JP5076327B2 - Adaptation of branched-chain amino acids to heart failure - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an effective composition (e.g. medicinal composition or food composition) for ameliorating symptom involving acute aggravation of chronic heart failure and to provide a composition for ameliorating symptoms involving acute aggravation of chronic heart failure not ameliorated by therapeutic agent for heart failure. <P>SOLUTION: The composition for ameliorating symptoms involving acute aggravation of chronic heart failure comprises three kinds of branched chain amino acids which are isoleucine, leucine and valine as active ingredients. The composition for ameliorating symptoms involving acute aggravation of chronic heart failure not ameliorated by therapeutic agent for heart failure comprises three kinds of branched chain amino acids which are isoleucine, leucine and valine as active ingredients. <P>COPYRIGHT: (C)2007,JPO&amp;INPIT

Description

  The present invention relates to a composition (for example, pharmaceutical composition, food composition) for improving symptoms associated with acute exacerbation of chronic heart failure.

  Heart failure is a symptom that represents various pathological conditions associated with a decrease in cardiac function, and is classified into acute heart failure that suddenly develops and chronic heart failure in which myocardial damage gradually progresses and becomes apparent over a long period of time.

  Chronic heart failure is due to low fatigue level and fatigue caused by low-energy conditions due to lack of oxygen throughout the body, as well as a marked decrease in QOL (Quality of Life) and a decrease in blood flow to the kidney due to circulatory failure (congestion) of body fluids. It presents symptoms such as a decrease in urine volume due to urine, (2) edema symptoms due to fluid accumulation throughout the body, and (3) systemic symptoms such as pulmonary edema and pleural effusion due to sitting and breathing difficulty. Chronic heart failure leads to a decrease in nutritional status due to decreased appetite and a state in which protein degradation such as skeletal muscle is enhanced (cardiac cachexia). Chronic heart failure patients often repeat hospital visits and therefore improve life prognosis and QOL are the goals of treatment. Chronic heart failure patients are more common in elderly people (1% or less in their 50s, 10% or more in their 80s), and in many cases, complex diseases such as hypertension, diabetes, hyperlipidemia, and cognitive impairment occur. In addition, the metabolic kinetics of drugs are different from those of young people, and therefore sufficient consideration is required for the safety of drugs.

  In the current pharmacotherapy for chronic heart failure, (1) diuretics for improving fluid retention and (2) improving blood flow for the purpose of enhancing heart pump function and improving symptoms such as edema. Angiotensin-converting enzyme inhibitor (ACE-I), (3) cardiotonic drugs such as digoxin preparations that enhance heart function and improve exercise capacity, (4) β-blockers for resting heart function and protecting the heart Therapies are combined with drugs such as. However, there are patients with chronic heart failure who have not improved their symptoms with these medications.

  Patent Document 1 describes a composition suitable for the treatment of heart failure, which contains a branched chain amino acid as an active ingredient. Patent Document 2 describes a composition for improving ventricular myocardial function in diabetic patients, which contains a branched chain amino acid as an active ingredient. However, in Patent Document 1, cardiac function is evaluated by an exercise load test using a bicycle ergometer. This method may be a good index for improving the pathological condition in healthy individuals and patients with mild heart failure. It is unclear whether the improvement of cardiac function seen in the improvement of ventricular ejection fraction diagnosed by ergometer will improve the pathology of various symptoms associated with heart failure in elderly patients and the elderly It is. This is because, according to the evidence obtained by recent clinical trials, heart failure treatment is performed by using a cardiotonic agent or vasodilator that improves cardiac pump function, a human atrial natriuretic hormone having a myocardial protective effect by resting the myocardium, ACE. This is because it has changed to -I and β antagonists. Similarly, regarding the improvement of cardiac output in echocardiography in Patent Document 2, it is still unclear whether it leads to improvement of various pathological conditions associated with heart failure for severe patients and elderly people. is there. In heart failure, which is regarded as a syndrome with various backgrounds, not only does it improve the heart pump function expressed by the ventricular ejection fraction and cardiac output, but also decreases the QOL such as decreased appetite, energy, and edema It is important to improve.

