JP2022033333A - Therapeutic or preventive agent for cardiometabolic disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide means for reducing a cardiometabolic risk factor in an elderly and improving a cardiometabolic profile.

SOLUTION: The present invention provides a composition used for reducing a cardiometabolic risk factor and improving a cardiometabolic profile, the composition containing a hydrogen gas as an active ingredient. The composition is used so that the hydrogen gas is inhaled by a subject.

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

Application for application of Article 30, Paragraph 2 of the Patent Act Date of publication / July 31, 2018 Publication address / https: // doi. org / 10.1007 / s41999-018-0087-6 Publication name / European Generic Medicine (2018) Publisher / Darinka Korovljev, Valdemar Stager, Dejan Javorac, Sergej. Ostojic

The present invention relates to therapeutic or prophylactic compositions for cardiovascular metabolic disorders. Furthermore, the present invention relates to a method for treating or preventing a cardiovascular metabolic disease.

In recent years, hydrogen gas (molecular hydrogen, H ₂ ) has been introduced as a medical gas in the field of clinical medicine (Non-Patent Document 1). The effects brought about by hydrogen gas in clinical medicine are considered to be due to the antioxidant, anti-apoptotic, and anti-inflammatory effects of hydrogen gas (Patent Document 1).

Regarding cardiovascular metabolic diseases, the effects of hydrogen-enriched water intake on blood LDL cholesterol levels and HDL function have been reported (Non-Patent Document 2).
Cardiorespiratory fitness, also known as cardiorespiratory endurance, is an objective and reproducible measure related to physical fitness and tenacity that allows you to continue a certain amount of exercise for a long time. It is considered to be one of the basic athletic abilities. Since cardiorespiratory fitness is closely related to the ability of aerobic exercise, it is possible to estimate the energy used by aerobic exercise by measuring oxygen consumption during exercise, so maximal oxygen uptake (VO ₂ ). It can be evaluated by an index such as max) (Non-Patent Documents 3 to 5).

Diabetes is a disease diagnosed based on blood glucose level and hemoglobin A1c (HbA1c) level, and is classified into type 1 and type 2. Type 2 diabetes is characterized by an increase in blood glucose level due to two factors, decreased insulin secretion and decreased sensitivity, and is understood to be a lifestyle-related disease that develops in association with genetic factors and lifestyle. 90% of diabetics have type 2 diabetes. Studies have been conducted on the effects of hydrogen on glucose metabolism (Non-Patent Document 6).

The decrease in muscle strength and mass due to aging has become an important issue in the health problems of the elderly. Decreased muscle strength is a factor that increases the risk of falls in the elderly. Studies have been conducted on methods for grasping the health condition of the elderly (Non-Patent Document 7).

WO2007 / 021034

Ohta S., et al., Methods Enzymol. 2015; 555: 289-317; Song G, Li M, Sang H et al., J Lipid Res. 2013; 54: 1884-93; JAMA. 2007 December 5; 298 (21): 2507-2516; Am J Epidemiol. 2007 June 15; 165 (12): 1413-1423; Doshisha Journal of Health & Sports Science, 7, 52-55 (2015); PLoS One. 2013; 8 (1): e53913; West Kyushu Journal of Rehabilitation Science 3, 23-26-2010.

In general, elderly people are at high risk of cardiovascular metabolic diseases, and there is a need for a method for lowering cardiometabolic risk factors and improving the cardiovascular metabolic profile in elderly people. In particular, arteriosclerotic cardiovascular disease may be accompanied by serious attacks at the onset, and there is a strong need for measures to prevent arteriosclerotic cardiovascular disease in elderly people at high risk of cardiovascular metabolic disease. Has been done.

Cardiorespiratory fitness, which is evaluated using maximal oxygen uptake (VO ₂ max) as an index, is considered as an index of cardiovascular disease and the life expectancy of the elderly (Non-Patent Documents 3 and 4). The present invention provides a means for improving cardiorespiratory fitness in one aspect of speed.

In addition, while diabetes may require continuous treatment with drug therapy, resistance to drugs may occur, which is a problem. There is a need for a new method for lowering blood glucose levels that does not place an excessive burden on patients, including side effects.

