Heart disease agent and method for improving heart disease

Abstract

[Problem] To provide a heart disease agent that is safe even when ingested over a long period of time and that can effectively improve heart disease. [Solution] Nicotinamide mononucleotide is an active component.

Description

Drugs for heart disease and methods for improving heart disease

[0001] The present invention relates to an agent for treating heart disease containing nicotinamide mononucleotide as an active ingredient and a method for improving heart disease.

[0002] The heart pumps blood to peripheral blood vessels and is the most important organ in the circulatory system. This pumping action is achieved by the alternating, regular contraction and expansion of the atria and ventricles. The heart contains a specialized cardiac muscle called the conduction system, which generates pulsed electrical signals and transmits these signals to individual cardiac muscle fibers. The heart is made of specialized muscle called the myocardium, which excites and functions when an electrical current flows through it. The conduction system begins at the sinoatrial node, which generates electrical signals approximately 70 times per minute, acting as a pacemaker for cardiac contraction. The electrical signal from the sinoatrial node then propagates to the atrial muscle, causing atrial contraction. The electrical impulse is then transmitted to the atrioventricular node, which then propagates to the His bundle and Purkinje fibers, transmitting the electrical impulse throughout the myocardium. In this way, electrical signals maintain a constant rhythm of cardiac contraction and expansion.

[0003] Arrhythmia occurs when this conduction system is disrupted, disrupting the rhythm of the heart's electrical signals. Arrhythmia can be broadly classified as tachycardia (a rapid heartbeat), bradycardia (a slow heartbeat), or premature contractions (a premature beat occurring at an abnormal location). Sudden abnormal heartbeats can not only cause palpitations, shortness of breath, chest discomfort, and dizziness, but can also be life-threatening in some cases, requiring appropriate treatment and response. Arrhythmia can be caused by aging, constitution, stress, lack of sleep, fatigue, alcohol consumption, smoking, and autonomic nervous system factors. Other causes of cardiac damage, such as myocardial infarction and angina, can also disrupt the conduction system, making arrhythmias more likely. Conversely, arrhythmias such as atrial fibrillation and ventricular fibrillation can lead to other heart conditions, including myocardial infarction, valvular disease, and ischemic heart disease. Furthermore, arrhythmias can also be caused by side effects of medications taken to treat heart disease.

[0004] Antiarrhythmic drugs are classified into categories based on the Sicilian Gambit classification, which takes into account the mechanism of arrhythmia and the action of each antiarrhythmic drug on molecular targets such as ion channels and receptors. A classification framework for antiarrhythmic drugs has been proposed to help select appropriate drugs. However, because incorrect indications and dosages can cause serious side effects and even sudden death, antiarrhythmic drugs are classified as high-risk drugs that require particular safety management. Therefore, it is important to thoroughly verify that the selection, dosage, and administration of antiarrhythmic drugs are appropriate.

[0005] Conventionally used antiarrhythmic drugs include sodium channel blockers (class Ia, Ib, and Ic), beta-blockers (class II), αβ-blockers, potassium channel blockers (class III), calcium channel blockers (class IV), and digitalis preparations. Furthermore, new antiarrhythmic drugs have been developed one after another in recent years. For example, by focusing on the signal transduction system downstream of the beta-adrenergic receptor, an antiarrhythmic drug containing 9-β-D-arabinofuranosylhypoxanthine, a metabolite of vidarabine, which is clinically used as an antiviral drug, or a pharmaceutically acceptable salt or solvate thereof has been proposed (Patent Document 1).

[0006] Re-table No. 2019-131308

[0007] Antiarrhythmic drugs are known to induce new arrhythmias (proarrhythmic effects). In particular, elderly patients are prone to severe drug-induced tachycardia and bradycardia proarrhythmic effects due to age-related changes in renal function and the myocardial conduction system. Furthermore, some antiarrhythmic drugs have been reported to cause various noncardiac side effects, such as urinary retention, optic nerve damage due to elevated intraocular pressure, general fatigue, sleep disorders, depression, and hypoglycemia. Therefore, careful electrocardiogram monitoring and blood biochemistry testing are essential for early detection and prevention of antiarrhythmic drug side effects. Furthermore, as mentioned above, improper use or dosage of antiarrhythmic drugs can cause serious side effects, including sudden death. Against this backdrop, there is a need for safer drugs with excellent arrhythmia-ameliorating properties and minimal side effects.

