phosphorus is a critical electrolyte, and when kidney function is lost by 85%, impaired phosphorus excretion and renal hyperparathyroidism can lead to elevated phosphorus levels. Because excessive cardiac medications can reduce renal function, it is important to monitor phosphorus levels in dogs receiving cardiac medications. In this study, no changes in phosphorus levels were observed before and after administration, and no dogs developed clinically significant hyperphosphatemia during the entire administration period.

[0131] 5. Biomarker index testing

[0132] As biomarker indicators tested in Example 1, changes in kidney markers (SDMA), pancreatitis markers (cPL), and heart failure markers (NT-proBNP) were tested. The main biomarker test results for dogs with heart failure caused by pulmonary hypertension were increased kidney markers (SDMA), increased pancreatitis markers (cPL), and increased heart failure markers (NT-proBNP).

[0133] SDMA, short for symmetric dimethylarginine, is the most widely used prognostic marker for kidney failure in veterinary clinical practice. Dogs with stage 1 kidney failure are classified as having an SDMA of 18 or less, dogs with stage 2 kidney failure have an SDMA of 18 to 35, dogs with stage 3 kidney failure have an SDMA of 36 to 54, and dogs with end-stage kidney failure have an SDMA of 54 or higher.

[0134] CPL, short for canine pancreatic lipase, is the most widely used prognostic marker for canine pancreatitis in veterinary clinical practice. A CPL of 200 or less indicates normal, a CPL of 200 to 400 indicates borderline pancreatitis, and a CPL of 400 or higher indicates pancreatitis.

[0135] NT-proBNP, short for N-terminal pro-brain natriuretic peptide, is the most widely used prognostic marker for canine heart failure in veterinary clinical practice. An NT-proBNP level of 900 or less indicates normal heart function, an NT-proBNP level of 900 to 1800 indicates borderline heart failure, and an NT-proBNP level of 400 or higher indicates heart failure.

[0136] This assessment tested the changes in biomarker indicators, and the results are shown in Table 6 and Figures 19 to 21 shown.

[0137]

Table 6

[0138] Test indicators / test time points Day 0 Day 7 Day 14 Day 28 Day 56 SDMA 17.27 15.80 15.60 16.13 17.40 NT-proBNP 5200.53 3353.33 2580.00 1796.67 1556.00 cPL 87.36 143.07 79.07 74.20 82.40

[0139] Figures 19 to 21 Graphs showing the test results of the biomarkers in Example 1. Figures 19 to 21 Changes in SDMA, NT-proBNP, and cPL as biomarkers are shown, respectively.

[0140] Refer to Table 6 and Figures 19 to 21 NT-proBNP, a marker of heart failure, gradually decreased after administration, with a trend of gradual decrease over time. In particular, after 56 days of administration, the average NT-proBNP concentration had dropped to one-third of the pre-administration level. The renal marker SDMA and pancreatic marker cPL did not show significant changes before and after administration. Because dogs with systemic diseases were excluded from the selection process for the test, there appeared to be no significant changes in the values ​​of renal and pancreatic markers before and after administration.

[0141] 6. Chest X-ray Evaluation

[0142] As the chest X-ray film evaluation in Example 1, the evaluation index VHS of the heart size, the evaluation index VLAS of the left atrial size, and the lung field morphology were evaluated.

[0143] The cardiac size assessment index VHS is the abbreviation of spinal cardiac scale, which is a method for quantitatively assessing cardiac size through X-rays.

[0144] VLAS is an indicator of left atrial size, short for vertical left atrial score, which is a method of assessing heart size on chest X-rays.

[0145] Lung field morphology is a method of assessing how visible the lung lobes are on X-rays and is primarily used to determine whether the lungs are filled with fluid or inflamed.

[0146] The chest X-ray assessment results are shown in Table 7 and Figures 22 to 24 shown.

[0147]

Table 7

[0148] Test indicators / test time points Day 0 Day 7 Day 14 Day 28 Day 56 VHS 11.98 11.52 11.12 11.02 10.71 VLAS 3.15 2.93 2.71 2.59 2.44 Lung field morphology 2.47 1.33 1.00 1.00 1.00

[0149] Figures 22 to 24 Graphs showing the evaluation results of chest X-rays in Example 1. Figures 22 to 24 Evaluation results of VHS, VLAS, and lung field morphology are shown as chest X-ray evaluation results, respectively.

[0150] Refer to Table 7 and Figures 22 to 24 , the heart size evaluation index VHS began to decrease from the 7th day of administration (Day 7) and continued to decrease until the 56th day of administration (Day 56), and the left atrial size evaluation index VLAS also began to decrease from the 7th day of administration (Day 7) and continued to decrease until the 56th day of administration (Day 56). At the test time point of 7 days of administration (Day 7), the lung infiltrates of most sick dogs also improved to normal lung lobe morphology, and no sick dogs with lung infiltrates were observed at the test time point of 14 days of administration (Day 14).