The present inventor conducted research to solve such a problem, found an effect of improving the cardiovascular metabolism profile in the elderly by inhaling hydrogen gas, and completed the following invention.
[1] A composition containing hydrogen gas as an active ingredient, which is used for lowering a cardiovascular metabolism risk factor or improving a cardiovascular metabolism profile.

[2] A composition containing hydrogen gas as an active ingredient, which is used for the prevention or treatment of cardiovascular metabolic diseases.
[3] The composition according to [2], which is used for the prevention of cardiovascular metabolic diseases.

[4] The composition according to [2] or [3], wherein the cardiovascular metabolic disease is arteriosclerotic cardiovascular disease.
[5] A composition containing hydrogen gas as an active ingredient, which is used for suppressing blood glucose level.

[6] A composition containing hydrogen gas as an active ingredient, which is used for improving cardiorespiratory fitness.
[7] The composition according to [6], wherein cardiorespiratory fitness is evaluated using the maximum oxygen consumption as an index.

[8] A composition containing hydrogen gas as an active ingredient, which is used for suppressing total cholesterol level in blood.
[9] A composition containing hydrogen gas as an active ingredient, which is used for increasing muscle mass or strength, or for suppressing muscle mass loss or muscle weakness.

[10] The composition according to any one of [1] to [9], which is used to be inhaled by a subject.
[11] The composition according to any one of [1] to [10], which is used for transpulmonary administration.

[12] The composition according to any one of [1] to [11], wherein the subject is a human aged 60 years or older.

[13] The composition according to any one of [1] to [12], wherein the subject is a human being 65 years or older.
[14] The composition according to any one of [1] to [13], wherein the hydrogen gas is inhaled in the form of a gas containing 3% by volume or more of the hydrogen gas.

[15] The composition according to any one of [1] to [14], wherein the hydrogen gas is inhaled in the form of a gas containing 0.5% by volume or more of the hydrogen gas.
[16] The composition according to any one of [1] to [15], wherein the hydrogen gas is inhaled in the form of a gas containing 4% by volume or more of the hydrogen gas.

[17] The composition according to any one of [1] to [16], which is used so that hydrogen gas is inhaled for 20 minutes or more per day.
[18] The composition according to any one of [1] to [17], wherein the inhalation of hydrogen gas is carried out for 4 weeks or more.

[19] The composition according to any one of [1] to [18], which is used as a pharmaceutical composition.

In one aspect of the invention, methods for reducing cardiovascular metabolism risk factors and methods for improving cardiovascular metabolism profiles are provided. In another aspect of the invention, techniques are provided for improving the cardiopulmonary profile. In yet another aspect of the invention, techniques for lowering blood glucose levels are provided.

The method provided by the present invention has few problems such as side effects, and is also excellent as a method for long-term implementation especially in elderly people.

In one aspect, the invention is used to reduce cardiometabolic risk factors or improve cardiometabolic profile. Cardiovascular metabolism risk factors and cardiovascular metabolism profiles can be evaluated, such as by measuring relevant biomarkers and the like. Examples of measured values are total blood cholesterol level, LDL-cholesterol level, HDL-cholesterol level, triglyceride level, blood glucose level (fasting blood glucose level, etc.), and blood pressure (systolic blood pressure, diastolic blood pressure). And so on.

In one aspect of the invention, cardiovascular risk factors and cardiovascular profile are shown by the American Heart Association and the American Cardiology Society for a 10-year risk for the first major event of arteriosclerotic cardiovascular disease. It can be evaluated by the score (hereinafter also referred to as the risk score) of the 2013 ACC / AHA Guideline on the Assessment of Cardiovascular Risk. For example, if the score shows an improvement with superiority, or if the change in the score shows an improvement tendency, it can be understood that the cardiovascular metabolism risk factor is decreased or the cardiovascular metabolism profile is improved. In one embodiment of the invention, the invention can be used to keep the above risk score below 4.0 points.