In order to improve life prognosis and QOL in severe acute heart failure conditions including acute exacerbation of chronic heart failure, edema and pleural effusion associated with cardiac cachexia and decreased circulatory function represented by decreased appetite associated with the pathological condition It is necessary to improve symptoms such as retention and decreased urine output. However, it has been unknown whether administration of branched chain amino acids has improved such symptoms associated with heart failure patients.
On the other hand, branched chain amino acids are known to improve appetite in cancer cachexia and renal dialysis patients as described in Non-Patent Document 1 and Non-Patent Document 2, and the like. The effect on appetite loss is not known, and it was unclear whether it would improve symptoms such as edema, pleural effusion, and decreased urine output.
JP-T-2004-501968 Japanese translation of PCT publication No. 2004-534073 Journal of the National Cancer Institute, Vol.88, No.8, p550-p552 (1996) Nephrology Dialysis Transplantation, Vol.16, p1856-p1862 (2001)

  The subject of this invention is related with providing the composition (for example, pharmaceutical composition, food composition) for the improvement of the symptom accompanying acute exacerbation of the chronic heart failure more effective.

  As a result of diligent research to solve the above-mentioned problems, the present inventors have found that a composition containing three kinds of branched chain amino acids of isoleucine, leucine and valine as an active ingredient improves symptoms associated with acute exacerbation of chronic heart failure. As a result, the present invention has been completed.

That is, the present invention provides the following.
(1) A composition for improving symptoms associated with acute exacerbation of chronic heart failure, comprising isoleucine, leucine and valine as active ingredients,
(2) Symptoms associated with acute exacerbation of chronic heart failure include cardiac cachexia, decreased appetite, hypoalbuminemia, hypoproteinemia, decreased urine output, congestive symptoms, pleural effusion, increased cardiothoracic ratio, The composition according to (1) above, which is at least one selected from the group consisting of lower limb or systemic edema and pericardial effusion,
(3) The composition according to (1) or (2) above, wherein the content of isoleucine, leucine and valine is 1 g or more per unit amount taken once,
(4) The composition according to (1) to (3) above, wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5 to 2.5: 0.8 to 1.7. object,
(5) The composition according to any one of (1) to (4), which is used in combination with a therapeutic agent for heart failure,
(6) The composition according to (5) above, which enhances the action of a therapeutic agent for heart failure.
(7) The composition according to (5) or (6) above, wherein the therapeutic agent for heart failure is at least one selected from the group consisting of diuretics, vasodilatory antihypertensives, β-blockers, and cardiotonic drugs,
(8) The composition according to any one of (1) to (7) above, wherein symptoms associated with acute exacerbation of chronic heart failure are not improved by a therapeutic agent for heart failure,
(9) The composition according to any one of (1) to (8), wherein the composition is a pharmaceutical.
(10) The composition according to any one of (1) to (8), which is a food product,
(11) The composition according to (10) above, wherein the food is a health functional food or a dietary supplement,
(12) The composition according to (11) above, wherein the health functional food is a food for specified health use or a nutritional functional food,
(13) The composition according to (10), wherein the food is a concentrated liquid food,
(14) The composition according to any one of (1) to (13) above, and the composition can or should be used to improve symptoms associated with acute exacerbation of chronic heart failure. A commercial package containing the described items,
(15) For prevention or treatment of heart failure, comprising at least one therapeutic agent selected from the group consisting of diuretics, vasodilatory antihypertensives, β-blockers, cardiotonic drugs and isoleucine, leucine and valine A combination of
(16) A method for improving symptoms associated with acute exacerbation of chronic heart failure, which comprises orally administering an effective amount of a composition for improving symptoms associated with acute exacerbation of chronic heart failure, comprising isoleucine, leucine and valine as active ingredients.

The composition comprising three types of branched chain amino acids, isoleucine, leucine and valine, provided by the present invention as active ingredients is used for improving symptoms associated with acute exacerbation of chronic heart failure. In particular, the compositions of the present invention are effectively used to ameliorate symptoms associated with acute exacerbations of chronic heart failure that are not improved by therapeutic agents for heart failure.
In addition, since the composition of the present invention contains amino acid as an active ingredient, it is highly safe and has few side effects, so it is extremely advantageous as a pharmaceutical product and food.