[0151] 7. Cardiac ultrasound assessment

[0152] As an example of the cardiac ultrasound assessment in Example 1, cardiac ultrasound was used to measure LA / Ao, LVIDDn, MVE, and MV E / E' to assess the function of the left cardiac system. Furthermore, cardiac ultrasound was used to measure TR velocity, PR velocity, RVOT ET / AT, and RVOT AT to assess the function of the right cardiac system.

[0153] LA / Ao, the abbreviation for the ratio of aorta to left atrial diameter, is an indicator of left atrial enlargement. Dogs with Isaac C1 heart failure have an LA / Ao value of 1.4 to 1.8, dogs with Isaac C11 heart failure have an LA / Ao value of 1.8 to 2.0, and dogs with Isaac C13 heart failure have an LA / Ao value of 2.0 or higher. A normal LA / Ao value is 1.2 to 1.4, and an LA / Ao value of 1.2 or less is considered normal and is primarily due to dehydration.

[0154] LVIDdN is an indicator for evaluating the left ventricular end-diastolic diameter and is not related to the weight of the sick dog. When LVIDdN is 20 or above, it is generally considered that the left ventricular end-diastolic diameter is enlarged.

[0155] MVE refers to the blood flow velocity when the mitral valve is filling, which increases mainly with the worsening of heart failure.

[0156] Dogs with ISACHC type I heart failure have an MVE of 0.8 to 1.0 m / s, dogs with ISACHC type II heart failure have an MVE of 1.0 to 1.2 m / s, and dogs with ISACHC type III heart failure have an MVE of 1.2 m / s or higher. Normal MVE is 0.8 m / s or lower.

[0157] The MVE / E' ratio, the ratio of mitral blood flow velocity to mitral annular tissue Doppler velocity, is a predictor of left atrial pressure. When the MVE / E' ratio is 9 or higher, the left atrial pressure is 20 mmHg; when it is 12 or higher, the left atrial pressure is 30 mmHg or higher. Normally, left atrial pressure should not exceed 20 mmHg. An increase in this value indicates an increase in left atrial pressure.

[0158] TR velocity is the regurgitation velocity of tricuspid valve blood flow (in dogs with pulmonary hypertension, blood in the tricuspid valve contracts in the opposite direction of its original direction due to increased resistance in the right heart system and pulmonary vasculature). The faster the regurgitation velocity, the more severe the pulmonary hypertension. When the TR velocity reaches or exceeds 2.8 m / s, pulmonary hypertension is diagnosed.

[0159] The PR velocity is the reverse flow rate of pulmonary artery blood flow (in dogs with pulmonary hypertension, due to increased resistance in the right heart system and pulmonary vascular system, the pulmonary artery blood flows in the opposite direction during contraction). The faster the blood flow reverses, the more severe the pulmonary hypertension. When the PR velocity reaches or exceeds 2.2 m / s, pulmonary hypertension is diagnosed.

[0160] In pulmonary artery blood flow measurement, RVOT ET / AT is mainly composed of acceleration time (AT), ejection time (ET), and deceleration time (DT). When pulmonary vascular resistance increases, the acceleration time becomes shorter and the ejection time becomes longer. AT / ET is an echocardiographic indicator that can assess the severity of pulmonary hypertension by comparing the acceleration time and ejection time. Normal AT / ET is 0.42 or higher, while dogs with severe pulmonary hypertension have a significantly reduced AT / ET to 0.30 or lower. In other words, the lower the AT / ET, the more severe the pulmonary hypertension.

[0161] In pulmonary artery blood flow measurement, RVOT AT is primarily composed of acceleration time (AT), ejection time (ET), and deceleration time (DT). When pulmonary vascular resistance increases, the acceleration time shortens. This parameter is an echocardiographic indicator that can assess the severity of pulmonary hypertension. Lower RVOT AT and shorter acceleration time indicate more severe pulmonary hypertension.

[0162] The cardiac ultrasound evaluation results of the present invention are shown in Table 8 and Figures 25 to 32 shown.

[0163]

Table 8

[0164] Test indicators / test time points Day 0 Day 7 Day 14 Day 28 Day 56 LA / Ao 2.48 2.02 1.89 1.90 1.83 LVID 22.41 20.53 20.42 20.24 19.59 MVE 1.15 1.05 0.95 0.86 0.83 MV E / E' 12.32 9.90 8.78 8.37 7.41 TR speed 0.45 0.50 0.49 0.52 0.52 PR speed 66.40 74.87 75.80 78.80 84.13 RVOT ET / AT 2.27 1.70 1.59 1.35 1.23 RVOT AT 1.09 0.67 0.65 0.62 0.59

[0165] Figures 25 to 32 : is a graph showing the cardiac ultrasound evaluation results of Example 1. Figures 25 to 32 The evaluation results of LA / Ao, LVIDDn, MVE, MV E / E', TR velocity, PR velocity, RVOT ET / AT and RVOTAT as the results of cardiac ultrasound evaluation are shown respectively. Figures 25 to 32 In this experiment, it was also confirmed that in the evaluation after 7 days of administration (day 7), the left heart system indicators were significantly improved, and this improvement effect lasted until 56 days of administration (day 56). Because the circulatory system of dogs and cats is a closed circulatory system, diseases occurring on the left or right side of the heart will eventually transmit pressure to the other side of the heart. Therefore, many dogs with left heart failure will develop right heart failure over time, and the main cause of this phenomenon is pulmonary hypertension. In this experiment, pulmonary hypertension was also observed in many sick dogs, and it can be confirmed that when the test drug was started to be administered to these sick dogs, the test indicators of pulmonary hypertension were significantly improved. In addition, it can be confirmed that this improvement effect lasted until 56 days after administration (day 56).