[0008] An object of the present invention is to provide an agent for cardiac diseases which is safe even when used over a long period of time and is useful for the prevention and treatment of cardiac diseases associated with arrhythmia.

[0009] As a result of intensive research to solve the above-mentioned problems, the present inventors discovered that nicotinamide mononucleotide, an intermediate metabolite involved in the biosynthesis of the coenzyme NAD (nicotinamide adenine dinucleotide), has excellent effects in preventing and improving heart disease, and thus completed the present invention.

[0010] The present invention provides the following: [1] A cardiac disease agent containing nicotinamide mononucleotide as an active ingredient. [2] The cardiac disease agent according to [1], wherein the cardiac disease is a condition presenting with arrhythmia, a disease that causes arrhythmia, or a disease caused by arrhythmia. [3] The cardiac disease agent according to [2], wherein the arrhythmia is bradyarrhythmia or tachyarrhythmia. [4] The cardiac disease agent according to [3], wherein the arrhythmia is any one of premature contractions, ventricular tachycardia, paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation, ventricular fibrillation, atrial tachycardia, bundle branch block, torsades de pointes, and atrioventricular block. [5] The cardiac disease agent according to [2], wherein the disease that causes arrhythmia is any one of myocardial infarction, angina pectoris, heart failure, cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, sarcoidosis, valvular disease, congenital heart disease, Brugada syndrome, long QT syndrome, and takotsubo cardiomyopathy. [6] The agent for cardiac disease according to [2], wherein the disease caused by arrhythmia is any of palpitations, dizziness, heart failure, myocardial lesions, cardiogenic cerebral embolism, cardiogenic syncope, and cardiogenic shock caused by arrhythmia. [7] The agent for cardiac disease according to any of [1] to [6], wherein the agent for cardiac disease is a food product for improving cardiac disease. [8] The agent for cardiac disease according to any of [1] to [6], wherein the agent for cardiac disease is a pharmaceutical product for improving cardiac disease. [9] The agent for cardiac disease according to any of [1] to [8], wherein the amount of nicotinamide mononucleotide administered per day to an adult is 1 mg to 500 mg.

[10] A method for improving cardiac disease (excluding medical procedures for humans), comprising administering an effective amount of nicotinamide mononucleotide to a subject in need thereof.

[0011] The agent for cardiac diseases according to the present invention is effective in preventing or treating cardiac diseases associated with arrhythmia, and also has an effect of suppressing NAD in vivo. ＋ It is safe and can be used for a long period of time because its active ingredient is nicotinamide mononucleotide, an intermediate metabolite involved in the biosynthesis of

[0012] Fig. 1 is an explanatory diagram showing a metabolic pathway involved in niacin (a collective term for nicotinamide and nicotinic acid). Fig. 2 is an explanatory diagram showing electrocardiogram results in an example. Fig. 3 is an explanatory diagram showing electrocardiogram results in an example.

[0013] The agent for cardiac disease according to the present invention contains nicotinamide mononucleotide (including its salts) as an active ingredient and has an effect of improving cardiac disease. In the present invention, improvement of cardiac disease does not only mean improvement of cardiac disease in the narrow sense, but also includes alleviation of symptoms caused by cardiac disease, prevention, halting of progression, and slowing down of cardiac disease. The detailed reasons why such effects can be obtained by using nicotinamide mononucleotide as an active ingredient are currently under investigation, but it is believed that NAD ＋ It is believed that nicotinamide mononucleotide promotes "sirtuins," typified by the neurotransmitter-dependent deacetylases Sirt1 and Sirt3, thereby eliminating the cause of the disorder in the conduction system and thereby exerting an improving effect on heart disease. The cardiac disease agent of the present invention, which thus brings about an improving effect on heart disease, can be used as a pharmaceutical product (including quasi-drugs) or a food product such as a functional food. The present invention will be described in detail below.