In one aspect, the invention is used for the prevention or treatment of cardiometabolic disorders, preferably for the prevention of cardiometabolic disorders. Cardiovascular metabolic disease is a concept that includes arteriosclerotic cardiovascular disease, such as ischemic heart disease (eg, coronary artery disease (angina, myocardial infarction, etc.), takotsubo myocardium, central lung). Hematology, etc.), and vascular diseases (eg, degenerative diseases (eg, arteriosclerosis, aortic aneurysm, lower extremity varices, superior aortic syndrome, etc.), and inflammatory diseases (eg, hyperan arteritis, thrombotic venous inflammation, etc.), etc. ) Can be mentioned. The therapeutic and preventive effects of cardiovascular metabolic diseases and arteriosclerotic cardiovascular diseases can be confirmed by comparing the risk scores before and after the treatment.

Cardiovascular metabolic diseases include cerebrovascular diseases (cerebral infarction, cerebral hemorrhage, submucosal hemorrhage, etc.) and ischemic heart diseases (anginalysis, myocardial infarction, etc.). Further, cardiovascular metabolic diseases include, for example, diabetes described below.

In one aspect, the invention is used for blood glucose suppression. The blood glucose level can be confirmed by collecting blood according to a conventional method. In one aspect of the invention, the invention is used for the treatment or prevention of diabetes, its complications, preferably its prevention. Diabetes includes type 1 diabetes and type 2 diabetes, as well as gestational diabetes. The present invention is used in one embodiment for type 2 diabetes. Diabetic complications include, for example, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, periodontal disease, arteriosclerosis, myocardial infarction (ischemic heart disease), cerebral infarction, peripheral arterial disease, foot necrosis and the like. ..

The compositions of the present invention may be applied to diabetic patients receiving drug therapy. The drug for treating diabetes may be an orally administered drug or an injectable drug (insulin injection, GLP-1 receptor agonist, etc.). Orally administered agents include, for example, sulfonylurea agents (eg, tolbutamide, acetohexamide, chlorpropamide, glibenclamide, glycladide, glymepyride, etc.), biguanide agents (eg, metformin, buformin, etc.), α-glucosidase inhibitors (eg, methformin, buformin, etc.). For example, acarbose, voglibose, miglitol, etc.)
, Thiazolidine drugs (eg, pioglitazone, etc.), fast-acting insulin-secreting drugs (eg, nategrinide, mitiglinide, repaglinide, etc.), DPP-4 inhibitors (eg, sitagliptin, bildagluptin, allogliptin, linagliptin, tenerigluptin, anagliptin, saxagliptin, treagliptin, saxagliptin, , Omarigliptin, etc.), SGLT2 inhibitors (eg, ipragliflozin, dapagliflozin, luseogliflozin, tohogliflozin, canagliflozin, empagliflozin, etc.) and the like.

The composition of the present invention prevents or treats dyslipidemia (hyperlipidemia), specifically, diseases such as hypercholesterolemia, high LDL cholesterolemia, low HDL cholesterolemia, and hypertriglyceridemia. Can be applied to. The compositions of the present invention can be used in combination with drug therapy. Drugs used in drug therapy for dyslipidemia include, for example, HMG-CoA reductase inhibitors (statins), fibrato drugs, anion exchange resins, nicotinic acid derivatives, probucol, omega 3-fatty acid preparations (EPA). , DHA), small intestinal cholesterol transporter inhibitor, PCSK9 inhibitor and the like.

The decrease in blood glucose level according to the present invention can be confirmed, for example, by the decrease in blood glucose level due to blood sampling on an empty stomach. The effect of the present invention can also be confirmed by a glucose tolerance test or measurement of postprandial hyperglycemia.

In blood sampling, numerical values such as total cholesterol level, LDL-cholesterol level, and HDL-cholesterol level can also be measured, and these measurements can be performed by a conventional method.