[0166] 8. Heart failure index assessment

[0167] As an assessment of heart failure indicators in Example 1, an ISACHC stage assessment was performed. The ISACHC stage assessment method uses the International Small Animal Cardiology Association's canine heart failure classification index, which is divided into five stages: 1. ISACHC IA, asymptomatic dogs with no cardiomegaly; 2. ISACHC IB, asymptomatic dogs with cardiomegaly; 3. ISACHC CII, mild to moderate heart failure; 4. ISACHC IIIA, severe heart failure with pulmonary edema; and 5. ISACHC IIIB, end-stage heart failure with recurrent pulmonary edema.

[0168] The results of the ISACHC stage evaluation are shown in Table 9 and Figure 33 shown.

[0169]

Table 9

[0170]

[0171] Figure 33 Graph showing the ISACHC stage evaluation results of Example 1.

[0172] Refer to Table 9 and Figure 33It can be seen that in this trial, most of the sick dogs were in ISACHCIIIA and ISACHC IIIB states, but their states improved significantly from the 7th day after administration (Day 7), and this improved state continued until the 56th day after administration (Day 56).

[0173] 9. Conclusions based on experimental results

[0174] From the evaluation results of Example 1, it can be seen that the composition for preventing and treating heart disease according to the embodiment can effectively prevent and treat heart disease in animals such as dogs and cats by containing the cardiotonic ingredient pimobendan, the vasodilator enalapril, and the diuretic ingredients torsemide and spironolactone.

[0175] The composition for preventing and treating animal heart disease according to an embodiment of the present invention has been shown in clinical test results to improve cardiac function in clinical indicators of heart failure and to be effective in treating heart failure. In particular, it can be seen that the composition according to the present invention also improves pulmonary hypertension, a complication caused by heart failure. No side effects related to the kidneys, liver, and electrolytes associated with drug administration were observed during administration. It can also be confirmed that the heart failure stage is gradually and continuously improved after administration.

[0176] <Example 2> Preparation of a composition for preventing and treating heart disease

[0177] In order to more specifically demonstrate the therapeutic effect of the composition of Example 1 on pulmonary hypertension, various comparative examples were prepared and evaluated similarly to the above.

[0178] Preparation Example 1 is for the treatment of heart disease A composition was prepared by mixing the components in Table 10 with each other. The unit in Table 10 is mg. The composition having the following composition was compressed to prepare tablets each having a content of 100 mg.

[0179] In addition, a preparation for treating heart disease The compositions of Comparative Examples 1 to 3 are shown in Table 11 in mg. The compositions having the following compositions were compressed to prepare tablets each containing 100 mg.

[0180]

Table 10

[0181] Element Content (100mg) Pimobendan 0.5mg Enalapril 1mg Torsemide 0.2mg Spironolactone 2mg preservative appropriate amount Other additives appropriate amount

[0182]

Table 11

[0183]

[0184] <Experimental Example 2> Confirmation of the Effect of Prevention and Treatment of Heart Disease

[0185] In order to confirm the preventive and therapeutic effects of the composition of Preparation Example 1 and the compositions of Comparative Examples 1-3 on heart disease, the following experiments were conducted.

[0186] <Experimental Methods>

[0187] A test group administered with the composition of Preparation Example 1 and the compositions of Comparative Examples 1 to 3 and a placebo group administered with a placebo were selected, and experiments were conducted to evaluate the efficacy and stability of the administration. 40 rats diagnosed with

[0188] The 40 experimental animals, all small dogs of the same sex, were selected from dogs with ISACHC III or higher heart failure as the test group and the placebo group. The animals were 20 females and 20 males.

[0189] Heart failure status in the selected experimental animals was classified by veterinary cardiologists based on clinical examination, chest X-ray, and direct examination of the heart using echocardiography, and the ACVIM guidelines for pulmonary hypertension. Dogs with other organ diseases during clinical examination were excluded.

[0190] As a test drug administration method, the tablets prepared in Example 1 and prepared in Example 2 were orally administered to experimental animals twice daily, with 1 / 2 tablet administered per kg of the experimental animal's body weight. The tablets were administered at the same interval of 12 hours each morning and evening, regardless of meals, for a 30-day administration period.

[0191] Tablets prepared in Comparative Examples 1-3, as described in Example 2, were also orally administered to experimental animals twice daily. However, the dosage for Comparative Example 1 was one tablet per 5 kg of the experimental animal's body weight, while the dosage for Comparative Examples 2 and 3 was one-half tablet per 1 kg of the experimental animal's body weight. The tablets were administered daily, morning and evening, at the same interval of 12 hours, regardless of meals, for a 30-day administration period.