Embodiments of the present invention will be described below.
The composition of the present invention is useful for improving symptoms associated with acute exacerbation of chronic heart failure. In this specification, “improvement” means “prevention / treatment”.

In the present specification, “chronic heart failure” refers to a state in which the heart failure is gradually progressing and is in an equilibrium state in which various compensation mechanisms are working.
“Acute exacerbation” is a failure of the compensation mechanism due to the worsening of heart failure symptoms due to any cause, organ failure due to systemic circulatory dysfunction, renal failure, liver failure, respiratory failure, multiple organ failure, lung obstruction Symptom and systemic obstruction, which often necessitates emergency hospitalization due to difficulty breathing or sitting breathing. In particular, in chronic heart failure in the elderly, repeated hospitalization due to acute exacerbation is one of the prominent features.
“Symptoms associated with acute exacerbation of chronic heart failure” include cardiac cachexia, decreased appetite, hypoalbuminemia, hypoproteinemia, decreased urine output, congestive symptoms, pleural effusion, increased cardiothoracic ratio, Lower limb or systemic edema, pericardial effusion, etc. If these symptoms do not improve, long-term hospitalization is required.

`` Cardiac cachexia '' means that the blood supply to systemic organs deteriorates due to heart failure, fluid accumulates in the liver and stomach, nausea and loss of appetite, and eventually the food is not fully absorbed, A condition in which appetite is reduced, weight is lost, and muscles are weakened.
“Hypoalbuminemia” and “hypoproteinemia” refer to a state in which malnutrition has occurred due to cardiac cachexia and the amount of protein in the blood has decreased.
The “decrease in urine volume” means a decrease in urine volume due to insufficient blood supply to the kidney due to heart failure, and as a result, water tends to be stored in the body.
“Congestion” is a state in which the volume of body fluid and the amount of circulating blood increase, and it stays in the organ. In heart failure, circulating pulmonary congestion often accompanies, and with increasing severity, symptoms such as exertional dyspnea / sitting breath, nighttime paroxysmal dyspnea, and pulmonary edema are accompanied. Venous congestion can cause symptoms such as lower limb and general edema, pleural effusion, and ascites. In addition, as a result of congestion occurring in various organs, it is one of the causes of organ dysfunction and dysfunction.
The “cardiothoracic ratio” is the ratio of the cardiac shadow on the chest radiograph and the width of the chest. When the cardiac function is reduced, the heart is compensably enlarged and the cardiothoracic ratio is increased.
“Pericardial effusion” is a collection of blood or body fluid in the pericardium (pericardial sac) around the heart, and is caused by cardiac congestion or pericardial inflammation. If the pericardial effusion accumulates, the heart is compressed and the pump function is impaired, further exacerbating the heart failure condition.

  Furthermore, the composition of the present invention is effective in ameliorating symptoms associated with acute exacerbation of chronic heart failure that is not improved or sufficiently improved by a therapeutic agent for heart failure.

  Here, “improvement” means symptoms associated with acute exacerbation of chronic heart failure, that is, “cardiac cachexia”, “decreased appetite”, “hypoalbuminemia”, “hypoproteinemia”, “decrease in urine volume” , "Congestive symptoms", "retention of pleural effusion", "increased cardiothoracic ratio", "edema of the lower limbs or whole body", "pericardial effusion" show signs of improvement in the direction of normalization is there. Therefore, “not improved by a therapeutic agent for heart failure” means that the symptoms associated with acute exacerbation of chronic heart failure do not show signs of improvement in the direction of normalization, even when taking the therapeutic agent, In the case of an inpatient, the symptoms cannot be improved enough to be discharged, and in the case of a patient requiring nursing or care, the nurse or caregiver Or it means that sufficient improvement of symptoms cannot be obtained to shorten the time required for care.

  Heart failure drugs are those commonly used in the treatment of heart failure, such as diuretics (loop diuretics, potassium-retaining diuretics, etc.), vasodilatory antihypertensives (angiotensin converting enzyme inhibitors (ACE-I)) , Angiotensin receptor II antagonists (ARB), etc.), β-blockers, cardiotonic drugs (catecholamine drugs, PDEIII inhibitors, digitalis preparations, etc.), antithrombotic drugs, aldosterone antagonists and the like.