Improvements in cardiorespiratory fitness can be evaluated, for example, using maximal oxygen uptake as an index. VO2 max indicates the maximum amount of oxygen taken into the body (mitochondria) during exercise, and there are direct and indirect methods for measuring it. In the direct method, the exhaled gas collected during exercise with maximum effort is analyzed using a bicycle ergometer, a treadmill, or the like, and the maximum amount of oxygen taken into the body in one minute is calculated. On the other hand, in the indirect method, the maximum oxygen uptake is estimated from the heart rate and exercise load. The average male 30-year-old is about 40 ml / kg / min per body weight, but the maximum oxygen uptake of elite long-distance runners reaches 90 ml / kg / min. The maximum oxygen uptake itself is also related to the morbidity and mortality rate of cardiovascular diseases, and is considered to be important not only as an evaluation value of physical fitness as general endurance but also as an index showing health.

In one aspect, the compositions of the invention can be used as pharmaceutical compositions. Since the method of the present invention can be carried out by inhalation of a composition that can be prepared by a hydrogen generator that can be installed at home, in another aspect, the composition of the present invention is a method other than medical practice or a therapeutic practice. Can be used in the above method.

In one aspect, the compositions of the invention can be used for muscle mass or strengthening, muscle loss or suppression of muscle loss, or maintenance of muscle mass. The effect of the present invention can be confirmed by measuring foot grip strength, quadriceps muscle strength, skeletal muscle mass, skeletal muscle mass, upper body raising, one-leg standing holding time, grip strength, etc., and the measurement is performed by a conventional method. be able to. It is known that the measurement result of grip strength has a correlation with the measurement value of various muscle strengths (Non-Patent Document 6).

The subject to which the present invention is applied is not particularly limited, but it can be targeted at elderly people who are generally considered to have a high risk of cardiometabolic diseases. Here, the elderly include, for example, an adult aged 60 or over, specifically an adult aged 65 or over.

The composition of the present invention contains hydrogen gas as an active ingredient. In one embodiment of the invention, the hydrogen gas is used in the form of a gas containing hydrogen gas.
The gas containing hydrogen gas may be, for example, air containing hydrogen gas or a mixed gas of hydrogen gas and oxygen gas. The concentration of hydrogen gas in the gas containing hydrogen gas is not particularly limited, but is, for example, 18.3% by volume or less, which is less than the lower limit of the explosion of hydrogen gas, for example, 0.5 to 18.3% by volume, specifically. Specifically, 1 to 10% by volume, more specifically, 2 to 8% by volume, more specifically, 3 to 6% by volume, more specifically, 4 to 6% by volume, and more specifically, 4 to 5%. By volume. The concentration of hydrogen gas in the gas containing hydrogen gas is preferably 1 to 10% by volume, 2 to 9% by volume, 3 to 8% by volume, and more preferably 3 to 5% by volume.

When the gas other than hydrogen gas is air, the concentration of air is, for example, in the range of 81.7 to 99.5% by volume. When the gas other than hydrogen gas is oxygen gas, the concentration of oxygen gas is, for example, in the range of 21 to 99.5% by volume. The gas containing hydrogen gas may contain two or more gases in addition to hydrogen, and examples thereof include gases such as air, oxygen gas, nitrogen gas, and carbon dioxide gas. Since hydrogen gas is flammable and explosive, it is preferable to use it at a concentration equal to or lower than the explosive limit of hydrogen gas from the viewpoint of safety.

The flow rate of the composition when inhaling the hydrogen gas composition diluted to a safe concentration is, for example, 1 to 10 L / min, 1 to 6 L / min, 1 to 4 L / min, specifically 2 to 4 L / min. Can be. In patients with hyperventilation, it can be 6-8 L / min. In one embodiment of the present invention, inhalation of a hydrogen gas composition is 70 ml / min or more, 80 ml / min or more, 140 ml / min or more, or 280 ml / min or more in terms of the amount of hydrogen contained in the composition. It can be done at the flow rate of.

The gas containing hydrogen gas can be filled in a pressure-resistant container (for example, an aluminum can, a PET bottle, etc.) and stored after being blended so as to have a predetermined hydrogen gas concentration. Alternatively, the gas containing hydrogen gas may be prepared on the spot using a known hydrogen gas supply device and used for inhalation.