[0192] In this experimental plan, dogs with heart failure due to various causes, including valvular disease, were administered the drug. ISACCH Stage III heart failure is a severe form of heart failure. The ISACCH Stage III group of dogs exhibited clear clinical signs of heart disease, such as pulmonary edema or syncope. Among these dogs, pulmonary hypertension, a complication of heart disease, was separately recorded, and the improvement observed with drug administration. If pulmonary edema or worsening of clinical symptoms occurred during administration, administration was discontinued and rescue medication (diuretics or cardiotonic agents) was administered. Only dogs whose administration remained unchanged until the end of the experiment were evaluated for these indicators, and the average values ​​were compared.

[0193] The drug administration test intervals were one day before administration (Day 0) and 30 days after administration (Day 30).

[0194] The specific observation items and test methods are as follows.

[0195] Observation Project

[0196] 1) X-ray assessment of heart and lung fields: VHS, VLAS, and lung field morphology

[0197] 2) Echocardiography: LA / Ao, LVIDdn, MVE, E / E', TR velocity, PR velocity, RVOT ET / AT, RVOT AT measurement

[0198] 3) Pulmonary hypertension assessment: none (0), mild (1), moderate (2), severe (3)

[0199] 4) Heart failure stage: ISACHC 1A(1), ISACHC 1B(2), ISACHC 2(3), ISACHC 3A(4), ISACHC 3B(5)

[0200] 5) As clinical test items, exercise intolerance (1 to 4; 1 is the best and 4 is the worst), appetite (1 to 4), labored breathing (1 to 4), coughing (1 to 4) and fainting (1 to 4) are checked with different numerical values.

[0201] The observational testing method involves testing clinical test items one day before administration (Day 0) and 30 days after administration (Day 30), with the test results recorded by a veterinarian and a caregiver. X-rays, cardiac ultrasounds, and biomarker tests for the observational items are performed at designated hospitals, and the test results are recorded.

[0202] The effect evaluation criteria based on the test results of each clinical test item are as follows.

[0203] 1) Effect evaluation criteria

[0204] - Whether clinical symptoms have improved: increased energy, decreased coughing, increased appetite, decreased labored breathing, decreased fainting

[0205] - Improvement in heart size and lung infiltrates on chest X-ray

[0206] - Improved cardiac test parameters on echocardiography

[0207] 2) Effect evaluation method

[0208] -Is clinical symptoms improved?: Evaluated through guardian records and veterinary examination records

[0209] - Improved CBC and serum biochemistry: Assessment of liver, kidney, pancreas, electrolytes, etc.

[0210] -Resolution of pulmonary hypertension on chest radiograph: determined by assessment of VHS (heart dimensions), VLAS (left atrial dimensions), and lung field morphology (lung field infiltrate findings)

[0211] - Improvements in cardiac ultrasound test parameters: LA / Ao (aorta to left atrial diameter ratio), LVIDdn (left ventricular end-diastolic diameter), MVE (mitral valve filling velocity), E / E' (mitral valve filling velocity to tissue Doppler velocity ratio)

[0212] - Reduction in pulmonary hypertension stage: determined by assessing TR velocity (tricuspid regurgitation velocity), PR velocity (pulmonary regurgitation velocity), RVOT ET / AT (right ventricular outflow tract ejection time / acceleration time), and RVOT AT (right ventricular outflow tract acceleration time)

[0213] - Improvement in heart failure stage: The International Small Animal Society of Cardiology (ISACHC) classification of heart failure stage decreased

[0214] 3) Statistical interpretation methods

[0215] - Each test indicator was tested for normal distribution by Kolmogorov-Smirnov test.

[0216] - The differences in test indicators among the groups were compared by Mann-Whitney U test, and the differences before and after administration were compared by Wilcoxson signed-rank test.

[0217] -P<0.05 was assessed as statistically significant.

[0218] <Experimental Results 2>

[0219] 1. Clinical testing

[0220] As a result of the clinical test of Example 2, the evaluation results of exercise intolerance, appetite, syncope, labored breathing and cough are shown in Tables 12 and Figures 34 to 38 .

[0221]

Table 12

[0222]

[0223] In Table 12, numerical values ​​1 to 4 of the clinical evaluation results were evaluated to represent the following cases, respectively.

[0224] - Exercise intolerance: 1. Not at all, 2. Feeling tired after long periods of walking, 3. Having trouble walking when walking, 4. Refusing to walk

[0225] - Appetite: 1 Very good, 2 Good, 3 Picky eater (will only eat delicious food), 4 Refuse to eat

[0226] - Breathing effort: 1 Not at all, 2 Hyperventilation after play, 3 Hyperventilation within 30 minutes even when resting, 4 Hyperventilation even during sleep

[0227] - Cough: 1 Not at all, 2 Cough when excited or drinking water, 3 Cough less than 10 times a day regardless of excitement or drinking water, 4 Cannot sleep due to cough

[0228] - Fainting: 1 Not at all, 2 Faint once or less per day after exercise or excitement, 3 Faint once or less per day regardless of exercise or excitement, 4 Faint once or more per day regardless of exercise or excitement

[0229] Figures 34 to 38 This is a graph showing the clinical test results of Example 2. Figures 34 to 38 Evaluation results of exercise intolerance, appetite, labored breathing, cough, and syncope for the test group and the placebo group are shown separately as clinical test results.