[0014] Nicotinamide mononucleotide (chemical formula: C １１ H １５ N ２ O ８ Nicotinamide mononucleotide (NMN) is a compound expressed by the following structural formula [Chemical Formula 1], which is produced in the bodies of many living organisms, including humans. It is commonly called NMN (nicotinamide mononucleotide) and is a coenzyme NAD ＋ It is known as an intermediate metabolite involved in the biosynthesis of

[0015]

[0016] Nicotinamide mononucleotide, the active ingredient of the agent for treating heart disease, is produced in vivo in the NAD metabolic pathway in liver tissue, i.e., in the pathway involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from quinolinic acid via the kynurenine pathway. This point will be specifically explained with reference to Figure 1. Figure 1 shows the relationship between vitamin B ３ This diagram shows the metabolic pathway involved in niacin (a collective term for nicotinamide and nicotinic acid), also known as niacin. Nicotinic acid ingested through diet is taken up by the liver and converted to nicotinamide, which is then distributed throughout the body via the bloodstream. Each cell takes in nicotinamide from the blood and converts it to NAD and NADP for use. Nicotinamide can also be biosynthesized from tryptophan.

[0017] As shown in Figure 1, in vivo, when tryptophan is used as the starting material, tryptophan is converted to quinolinic acid (QA) via the kynurenine pathway, which is the tryptophan metabolic pathway, and then to nicotinic acid mononucleotide (NaMN). On the other hand, when nicotinic acid (Na) is used as the starting material, nicotinic acid is directly converted to NaMN. NaMN then passes through nicotinic acid adenine dinucleotide (NaAD) and is interconverted to NAD, nicotinamide (NaM), and nicotinamide mononucleotide via the NAD cycle. Nicotinamide (NaM) is converted to nicotinamide mononucleotide by nicotinamide phosphoribosyltransferase (NAMPT), and nicotinamide mononucleotide is then converted by nicotinamide mononucleotide adenyltransferase (NMNAT) to produce NAD. Nicotinamide mononucleotide can also be produced from nicotinamide riboside (NR), an NAD intermediate metabolic product.

[0018] Nicotinamide mononucleotide exists as two optical isomers, α- and β-, and the β-isomer is used in the present invention. Nicotinamide mononucleotide can be obtained, for example, by synthesizing nicotinamide riboside from nicotinamide and ribose (see Bioorg. Med. Chem. Lett., 12, 1135-1137 (2002)), followed by phosphorylating the 5-hydroxyl group of the ribose moiety (see Chem. Comm., 1999, 729-730). Specifically, for example, nicotinamide and L-ribose tetraacetate are first dissolved in anhydrous acetonitrile, and an excess amount of trimethylsilyltrifluorosulfonic acid is added under a nitrogen stream. The mixture is stirred at room temperature, and the reaction is terminated by adding methanol. The reaction solution is then loaded onto a column packed with activated carbon, washed with distilled water, and eluted with methanol to recover the product. Next, to phosphorylate the 5-hydroxyl group of the L-ribose moiety of this product, the product is dissolved in trimethoxyphosphate, and phosphorus oxychloride is added dropwise under ice cooling. The mixture is stirred under a nitrogen stream, and aqueous sodium hydroxide is added to neutralize the reaction. To the resulting reaction solution, a cold acetonitrile-ether solution is added. The lower layer (aqueous phase) is then passed through an anion exchange resin to recover the reaction product, which is then further purified with a cation exchange resin to recover highly pure nicotinamide mononucleotide. Nicotinamide mononucleotide is commercially available, and such commercially available products can be purchased and used.

[0019] The agent for treating cardiac diseases according to the present invention can be easily produced by using nicotinamide mononucleotide alone or by mixing it with other ingredients, which are not particularly limited as long as the agent for treating cardiac diseases exhibits the effects of the present invention.