The active ingredient (branched chain amino acid) of the present invention, isoleucine, leucine and valine, can be used in any of L-form, D-form and DL-form, respectively, preferably L-form and DL-form. -Form, more preferably L-form.
Further, isoleucine, leucine and valine can be used not only in free form but also in salt form. Examples of the salt form include acid addition salts and salts with bases, and it is preferable to select pharmaceutically acceptable salts of isoleucine, leucine and valine.
Examples of acids that are added to isoleucine, leucine, and valine to form pharmaceutically acceptable salts include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; acetic acid, lactic acid, citric acid, tartaric acid, Organic acids such as maleic acid, fumaric acid, monomethyl sulfuric acid and the like can be mentioned.
Examples of pharmaceutically acceptable bases for isoleucine, leucine and valine include, for example, metal hydroxides or carbonates such as sodium, potassium and calcium, or inorganic bases such as ammonia; ethylenediamine, propylenediamine, ethanolamine, Examples include organic bases such as monoalkylethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine.

  The composition of the present invention contains three types of branched chain amino acids, isoleucine, leucine and valine, as active ingredients. The content of these three types of amino acids is a viewpoint of an effect of improving symptoms associated with acute exacerbation of chronic heart failure. Therefore, when applied to humans, it is 0.1 g or more, preferably 1 g or more per unit dose. Further, from the viewpoint of ease of ingestion in actual ingestion, the content is preferably 100 g or less, more preferably 10 g or less. Here, the “unit dose once taken” is an amount to be administered at a time when the composition of the present invention is a medicine, and an amount to be consumed at a time when the composition of the present invention is a food. It is.

  The composition of the present invention contains three kinds of branched chain amino acids of isoleucine, leucine and valine as active ingredients, and the mixing ratio of the three kinds of amino acids is usually from 1: 1.5 to It is the range of 2.5: 0.8-1.7, Most preferably, it is the range of 1: 1.9-2.2: 1.1-1.3. Outside this range, it is difficult to obtain an effective action effect.

  The composition of the present invention can also be used in combination with a therapeutic agent for heart failure. When used in combination with a therapeutic agent for heart failure, the therapeutic agent for heart failure is not particularly limited as long as it is a therapeutic agent usually used in the treatment of heart failure. Specifically, diuretics (loop diuretics, potassium-retaining diuretics). Drugs), vasodilatory antihypertensive drugs (angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor II antagonist (ARB), etc.), beta blockers, cardiotonic drugs (catecholamine drugs, PDEIII inhibitors, digitalis preparations, etc.) ), Antithrombotic drugs, aldosterone antagonists and the like.

  The composition of the present invention can also enhance the action of a therapeutic agent for heart failure. Here, the “effect of the therapeutic agent for heart failure” does not include the side effects of the therapeutic agent for heart failure. The composition of the present invention preferably enhances the ameliorating action of the above-mentioned therapeutic agent for heart failure on symptoms associated with acute exacerbation of chronic heart failure.

  The composition of the present invention is useful as a medicine, food and drink, and the administration target includes mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.). Can be mentioned. In addition, when adapting to mammals other than a human, the intake of the composition of this invention should just be adjusted suitably according to the body weight or magnitude | size of an animal.

  Here, the administration form of the composition of the present invention when used as a pharmaceutical is not particularly limited, but can be via a general administration route such as oral administration, rectal administration, injection, administration by infusion. Oral dosage forms include granules, fine granules, powders, coated tablets, tablets, suppositories, powders, (micro) capsules, chewables, syrups, juices, liquids, suspensions, emulsions, etc. Also, as an injection, general dosage forms of pharmaceutical preparations such as direct intravenous injection, infusion administration, preparations for prolonging the release of active substances and the like can be adopted.

  These medicaments are prepared by formulating them by a conventional method. Various pharmaceutical substances that are pharmacologically acceptable can be blended as required in the preparation. The substance for the preparation can be appropriately selected depending on the dosage form of the preparation. For example, the excipient, the diluent, the additive, the disintegrant, the binder, the coating agent, the lubricant, the lubricant, the lubricant, and the flavoring agent. , Sweeteners, solubilizers and the like. Furthermore, specific examples of the pharmaceutical substance include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents, Examples include sterilized water and mono- or polyhydric alcohols such as glycerol.