[0230] Reference Figures 34 to 38 In terms of exercise intolerance assessment, at the end of the test (day 30), the exercise intolerance symptoms of the groups administered with the composition of Preparation Example 1 or Comparative Example 3 were significantly improved, while the exercise intolerance symptoms of the groups administered with the compositions of Comparative Example 1 and Comparative Example 2 were not significantly improved. A symptom-improving effect was clearly observed in the group administered with the composition of Preparation Example 1.

[0231] In terms of appetite assessment, at the end of the test (day 30), the appetite of the groups administered with the composition of Preparation Example 1 or Comparative Example 3 was significantly improved, while the appetite of the groups administered with the compositions of Comparative Example 1 and Comparative Example 2 was not significantly improved. This symptom-improving effect was most significant in the group administered with the composition of Preparation Example 1.

[0232] In terms of respiratory effort assessment, at the end of the test (day 30), respiratory effort symptoms were significantly improved in the groups administered with the composition of Preparation Example 1 or Comparative Example 3, a partial improvement in respiratory effort symptoms was observed in the group administered with the composition of Comparative Example 2, and no significant improvement in respiratory effort symptoms was observed in the group administered with the composition of Comparative Example 1. This symptom improvement effect was most significant in the groups administered with the compositions of Preparation Example 1 and Comparative Example 3, and the improvement effects observed in these two groups were similar.

[0233] In terms of cough assessment, at the end of the test (day 30), cough symptoms were significantly improved in the groups administered with the composition of Preparation Example 1 or Comparative Example 3, a partial improvement in cough symptoms was observed in the group administered with the composition of Comparative Example 2, and no significant improvement in cough symptoms was observed in the group administered with the composition of Comparative Example 1. This symptom improvement effect was most significant in the group administered with the composition of Preparation Example 1.

[0234] In terms of syncope evaluation, an improving effect on syncope symptoms was observed in most of the drug-administered groups, but an improving effect on syncope symptoms was clearly observed in the group to which the composition of Preparation Example 1 was administered.

[0235] As described above, from the results of 1. Clinical Test, it can be seen that the composition of Preparation Example 1 showed improved effects in the evaluation of exercise intolerance, appetite, labored breathing, cough, syncope, etc. compared with the compositions of Comparative Examples 1 to 3.

[0236] 2. Chest X-ray evaluation

[0237] As the chest X-ray film evaluation in Example 2, the evaluation index VHS of the heart size, the evaluation index VLAS of the left atrial size, and the lung field morphology were evaluated.

[0238] The cardiac size assessment index VHS is the abbreviation of spinal cardiac scale, which is a method for quantitatively assessing cardiac size through X-rays.

[0239] VLAS is an indicator of left atrial size, short for vertical left atrial score, which is a method of assessing heart size on chest X-rays.

[0240] Lung field morphology is a method of assessing how visible the lung lobes are on X-rays and is primarily used to determine whether the lungs are filled with fluid or inflamed.

[0241] The chest X-ray assessment results are shown in Table 13 and Figures 39 to 41 shown.

[0242]

Table 13

[0243]

[0244] Figures 39 to 41 Graphs showing the chest X-ray evaluation results of Example 2. Figures 39 to 41 Evaluation results of VHS, VLAS, and lung field morphology (PE) as chest X-ray evaluation results are shown respectively.

[0245] As heart failure progresses, the heart becomes larger and the left atrium dilates. When the left atrium is too large, the blood vessels in the lungs dilate, allowing fluid to seep into the lungs, causing pulmonary edema, which can cause symptoms such as coughing or difficulty breathing.

[0246] Figure 39 The VHS evaluation results can also be quantitative evaluation of the heart size on X-ray films. Figure 39 For the evaluation index VHS of heart size, compared with before administration, at the end of the test (the 30th day), no significant change in heart size was observed in the groups administered with the compositions of Comparative Examples 1 and 2; whereas at the end of the test (the 30th day), a significant decrease in heart size was observed in the groups administered with the compositions of Preparation Example 1 and Comparative Example 3.

[0247] Figure 40 The VLAS assessment result can be the result of evaluating the left atrial size on chest X-ray. Figure 40 For the left atrial size evaluation index VLAS, compared with before administration, at the end of the test (the 30th day), no significant change in the left atrial size was observed in the groups administered with the compositions of Comparative Examples 1 and 2; while at the end of the test (the 30th day), a significant decrease in the left atrial size was observed in the groups administered with the compositions of Preparation Example 1 and Comparative Example 3.