[0020] Examples of other ingredients include sodium channel blockers (class Ia, Ib, and Ic), beta-blockers (class II), alpha-beta-blockers, potassium channel blockers (class III), calcium channel blockers (class IV), and digitalis preparations commonly used as antiarrhythmic drugs, including lidocaine, mexiletine, procainamide, disopyramide, quinidine, propafenone, aprindine, cibenzoline, pirmenol, landiolol, esmolol, flecainide, pilsicainide, bepridil, verapamil, diltiazem, sotalol, amiodarone, nifekalant, nadolol, propranolol, atropine, ATP, and digoxin. Other ingredients may also be included, such as supplementary ingredients commonly used in the food industry, such as various vitamins, trace elements, citric acid, malic acid, flavorings, and inorganic salts.

[0021] The agent for cardiac diseases according to the present invention can be used for the purpose of improving various cardiac diseases, but is primarily used for the purpose of improving pathological conditions presenting with arrhythmia, diseases that cause arrhythmia, or diseases caused by arrhythmia.

[0022] In the present invention, the target arrhythmias include both arrhythmias requiring medical treatment and arrhythmias not requiring medical treatment, and also include both bradyarrhythmia (heart rate of 50 beats / min or less) and tachyarrhythmia (heart rate of 100 beats / min or more).

[0023] The condition presenting with arrhythmia broadly refers to a condition in which arrhythmia is present, regardless of the presence or absence of underlying diseases or complications related to arrhythmia. Therefore, it also includes conditions in which arrhythmia occurs unrelated to illness, such as aging, constitution, fatigue, stress, and lack of sleep. Examples of conditions presenting with arrhythmia include premature contractions, ventricular tachycardia, paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation, atrial tachycardia, bundle branch block, torsades de pointes, and atrioventricular block.

[0024] Specific examples of diseases that cause arrhythmia include myocardial infarction, angina pectoris, heart failure, cardiomyopathy (dilated, hypertrophic), arrhythmogenic right ventricular mycosis, cardiac sarcoidosis, valvular disease, congenital heart disease, Brugada syndrome, long QT syndrome, and takotsubo cardiomyopathy.

[0025] Examples of the diseases caused by arrhythmia include palpitations caused by arrhythmia, dizziness caused by arrhythmia, sudden death caused by arrhythmia, heart failure caused by arrhythmia, myocardial lesions caused by arrhythmia, cardiogenic cerebral embolism caused by arrhythmia, cardiogenic syncope caused by arrhythmia, and cardiogenic shock caused by arrhythmia.

[0026] The method for producing the agent for cardiac disease is not particularly limited, and a general production method used for producing the agent may be appropriately selected depending on its form. For example, if the agent is in the form of a powder, it can be produced by appropriately blending and uniformly dispersing and kneading nicotinamide mononucleotide, other medicinal ingredients, bulking agents, sweeteners, preservatives, pH adjusters, flavorings, etc., using equipment with sufficient shearing force and kneading force for production. Note that the active ingredient, nicotinamide mononucleotide, is distributed on the market and can be commercially obtained. In particular, with regard to nicotinamide mononucleotide, a quality control system and mass production system have been established in recent years, making it possible to supply it as a raw material for food compositions, and its stability as a food composition has also been confirmed.

[0027] The agent for cardiac disease according to the present invention can be used in the pharmaceutical field as a drug (including quasi-drugs) for improving cardiac disease, and can be administered orally or parenterally. When administered orally, the dosage form of the agent for cardiac disease is not particularly limited, and examples thereof include powders, tablets, sustained-release tablets, chewable tablets, effervescent tablets, troches, buccal tablets, sublingual tablets, capsules, fine granules, granules, pills, dry syrup, liquids, suspensions, syrups, and elixirs. Among these, oral administration preparations such as powders, tablets, and capsules are preferred in terms of ease of administration and stability of the active ingredient.

[0028] On the other hand, when the agent for treating cardiac diseases according to the present invention is administered parenterally, the dosage form of the agent for treating cardiac diseases may be, for example, an external preparation, an injection, or an infusion, but an external preparation is preferred because the active ingredient can be applied directly to the oral cavity. Specific examples of the external preparation include an ointment, cream, dentifrice, mouthwash, and mouth spray.