  The dosage when the composition of the present invention is used as a pharmaceutical agent varies depending on the age, weight or disease state, dosage form, administration method, etc. of the subject patient, but per adult day from 0.005 g / kg body weight to isoleucine. As a guide, 5 g / kg body weight, leucine 0.01 g / kg body weight to 10 g / kg body weight, and valine 0.005 g / kg body weight to 5 g / kg body weight. In the case of general adults, preferably, the daily dose for adults is 0.01 g / kg body weight to 1 g / kg body weight, 0.02 g / kg body weight to 2 g / kg body weight leucine, 0.01 g / kg body weight to 1 g / kg body weight. kg body weight, more preferably, isoleucine 0.02 g / kg body weight to 0.2 g / kg body weight, leucine 0.04 g / kg body weight to 0.4 g / kg body weight, valine 0.02 g / kg body weight to 0.2 g / kg It is body weight, and the total amount of amino acids is preferably about 0.01 to 2 g / kg body weight per day. The daily dose can be administered at once or in several divided doses. It does not matter before meals, after meals, and between meals. The administration period is not particularly limited.

When calculating the dose (intake) of the branched chain amino acid that is the active ingredient of the present invention, the value is the amount of the active ingredient of the drug used for the purpose of treatment or prevention of the disease targeted by the present invention. As for the branched chain amino acids to be ingested or administered for other purposes, for example, from the necessity of normal eating habits, or for the purpose of treating other diseases. Need not be included in the calculation.
For example, it is not necessary to subtract the amount of branched chain amino acids per day taken from the normal diet from the daily dose of the active ingredient in the present invention.

  Isoleucine, leucine and valine, which are the active ingredients of the present invention, may be contained in the preparation alone or in any combination, or all may be contained in one kind of preparation. When separately formulated and administered, their administration route and dosage form may be the same or different, and the timing of administration of each may be the same or different. It is determined as appropriate depending on the type and effect of the drug used in combination. That is, the pharmaceutical of the present invention may be a preparation containing a plurality of branched chain amino acids at the same time, or may be a combined preparation in which each is separately formulated and used together. All these forms are included. In particular, an embodiment containing all branched chain amino acids in the same preparation is preferable because it can be easily administered.

  In the present invention, the “weight ratio” indicates the weight ratio of each component in the preparation. For example, when each active ingredient of isoleucine, leucine and valine is included in one preparation, it is the ratio of individual contents, and each active ingredient is included in multiple preparations alone or in any combination The ratio of the weight of each active ingredient included in each formulation.

  In the present invention, the actual dose ratio is the ratio of a single dose or daily dose of each active ingredient per administration subject (ie, patient). For example, when each active ingredient of isoleucine, leucine and valine is included in one preparation and is administered to an administration subject, the weight ratio corresponds to the dose ratio. When each active ingredient is administered alone or in any combination in a plurality of preparations, the ratio of the total amount of each active ingredient in each preparation administered once or daily corresponds to the weight ratio.

  The medicament of the present invention may be blended with other drugs such as a therapeutic drug for heart failure.

  In addition, the composition of the present invention includes diuretics (loop diuretics, potassium-retaining diuretics, etc.), vasodilatory antihypertensives (angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor II antagonists (ARB). )), Β blockers, cardiotonic drugs (catecholamine drugs, PDEIII inhibitors, digitalis preparations, etc.), antithrombotic drugs, aldosterone antagonists, etc. You can also When the composition of the present invention is blended with a therapeutic agent, the blending ratio of the composition of the present invention and the therapeutic agent is a weight ratio, usually in the range of 1: 0.1 to 1,000,000, particularly preferably. Is in the range of 1: 1 to 1,000.