[0248] Figure 41 The lung field morphology (PE) assessment result is a method to evaluate the visibility of the lung lobes on X-rays, mainly used to confirm whether the lungs are edematous or inflamed. Figure 41 At the end of the test (day 30), in the groups administered with the compositions of Comparative Examples 1 and 2, the lung field morphology (PE) results were not significantly improved. In particular, it can be seen that the lung field morphology (PE) in the group administered with the composition of Comparative Example 1 was more severe than before administration. At the end of the test (day 30), the lung field morphology (PE) results in the groups administered with the compositions of Preparation Example 1 and Comparative Example 3 were significantly improved compared to before administration.

[0249] 3. Cardiac ultrasound assessment

[0250] As a cardiac ultrasound assessment in Example 2, cardiac ultrasound was used to measure LA / Ao, LVIDDn, MVE, and MV E / E' to evaluate the function of the left cardiac system. In addition, cardiac ultrasound was used to measure TR velocity, PR velocity, RVOT ET / AT, and RVOT AT to evaluate the function of the right cardiac system.

[0251] LA / Ao, the abbreviation for the ratio of aorta to left atrial diameter, is an indicator of left atrial enlargement. Dogs with ISACHCI heart failure have LA / Ao values ​​of 1.4 to 1.8, dogs with ISACHCII heart failure have LA / Ao values ​​of 1.8 to 2.0, and dogs with ISACHCIIII heart failure have LA / Ao values ​​of 2.0 or higher. A normal LA / Ao is 1.2 to 1.4, and an LA / Ao of 1.2 or less is considered normal and is primarily due to dehydration.

[0252] LVIDdN is an indicator for evaluating the left ventricular end-diastolic diameter and is not related to the weight of the sick dog. When LVIDdN is 20 or above, it is generally considered that the left ventricular end-diastolic diameter is enlarged.

[0253] MVE, which represents the velocity of blood flow as the mitral valve fills, increases primarily with the severity of heart failure. Dogs with ISACHCI heart failure have an MVE of 0.8 to 1.0 m / s, dogs with ISACHCII heart failure have an MVE of 1.0 to 1.2 m / s, and dogs with ISACHCI III heart failure have an MVE of 1.2 m / s or higher. Normal MVE is 0.8 m / s or lower.

[0254] The MVE / E' ratio, the ratio of mitral blood flow velocity to mitral annular tissue Doppler velocity, is a predictor of left atrial pressure. When the MVE / E' ratio is 9 or higher, the left atrial pressure is 20 mmHg; when it is 12 or higher, the left atrial pressure is 30 mmHg or higher. Normally, left atrial pressure should not exceed 20 mmHg. An increase in this value indicates an increase in left atrial pressure.

[0255] The results of cardiac ultrasound assessment are shown in Table 14 and Figures 42 to 45 shown.

[0256]

Table 14

[0257]

[0258] Figures 42 to 45 1 is a diagram showing the results of cardiac ultrasound evaluation in Example 2. Figures 42 to 45 The results of echocardiography evaluations for LA / Ao, LVIDDn, MVE, and MV E / E' are shown. As heart failure progresses, the heart becomes larger, and the left atrium dilates. Therefore, the primary echocardiography test indicators used are LA / Ao to assess the degree of left atrial enlargement, LVIDDn to assess the degree of left ventricular enlargement, and MVE and MV E / E' to assess elevated left atrial pressure.

[0259] Refer to Table 13 and Figures 42 to 45In the LA / Ao assessment for evaluating the degree of left atrial enlargement, no significant change in left atrial size was observed in the groups administered with the compositions of Comparative Examples 1 and 2 at the end of the test (Day 30), compared with before administration; whereas, at the end of the test (Day 30), the left atrial size was significantly reduced in the groups administered with the compositions of Preparation Example 1 and Comparative Example 3.

[0260] In the LVIDDn assessment, which evaluates the degree of left ventricular enlargement, no significant change in left ventricular size was observed in the groups administered with the compositions of Comparative Examples 1 and 2 at the end of the test (Day 30), compared with before administration; whereas, at the end of the test (Day 30), the left ventricular size was significantly reduced in the groups administered with the compositions of Preparation Example 1 and Comparative Example 3.

[0261] In the MVE and MV E / E' assessments, which assess the increase in left atrial pressure, no significant changes in mitral valve blood flow velocity or left atrial pressure were observed in the groups administered with the compositions of Comparative Examples 1 and 2 at the end of the test (Day 30), compared to before administration. However, at the end of the test (Day 30), significant decreases in mitral valve blood flow velocity and left atrial pressure were observed in the groups administered with the compositions of Preparation Example 1 and Comparative Example 3. In particular, a clear decrease in left atrial pressure was observed in the group administered with the composition of Preparation Example 1.

[0262] 4. Assessment of pulmonary hypertension indicators

[0263] As an evaluation of pulmonary hypertension and heart failure in Example 2, TR velocity, PR velocity, RVOT ET / AT, and RVOT AT were measured using cardiac ultrasound to evaluate the function of the right cardiac system.

[0264] TR velocity is the regurgitation velocity of tricuspid valve blood flow (in dogs with pulmonary hypertension, blood in the tricuspid valve contracts in the opposite direction of its original direction due to increased resistance in the right heart system and pulmonary vasculature). The faster the regurgitation velocity, the more severe the pulmonary hypertension. When the TR velocity reaches or exceeds 2.8 m / s, pulmonary hypertension is diagnosed.