[0029] The pharmaceutical may be appropriately blended with known pharmaceutically acceptable additives suitable for the dosage form, taking into consideration physicochemical properties, biological properties, etc. Examples of such additives include excipients (lactose, starch, crystalline cellulose, sodium phosphate, etc.), solvents (water, soybean oil, saline, non-aqueous solvents for injection, etc.), binders (starch, gelatin, gum arabic, sodium alginate, carmellose sodium, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), disintegrants (starch, carmellose sodium, etc.), lubricants (talc, magnesium stearate, calcium stearate, macrogol, sucrose fatty acid esters, etc.), coating agents (sucrose, HPC, shellac, gelatin, glycerin, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, etc.), stabilizers (sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutylhydroxybenzoate, etc.), and the like. Examples of the additives include benzoyl perfluorooctyl alcohol (e.g., benzoyl perfluorooctyl alcohol), preservatives (e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, thimerosal), thickeners (e.g., methylcellulose, carmellose sodium, chondroitin sulfate, sodium alginate), suspending agents (various nonionic surfactants, methylcellulose, carmellose sodium), emulsifiers (e.g., gum arabic, cholesterol, sorbitan sesquioleate, polysorbate 80, sodium lauryl sulfate), buffers (citric acid, acetic acid, sodium phosphate, boric acid), surfactants (e.g., hydrogenated castor oil, polysorbate 80), colorants (e.g., water-soluble food dyes, lake dyes), flavoring agents (e.g., lactose, sucrose, glucose, mannitol), odorants (e.g., aromatic essential oils), and plasticizers (e.g., phthalate esters, vegetable oils, polyethylene glycol).

[0030] The dosage of the pharmaceutical varies depending on the age, sex, weight, expected effects, symptoms, etc. of the recipient and cannot be uniformly defined. However, the dosage of the pharmaceutical is typically 1 mg to 500 mg, preferably 5 mg to 250 mg, and more preferably 50 mg to 200 mg, of nicotinamide mononucleotide per adult per day. If the dosage is less than 1 mg, the effects of the present invention may not be achieved. On the other hand, if the dosage is more than 500 mg, the effects obtained will not change significantly and it will be economically disadvantageous. The proportion of nicotinamide mononucleotide in the pharmaceutical can be appropriately determined depending on the dosage form and frequency of administration of the pharmaceutical, so long as the amount of nicotinamide mononucleotide administered per adult per day falls within the above range.

[0031] The number of times the pharmaceutical is administered can be appropriately determined depending on the age, weight, symptoms, and dosage of the pharmaceutical per administration of the subject, etc. One example of the number of times the pharmaceutical is administered per day is 1 to 3 times.

[0032] The agent for cardiac disease according to the present invention can also be used as a food. When used as a food, the agent for cardiac disease can be provided in the food industry as a food for improving cardiac disease. When taken daily in the form of a food, the effect of improving cardiac disease is continuously exerted, making it particularly effective in improving cardiac disease. The type of food that can be used in the present invention is not particularly limited, and in addition to general foods, functional foods, foods for specified health uses, nutritional supplements, supplements, food additives, feed, nursing care foods, dietary foods, therapeutic foods, and diet foods can be used. The form of the food is also not limited, and in particular, functional foods and foods for specified health uses can be provided in the form of powders, tablets, pills, granules, hard capsules, soft capsules, jellies, liquids, pastes, chewing gum, and the like.

[0033] The intake amount of the food varies depending on the type of food, the age, sex, and weight of the person taking it, the expected effects, symptoms, etc., but the recommended daily amount of nicotinamide mononucleotide contained in the food for an adult is usually 1 mg to 500 mg, preferably 5 mg to 250 mg, and more preferably 50 mg to 200 mg. If the amount is less than 1 mg, the effects of the present invention may not be achieved, while if the amount is more than 500 mg, the obtained effects will not change significantly and it will be economically disadvantageous. The blending ratio of nicotinamide mononucleotide in the food can be appropriately set within a range of 100% or less of the total weight of the food so that the amount of nicotinamide mononucleotide ingested per day by an adult is within the above range.