The hydrogen gas supply device makes it possible to mix the hydrogen gas generated by the reaction between the hydrogen generating agent (for example, metallic aluminum) and water with the diluting gas (for example, air, oxygen, etc.) in a predetermined ratio. (Patent No. 5228142). Alternatively, the device makes it possible to mix the hydrogen gas generated by utilizing the electrolysis of water with the diluting gas (Patent No. 5502973, No. 5900688). Thereby, a gas containing hydrogen gas in the range of 0.5 to 18.5% by volume can be prepared.

In the present invention, hydrogen gas is administered to a subject by inhalation. It is assumed that the administered hydrogen gas is absorbed through the mucous membrane in the respiratory tract and lungs until it reaches the lungs after administration. Hydrogen gas taken up from the lungs and the like can be delivered not only to its predecessor via blood but also to each tissue by diffusion from the lungs. The compositions of the present invention may be used for transpulmonary administration.

When inhaling hydrogen gas, a mask-type device covering the mouth and nose, a nasal cannula, or the like can be used.
Hydrogen gas taken into the body by inhalation is widely distributed in the brain, lungs, and muscles, and the area under the curve (AUC) is another administration such as oral administration, intraperitoneal administration, and intravenous administration. Greater than the method. Comparing the case where humans drink as hydrogen water and the case where they are inhaled as hydrogen gas, most of the hydrogen molecules reach the abdominal tissues and organs by diffusion from the stomach and intestinal tract when drinking hydrogen water. The part is absorbed from the intestinal wall and distributed to the predecessor tissues and organs by blood flow. On the other hand, in the case of inhalation of hydrogen gas, hydrogen molecules are mixed with [1] inhalation and migrate to lung tissue, and are distributed by diffusion to surrounding tissues, and [2] dissolved in blood by gas exchange in the lung. There is a route that is transferred to the whole body, and [3] a route that is directly transferred from the nasal mucosa to the whole tissue without passing through the blood-brain barrier (BBB).

The gas having the above hydrogen concentration may be administered once or multiple times (for example, 2 to 3 times) per day. As the administration period, for example, a period of 1 week or more, 2 weeks or more, 4 weeks or more, 2 months or more, and 3 months or more can be set. As the administration time per administration, for example, a time of 5 minutes or more, 10 minutes or more, 15 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, 1 hour or more, and 2 hours or more can be set. .. The administration time may be continuous or may be divided into a plurality of doses. The administration period and administration time may be appropriately set in consideration of the condition of the subject. Inhalation of hydrogen gas is suitable for long-term treatment because it has a light burden on the subject's health and there are few reports of adverse events.

Ingestion of hydrogen gas by the subject can also be realized by the subject spending a certain period of time in a space filled with a gas containing hydrogen gas. The atmospheric pressure in the space may be a standard atmospheric pressure (about 1.013 atmospheric pressure), or a pressurized state in the range of 7 atmospheric pressure or less, for example, 1.02 atmospheric pressure to 7.0 atmospheric pressure, specifically. It may be 1.02 atm to 5.0 atm, more specifically 1.02 atm to 4.0 atm, and more specifically 1.02 atm to 1.35 atm. Hydrogen intake in a high pressure environment is preferred in that it promotes the absorption of hydrogen in the subject. Anticyclone capsules designed to have sufficient strength can be used for hydrogen uptake under pressure.

As used herein, the subject is a mammal, for example, a primate including a human; a rodent such as a mouse or a rat; a companion animal such as a dog or a cat, or an ornamental animal such as an animal kept in a zoo. include. The subject of the present invention is preferably a human.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples.
We evaluated the effects of hydrogen gas inhalation on men and women aged 65 and over living in Serbia. The study was conducted in accordance with the Declaration of Helsinki and was conducted as an open-label intervention study with the approval of the Institutional Review Board. 16 elderly men and women over 65 years old as volunteers (n = 16)
(Age 68.1 ± 5.3 years; BMI 27.6 ± 5.3 kg / m ² ) participated. All participants used a hydrogen generator (MHG-2000, manufactured by Miz Co., Ltd.) to generate hydrogen gas with a concentration of 4% at a hydrogen gas composition flow rate of 2 L / min (hydrogen gas equivalent flow rate: 80 ml / min). It was inhaled for 20 minutes per day for 4 weeks, and the situation was supervised by the research staff. Cardiovascular metabolic outcomes and adverse event assessments, including blood draws and fasting blood glucose measurements, were performed at baseline and at 4 weeks of follow-up. During the test period, participants were urged to eat and exercise as usual.