Furthermore, the composition of the present invention can be easily used in the form of food. When used as a food, any form may be used as long as it is a general meal form containing the active ingredient of the present invention. For example, drinks such as soft drinks and powdered drinks can be prepared by adding an appropriate flavor. Specifically, for example, it can be eaten and eaten mixed with juice, milk, confectionery, jelly, yogurt, candy and the like.
It is also possible to provide such foods as health functional foods or dietary supplements. This health functional food includes food for specified health use and food with nutritional function. The food for specified health use is a food that can indicate that a specific health purpose can be expected, such as improvement of symptoms associated with acute exacerbation of chronic heart failure. In addition, functional nutritional food is a food that can indicate the function of the nutritional component when the amount of nutritional component included in the daily intake standard amount conforms to the national and national standards for upper and lower limits. is there. Dietary supplements include so-called nutritional supplements or health supplements. In the present invention, the food for specified health use is described as a food with a label indicating that it is used for applications such as improvement of symptoms associated with acute exacerbation of chronic heart failure, and further used for such applications. Foods that include documents (so-called Noh) as packages are also included.
Furthermore, the composition of the present invention can be used as a concentrated liquid food or a food supplement. When used as a food supplement, it can be prepared in the form of tablets, capsules, powders, granules, suspensions, chewables, syrups and the like. The food supplement in the present invention refers to those taken for the purpose of supplementing nutrition in addition to those taken as food, and also includes nutritional supplements and supplements.

  In addition, “rich liquid food” is adjusted to a concentration of about 1 kcal / ml, and the qualitative composition of each nutrient is sufficiently considered so that no significant excess or deficiency of nutrients is caused even by long-term single intake. It is a comprehensive nutritional food (liquid food) designed based on the nutritional requirements of food.

  When ingested as food, the intake varies depending on the symptom, age, weight, dosage form, method of intake, etc. of the subject of intake, but for adults per day, isoleucine 0.005 g / kg body weight to 5 g / kg body weight, leucine 0.01 g / Kg body weight to 10 g / kg body weight, valine 0.005 g / kg body weight to 5 g / kg body weight as a guide. In the case of general adults, preferably, the daily dose for adults is 0.01 g / kg body weight to 1 g / kg body weight, 0.02 g / kg body weight to 2 g / kg body weight leucine, 0.01 g / kg body weight to 1 g / kg body weight. kg body weight, more preferably, isoleucine 0.02 g / kg body weight to 0.2 g / kg body weight, leucine 0.04 g / kg body weight to 0.4 g / kg body weight, valine 0.02 g / kg body weight to 0.2 g / kg It is body weight, and the total amount of amino acids is preferably about 0.01 to 2 g / kg body weight per day. In the food of the present invention, the amount per day can be taken at once or divided into several times. The intake period is not particularly limited.

Isoleucine, leucine, and valine have already been widely used in the pharmaceutical and food fields, and safety has been established. For example, the acute toxicity (LD ₅₀ ) of a formulation containing these amino acids in a ratio of 1: 2: 1.2 is 10 g / kg or more upon oral administration to mice.

  In the present invention, the composition for improving symptoms associated with acute exacerbation of chronic heart failure, comprising three branched chain amino acids of isoleucine, leucine and valine as active ingredients, is used to improve symptoms associated with acute exacerbation of chronic heart failure. Commercial packages are also included, including descriptions that can be used or should be used.

  The contents of all publications, including patents and patent application specifications cited in this specification, are hereby incorporated by reference herein to the same extent as if all were explicitly stated. Is.

  The present invention will be described more specifically by the following examples. However, the examples are merely illustrative of the present invention and do not limit the scope of the present invention.

Clinical trial examples:
Patients who have been hospitalized due to acute exacerbation of chronic heart failure and who have undergone usual treatment with pharmacotherapy such as diuretics, antihypertensives, and cardiotonic drugs (Table 1: 8 patients, For an average age of 80.75 years old, one male and seven females), once a branched-chain amino acid granule (trade name: Rebact Granule, manufactured by Ajinomoto Co., Inc.) containing the following ingredients: Orally administered 3 times a day after meals.

The following symptoms associated with chronic heart failure and cardiac cachexia before and after administration were analyzed.
1) Dietary intake 2) Serum albumin 3) Serum total protein 4) Urine volume 5) Cardiothoracic ratio 6) Degree of pleural effusion 7) Degree of edema 8) Pericardial effusion volume in case 2

(1) Changes in dietary intake during 10 days before and after BCAA granule administration In the total number of meals (30 meals) in 10 days before and after BCAA granule administration, the number of times (A) and almost all meals were consumed. The number of failed times (B) was counted, and the ratio was compared before and after administration and plotted in FIG. In the graph, 1 on the horizontal axis indicates data before administration, and 2 indicates data after administration. Cases 1 and 4 were excluded from the analysis because data on food intake could not be obtained. The BCAA granule administration increased the number of meals in which almost the entire amount could be ingested, while the number of meals in which it was hardly ingested decreased. From this, it is clear that the administration of BCAA granules improved anorexia, the main symptom of cardiac cachexia.