[0034] Since the food is safe and has no particular side effects, it can be taken over a long period of time not only for the purpose of treating heart disease but also for the purpose of preventing heart disease, and therefore can be applied not only to subjects for whom treatment of heart disease is desired, but also to healthy subjects to prevent heart disease.

[0035] As described above, nicotinamide mononucleotide has the effect of improving cardiac disease. Therefore, the present invention further provides a method for improving cardiac disease, comprising administering an effective amount of nicotinamide mononucleotide to a subject in need thereof. That is, this method improves cardiac disease in a subject by administering the agent for cardiac disease of the present invention. Preferred subjects include mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys, with humans being particularly preferred. In this method, the amount of nicotinamide mononucleotide to be administered, the number of times per day to be administered, and the like are the same as those described for the agent for cardiac disease. Furthermore, the agent for cardiac disease can be administered at any time and in any circumstances, and can be administered to a subject over a long period of time.

[0036] (Example) On June 4, 2020, a subject (64 years old, male) was placed in a supine position, clips were attached to his limbs, and electrodes were attached to his chest. An electrocardiogram was performed using an electrocardiograph (product name: electrocardiograph ECG-2250, manufactured by Nihon Kohden Corporation) in leads I to III and aVR, aVL, and aVF. The electrocardiogram paper feed speed was set to 25 mm / sec, and the vertical axis was set to 1 mV = 10 mm. The results are shown in the electrocardiogram in Figure 2 (horizontal axis: time (seconds), vertical axis: potential (mV)). The recorded electrocardiogram showed a P wave that appeared earlier than a normal pulse, and a QRS wave with a wide and strange waveform. Therefore, the findings of the recorded electrocardiogram suggested premature ventricular contractions. Subsequently, starting October 18, 2020, the subject took one capsule of NMN Pure 3000 Plus (NMN 50 mg / capsule, Mirai Lab Biosciences, Inc., trade name) per day for 47 consecutive days. Then, on January 4, 2021, the subject underwent another electrocardiogram test similar to that described above. The results are shown in the electrocardiogram in Figure 3 (horizontal axis: time (seconds), vertical axis: potential (mV)). As a result, as can be seen from Figure 2, the waveform appeared regular and well-formed, the previously observed wide and strangely shaped QRS wave was not observed, and the heart rate also decreased (69 → 57 bpm). This confirmed that NMN intake is effective against electrocardiogram abnormalities and arrhythmias.

Claims

1. A drug for heart disease whose active ingredient is nicotinamide mononucleotide.

2. 2. The agent for cardiac diseases according to claim 1, wherein the cardiac disease is a condition presenting with arrhythmia, a disease that causes arrhythmia, or a disease that is caused by arrhythmia.

3. 2. The agent for cardiac diseases according to claim 1, wherein the arrhythmia is bradyarrhythmia or tachyarrhythmia.

4. 4. The agent for cardiac diseases according to claim 3, wherein the arrhythmia is any one of premature contractions, ventricular tachycardia, paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation, ventricular fibrillation, atrial tachycardia, bundle branch block, torsades de pointes, and atrioventricular block.

5. 3. The agent for cardiac diseases according to claim 2, wherein the disease that causes arrhythmia is any one of myocardial infarction, angina pectoris, heart failure, cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, sarcoidosis, valvular disease, congenital heart disease, Brugada syndrome, long QT syndrome, and takotsubo cardiomyopathy.

6. 3. The agent for cardiac diseases according to claim 2, wherein the disease caused by arrhythmia is any one of palpitations, dizziness, heart failure, myocardial lesions, cardiogenic cerebral embolism, cardiogenic syncope, and cardiogenic shock caused by arrhythmia.

7. The agent for cardiac diseases according to claim 1 , which is a food for improving cardiac diseases.

8. The agent for treating heart diseases according to claim 1 , which is a pharmaceutical for improving heart diseases.

9. 2. The agent for cardiac diseases according to claim 1, wherein the amount of nicotinamide mononucleotide administered to an adult per day is 1 mg to 500 mg.

10. A method for improving heart disease (excluding medical procedures for humans), comprising administering an effective amount of nicotinamide mononucleotide to a subject in need thereof.