Cardiorespiratory fitness was evaluated using maximum oxygen consumption as an index. For the maximum oxygen consumption, a multi-step load was applied to the subjects by the Bruce method using a treadmill (COSMED model T 170), and the estimated value of VO ₂ max was calculated. The multi-step load protocol is shown in Table 1 below.

In the test, the subjects were warmed up for 10 minutes. The assistant set the speed of the treadmill to 2.74 km / hour, set the slope to 10%, and measured the time at the same time as the start of the test. The load was increased according to the protocol in the above table, and the time until the subject became unable to run was measured. From the measurement time (T), the VO ₂ max value was calculated using the following formula.

[Male] VO ₂ max = 14.8-(1.379 x T) + (0.451 x T ² )-(0.012 x T ³ )
[Female] VO ₂ max = (4.38 × T) --3.9
Maximum oxygen consumption, an indicator of cardiorespiratory fitness, increased from 31.9 ml / kg / min to 39.0 ml / kg / min on average after H ₂ gas inhalation, 22.4% (95% confidence interval 7.6 ± 37.2%; P = 0.01) Increased. Grip strength also increased by 4.6% (95% confidence interval -0.3 ± 9.5%; P = 0.05), with mean increase from 55.3 kg to 57.8 kg.

By inhaling hydrogen gas, the total serum cholesterol level changed from 6.3 ± 0.9 mmol / L to 5.4 ± 2.1 mmol / L (P = 0.13, converted value: 278.04 mg / dL → 230.09 mg / dL), and the fasting blood glucose level. Showed a tendency to decrease from 5.7 ± 0.7 mmol / L to 4.6 ± 1.9 mmol / L (P = 0.12, converted value: 278.04 mg / dL → 230.09 mg / dL). None of the participants reported adverse events associated with inhalation of hydrogen gas.

Claims (19)

A composition comprising hydrogen gas as an active ingredient used to reduce cardiometabolic risk factors or improve cardiometabolic profile. A composition containing hydrogen gas as an active ingredient used for the prevention or treatment of cardiovascular metabolic diseases. The composition according to claim 2, which is used for the prevention of cardiovascular metabolic diseases. The composition according to claim 2 or 3, wherein the cardiovascular metabolic disease is arteriosclerotic cardiovascular disease. A composition containing hydrogen gas as an active ingredient used for suppressing blood sugar levels. A composition containing hydrogen gas as an active ingredient used to improve cardiorespiratory fitness. The composition according to claim 6, wherein cardiorespiratory fitness is evaluated using maximum oxygen consumption as an index. A composition containing hydrogen gas as an active ingredient used for suppressing total cholesterol level in blood. A composition containing hydrogen gas as an active ingredient, which is used for increasing muscle mass or strength, or for suppressing muscle mass loss or muscle weakness. The composition according to any one of claims 1 to 9, which is used to be inhaled by a subject. The composition according to any one of claims 1 to 10, which is used for transpulmonary administration. The composition according to any one of claims 1 to 11, wherein the subject is a human being 60 years or older. The composition according to any one of claims 1 to 12, wherein the subject is a human being 65 years or older. The composition according to any one of claims 1 to 13, wherein the hydrogen gas is inhaled in the form of a gas containing 3% by volume or more of the hydrogen gas. The composition according to any one of claims 1 to 14, wherein the hydrogen gas is inhaled in the form of a gas containing 0.5% by volume or more of the hydrogen gas. The composition according to any one of claims 1 to 15, wherein the hydrogen gas is inhaled in the form of a gas containing 4% by volume or more of the hydrogen gas. The composition according to any one of claims 1 to 16, wherein hydrogen gas is used so as to be inhaled for 20 minutes or more per day. The composition according to any one of claims 1 to 17, wherein the inhalation of hydrogen gas is carried out for 4 weeks or more. The composition according to any one of claims 1 to 18, which is used as a pharmaceutical composition.