(2) Change in serum albumin value (g / dl) one month after BCAA granule administration The serum albumin value (g / dl) before and one month after BCAA granule administration was measured and plotted in FIG. Cases 1 and 5 were excluded from the analysis because no data was available. In the graph, 1 on the horizontal axis indicates data before administration, and 2 indicates data after administration. In the average of 6 cases to be analyzed, the serum albumin level was improved to 3.57 g / dl after one month compared to 2.85 g / dl before administration.

(3) Change in serum total protein amount (g / dl) one month after BCAA granule administration The serum total protein value (g / dl) before and one month after BCAA granule administration was measured and plotted in FIG. . Case 5 was excluded from the analysis because no data was available. In the graph, 1 on the horizontal axis indicates data before administration, and 2 indicates data after administration. In the average of 7 cases to be analyzed, the serum total protein level was improved to 6.71 g / dl after one month compared to 5.98 g / dl before administration.
From these results of improving serum albumin levels and serum total protein levels, it is clear that administration of BCAA granules improved protein malnutrition, which is a major symptom of cardiac cachexia associated with heart failure.

(4) Change in average daily urine volume for 5 days and 10 days before and after BCAA granule administration The daily urine volume (ML) was measured for 5 days and 10 days before and after BCAA granule administration, and the average value was measured. Are plotted in FIG. 4 and FIG. In the graph, 1 on the horizontal axis indicates data before administration, and 2 indicates data after administration. Cases 1 and 4 were excluded from the analysis because no data was available. In the average of 6 cases to be analyzed, as shown in FIG. 4, an increase in urine volume was recognized as 1564 ml on average for 5 days after administration, compared to an average value of 1290 ml for 5 days before administration, As shown in FIG. 5, an increase was observed in the average of 10 days after administration as in 1644 ml, compared to the average value of 1259 ml in 10 days before administration. In all patients, treatment with diuretics listed in Table 1 was already performed, but sufficient improvement in urine volume was not observed, but in addition to conventional treatment It is clear that administration of BCAA granule improves the decrease in urine volume associated with decreased circulatory function due to the heart failure condition.

(5) Changes in cardiothoracic ratio before and after BCAA granule administration X-ray examination was performed at appropriate times before and after BCAA granule administration, cardiothoracic ratio (CTR,%) was measured, and the change was plotted in FIG. did. In the graph, 1 on the horizontal axis indicates data before administration, and 2 indicates data after administration. In cases 4 and 8, since no pleural effusion was observed even before administration, data were not acquired and excluded from the analysis. In all 6 cases to be analyzed, CTR improvement was observed, and the average improvement rate before and after administration of BCAA granules was 5.1%. The period required for improvement was as follows. Case 1 is 2.5 months, Case 2 is 5 days, Case 3 is 1.5 months, Case 5 is 10 days, Case 6 is 10 days, Case 8 is 9 days. From this result, it is clear that administration of BCAA granule improves cardiac hypertrophy that compensates for a decrease in circulatory function due to a heart failure condition.

(6) Change in the degree of pleural effusion before and after BCAA granule administration Based on the above X-ray examination results, the degree of pleural effusion retention on the image is quantified in five steps as shown below, and the change before and after administration is shown in FIG. Plotted.
<Degree of pleural effusion>
1: CTA looks sharp 2: CTA looks Dull 3: Pleural fluid accumulates to the diaphragm level 4: Pleural fluid accumulates and the diaphragm cannot follow, but the heart shadow can follow the boundary 5: The chest shadow cannot follow the shadow thing

  In the graph, 1 on the horizontal axis indicates data before administration, and 2 indicates data after administration. In cases 4 and 8, since no pleural effusion was observed even before administration, data were not acquired and excluded from the analysis. The pleural effusion level improved in 5 out of 6 cases to be analyzed. The pleural effusion level was analyzed in the next period after administration. Case 1 is 2.5 months, Case 2 is 5 days, Case 3 is 1.5 months, Case 5 is 10 days, Case 6 is 10 days, Case 8 is 9 days. From this result, it is clear that administration of BCAA granule improves pleural effusion retention due to decreased circulatory function due to heart failure condition.