[0265] The PR velocity is the reverse flow rate of pulmonary artery blood flow (in dogs with pulmonary hypertension, due to increased resistance in the right heart system and pulmonary vascular system, the pulmonary artery blood flows in the opposite direction during contraction). The faster the blood flow reverses, the more severe the pulmonary hypertension. When the PR velocity reaches or exceeds 2.2 m / s, pulmonary hypertension is diagnosed.

[0266] In pulmonary artery blood flow measurement, RVOT ET / AT is mainly composed of acceleration time (AT), ejection time (ET), and deceleration time (DT). When pulmonary vascular resistance increases, the acceleration time becomes shorter and the ejection time becomes longer. AT / ET is an echocardiographic indicator that can assess the severity of pulmonary hypertension by comparing the acceleration time and ejection time. Normal AT / ET is 0.42 or higher, while dogs with severe pulmonary hypertension have a significantly reduced AT / ET to 0.30 or lower. In other words, the lower the AT / ET, the more severe the pulmonary hypertension.

[0267] In pulmonary artery blood flow measurement, RVOT AT is primarily composed of acceleration time (AT), ejection time (ET), and deceleration time (DT). When pulmonary vascular resistance increases, the acceleration time shortens. This parameter is an echocardiographic indicator that can assess the severity of pulmonary hypertension. Lower RVOT AT and shorter acceleration time indicate more severe pulmonary hypertension.

[0268] The results of cardiac ultrasound examination are shown in Table 15 and Figure 46 As shown in Table 15 and Figure 46 In the evaluation results, the severity of pulmonary hypertension was assessed by comprehensively evaluating the results of TR velocity, PR velocity, RVOT ET / AT and RVOT AT.

[0269]

Table 15

[0270]

[0271] Figure 46 This is a graph showing the results of the severity evaluation of pulmonary hypertension in Example 2. Figure 46 The changes in severity of pulmonary hypertension assessed based on the evaluation results of TR velocity, PR velocity, RVOT ET / AT, and RVOT AT are shown. Figure 46 In the group administered with the composition of Comparative Example 1, pulmonary hypertension was more severe than before administration, whereas in the group administered with the composition of Comparative Example 2, there was no significant difference before and after administration. Compared to before administration, the severity of pulmonary hypertension was significantly reduced in the groups administered with the compositions of Preparation Example 1 and Comparative Example 3. In particular, in the group administered with the composition of Preparation Example 1, a significant reduction in the severity of pulmonary hypertension was observed after administration compared to before administration.

[0272] 5. Assessment of Heart Failure Indicators

[0273] As an evaluation of heart failure indicators in Example 2, an ISACHC stage assessment was performed. The ISACHC stage assessment method uses the International Small Animal Cardiology Association's canine heart failure classification index, which is divided into five stages: 1. ISACHCIA (asymptomatic dogs without cardiomegaly); 2. ISACHCIB (asymptomatic dogs with cardiomegaly); 3. ISACHCII (mild to moderate heart failure); 4. ISACHCIIIA (severe heart failure with pulmonary edema); and 5. ISACHCIIIB (end-stage heart failure with recurrent pulmonary edema).

[0274] The results of the ISACHC stage evaluation are shown in Tables 16 and Figure 47 shown.

[0275] Table 16

[0276]

[0277] Figure 47 Graph showing the ISACHC stage evaluation results of Example 2.

[0278] Refer to Table 16 and Figure 47 In the group administered with the composition of Comparative Example 1, heart failure was more severe than before administration, whereas in the group administered with the composition of Comparative Example 2, there was no significant difference before and after administration. Compared with before administration, an effect of alleviating heart failure was observed in the groups administered with the compositions of Preparation Example 1 and Comparative Example 3, and the most significant effect of improving heart failure was observed in the group administered with the composition of Preparation Example 1.

[0279] 6. Test end time

[0280] In this experiment, if pulmonary edema appeared or clinical symptoms worsened during administration, the administration was stopped and rescue drugs (diuretics or cardiotonic drugs) were used instead. The number of dogs that were given rescue drugs during the administration period in the groups administered with the compositions of Preparation Example 1 and Comparative Examples 1 to 3 was compared.

[0281] In the group administered with the composition of Comparative Example 1, only 2 of a total of 10 sick dogs reached the final experimental end time (Day 30), 3 of a total of 10 sick dogs required specific drug administration due to worsening clinical symptoms or the occurrence of pulmonary edema after only 1 week of administration, 3 of a total of 10 sick dogs required specific drug administration due to worsening clinical symptoms or the occurrence of pulmonary edema after only 2 weeks of administration, and 2 of a total of 10 sick dogs required cessation of test drug administration and required administration of specific rescue drugs due to worsening clinical symptoms or the occurrence of pulmonary edema after only 3 weeks of administration.