(7) Change in the degree of edema before and after BCAA granule administration The degree of edema was evaluated according to the following criteria at appropriate times before and after BCAA granule administration.

  The transition of edema before and after administration in each case is shown below.

  Case 8 was excluded from the analysis because edema was not evaluated. An improvement in the degree of edema was observed in all 7 cases analyzed. From this result, it is clear that administration of BCAA granule improves edema associated with fluid retention due to decreased circulatory function due to heart failure pathology.

(8) Change in pericardial effusion volume in case 2 before and after BCAA granule administration The pleural effusion and edema caused by fluid retention due to circulatory insufficiency in the state of heart failure were improved prior to the increase in serum albumin by BCAA administration. In case 2, as is apparent from FIGS. 2, 3, 4, and 5, the improvement in serum albumin and total protein is minimal, and the improvement in urine volume is also small. In this case, since pericardial effusion was prominent, changes in pericardial effusion caused by BCAA administration were evaluated by long-axis tomographic images in echocardiographic diagnosis, and the changes over time were plotted in FIG. Two weeks (14 days) after BCAA administration, the accumulation of pericardial effusion almost decreased to the standard level, and it became clear that symptoms associated with the heart failure pathological condition were improved.

  From the above results, it is clear that oral administration of BCAA is useful for the prevention or treatment of symptoms associated with acute exacerbation of chronic heart failure.

(A) Percentage of meals that were able to ingest almost the entire amount for 10 days before and after BCAA administration. (B) Percentage of meals that were hardly ingested for 10 days before and after BCAA administration. 1: Before, 2: After It is a figure which shows transition (1 month after administration) of Serum Albumin before and after BCAA administration. 1: Before, 2: After It is a figure which shows transition (1 month after administration) of Total Protein before and after BCAA administration. 1: Before, 2: After It is a figure which shows the change of the urine volume for 5 days before and after BCAA administration. 1: Before, 2: After It is a figure which shows the change of the urine volume of 10 days before and after BCAA administration. 1: Before, 2: After It is a figure which shows the change of the cardiothoracic ratio before and behind BCAA administration. 1: Before, 2: After It is a figure which shows the change of the pleural effusion degree before and after BCAA administration. 1: Before, 2: After It is a figure which shows the pericardial effusion volume (left ventricular posterior wall) by the echocardiogram long-axis tomogram.

Claims (6)

Active ingredient comprises isoleucine, leucine and valine, a pharmaceutical composition for improving the symptoms associated with acute exacerbations of chronic heart failure, Ri symptoms der the symptoms do not improve by the heart failure treatment, and decreased urine volume, congestive Symptom, pleural effusion, increased cardiothoracic ratio and pericardial effusion, at least one selected from the group consisting of diuretics, vasodilatory antihypertensives, β-blockers and cardiotonic drugs At least Tanedea Ru composition selected from the group consisting of. The composition according to claim 1, wherein the content of isoleucine, leucine and valine is 1 g or more per unit dose. The composition according to claim 1 or 2 , wherein the weight ratio of isoleucine, leucine and valine is 1: 1.5 to 2.5: 0.8 to 1.7. The composition according to any one of claims 1 to 3 , which is used in combination with a therapeutic agent for heart failure. The composition according to claim 4 , wherein the therapeutic agent for heart failure is at least one selected from the group consisting of diuretics, vasodilatory antihypertensives, β-blockers and cardiotonic drugs. Chronic unimproved by a heart failure remedy characterized by comprising at least one heart failure remedy selected from the group consisting of diuretics, vasodilatory antihypertensives, beta-blockers and cardiotonics and isoleucine, leucine and valine A combination drug for preventing or treating symptoms associated with acute exacerbation of heart failure , wherein the symptoms are selected from the group consisting of decreased urine output, congestive symptoms, pleural effusion, increased cardiothoracic ratio, and pericardial effusion A compounding agent that is at least one kind .

Images