[0282] In the group administered with the composition of Comparative Example 2, only 4 of a total of 10 sick dogs reached the final experimental end time (Day 30), 2 of a total of 10 sick dogs required specific drug administration due to worsening clinical symptoms or the occurrence of pulmonary edema after only 1 week of administration, 2 of a total of 10 sick dogs required specific drug administration due to worsening clinical symptoms or the occurrence of pulmonary edema after only 2 weeks of administration, and 2 of a total of 10 sick dogs required cessation of test drug administration and required administration of specific rescue drugs due to worsening clinical symptoms or the occurrence of pulmonary edema after only 3 weeks of administration.

[0283] In the group administered with the composition of Comparative Example 3, 9 of a total of 10 sick dogs reached the final end of the experiment (Day 30), and only 1 of a total of 10 sick dogs required administration of specific rescue drugs due to worsening clinical symptoms or the occurrence of pulmonary edema at 3 weeks of administration.

[0284] In contrast, in the group administered with the composition of Preparation Example 1, all 10 sick dogs reached the final experimental endpoint (Day 30).

[0285] 7. Conclusions based on experimental results

[0286] From the evaluation results of Example 2, it can be seen that the composition for preventing and treating heart disease according to the embodiment can effectively prevent and treat heart disease in animals such as dogs and cats by comprising the cardiotonic ingredient pimobendan, the vasodilator enalapril, and the diuretic ingredients torsemide and spironolactone.

[0287] When comparing the number of dogs that did not use rescue drugs until the end of the test (day 30) in this test, the results show that when the composition according to the embodiment (e.g., Preparation Example 1) is administered, the addition of other types of drugs is more effective in controlling severe heart failure (pulmonary hypertension) than the administration of the cardiotonic drug pimobendan alone. In addition, the composition of Comparative Example 2, to which no diuretic is added, is less effective in controlling symptoms. Similarly, when a diuretic is added, it can be seen that the composition of the two diuretics mixed with each other in Preparation Example 1 is more conducive to preventing symptom deterioration and improving survival rate than a single diuretic.

[0288] In the group using the composition of Comparative Example 1, that is, only using the group of pimobendan, a slight improvement effect of clinical symptoms was observed in dogs suffering from severe heart failure (pulmonary hypertension), but for most dogs suffering from severe heart failure, this improvement effect was short-term and temporary, and the symptoms eventually increased. In the compound formulation (Preparation Example 1 and Comparative Example 2, 3) of additional enalapril administration, the improvement effect of the clinical symptoms associated with heart failure was better, particularly in the compound formulation group (Preparation Example 1 and Comparative Example 3) using diuretics at the same time, the improvement effect was the most obvious. In particular, the clinical index improvement effect of the compound formulation of four drugs (Preparation Example 1) was the most excellent. In addition, it can also be seen from the evaluation results of chest X-ray assessment, cardiac ultrasound, particularly heart failure and pulmonary hypertension that the composition of Preparation Example 1 shows a more excellent effect than other compositions of Comparative Example.

[0289] The composition according to the embodiment can effectively treat heart failure and pulmonary hypertension in animals by comprising pimobendan, enalapril, torsemide and spironolactone, and can more easily control sick dogs by further comprising drugs having different mechanisms of action.

[0290] While the embodiments of the present invention have been described above with reference to the accompanying drawings, it will be understood by those skilled in the art that various modifications and variations may be made without departing from the technical spirit or essential features of the present invention. Therefore, it should be understood that the above embodiments are merely illustrative and are not intended to be limiting in any respect.

Claims

1. A composition for preventing and treating animal heart disease and pulmonary hypertension, comprising: Pimobendan; Enalapril; torsemide; and Spironolactone.

2. The composition for preventing and treating animal heart disease and pulmonary hypertension according to claim 1, wherein: The composition comprises 0.5 mg of pimobendan, 1 mg of enalapril, 0.2 mg of torsemide, and 2 mg of spironolactone.

3. The composition for preventing and treating animal heart disease and pulmonary hypertension according to claim 1, wherein: Based on the subject's body weight, a single administration dose of pimobendan was 0.25 mg / kg, a single administration dose of enalapril was 0.5 mg / kg, a single administration dose of torsemide was 0.1 mg / kg, and a single administration dose of spironolactone was 1 mg / kg, and pimobendan, enalapril, torsemide, and spironolactone were administered twice daily.

4. The composition for preventing and treating animal heart disease and pulmonary hypertension according to claim 3, wherein: The target object is a dog or a cat.

5. A functional preparation for preventing and treating animal heart disease and pulmonary hypertension, comprising: Pimobendan; Enalapril; torsemide; and Spironolactone.

6. The functional preparation for preventing and treating animal heart disease and pulmonary hypertension according to claim 5, wherein: The functional preparation contains 0.5 mg of pimobendan, 1 mg of enalapril, 0.2 mg of torsemide and 2 mg of spironolactone.

7. The functional preparation for preventing and treating animal heart disease and pulmonary hypertension according to claim 5, wherein: Based on the subject's body weight, a single administration dose of pimobendan was 0.25 mg / kg, a single administration dose of enalapril was 0.5 mg / kg, a single administration dose of torsemide was 0.1 mg / kg, and a single administration dose of spironolactone was 1 mg / kg, and pimobendan, enalapril, torsemide, and spironolactone were administered twice daily.

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