Agent for preventing or treating arrhythmia and device for preventing or treating arrhythmia

Abstract

To provide a technique for preventing or treating an arrhythmia, which has a low risk of side effects and can be performed simply.SOLUTION: Provided is an agent for reducing an increase in the number of arrhythmias, comprising hydrogen as an active ingredient, for use with inhaled nitric oxide. Also provided are: a composition comprising hydrogen and nitric oxide for administering nitric oxide while reducing an increase in the number of arrhythmias; and a device for administering the composition by inhalation.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for preventing or treating arrhythmia and an apparatus for preventing or treating arrhythmia. This application claims priority based on Japanese Patent Application No. 2019-203385, filed on November 8, 2019, the contents of which are incorporated herein by reference. [Background technology]

[0002] Sinus rhythm is a state in which electrical impulses generated in the sinus node in the right atrium of the heart are transmitted correctly to the atria, atrioventricular node, and ventricles, and repeated at a regular rhythm. Arrhythmia is a state in which the heart deviates from regular sinus rhythm.

[0003] Arrhythmias that occur during acute myocardial infarction, after treatment for acute myocardial infarction, or after rehabilitation are often fatal. Therefore, if arrhythmias can be prevented, unexpected deaths could be reduced.

[0004] Conventionally, antiarrhythmic agents that have been used include sodium channel blockers, β-adrenergic blockers, calcium antagonists, etc. For example, as exemplified in Patent Document 1, many of the antiarrhythmic agents are low molecular weight compounds. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 5039236 Summary of the Invention [Problem to be solved by the invention]

[0006] However, the administration of conventional antiarrhythmic agents can cause side effects such as hypoglycemia, liver damage, skin disorders, etc., and further improvements are needed. Therefore, an object of the present invention is to provide a technique for preventing or treating arrhythmia that has little risk of side effects and can be easily carried out. [Means for solving the problem]

[0007] The present invention includes the following aspects. [1] An agent for preventing or treating arrhythmia, characterized by containing hydrogen. [2] The arrhythmia preventive or therapeutic agent according to [1], further comprising nitric oxide. [3] A device for preventing or treating arrhythmia, comprising a hydrogen gas supply source, a pressure regulator and a flow meter connected to the hydrogen gas supply source, and a supply path for supplying the hydrogen gas from the supply source, and for administering the arrhythmia preventive or therapeutic agent described in [1] by inhalation to a patient directly or via an artificial respirator. [4] A device for preventing or treating arrhythmia, comprising a hydrogen gas supply source and a nitric oxide gas supply source, a pressure regulator and a flow meter connected to the hydrogen gas supply source and the nitric oxide gas supply source, and supply paths for supplying each gas from the supply sources, wherein all gas supply paths are arranged to merge to form a mixed gas before administration, and wherein the arrhythmia preventive or therapeutic agent described in [2] is administered by inhalation to a patient directly or via a ventilator. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a technique for preventing or treating arrhythmia that has little risk of side effects and can be easily carried out. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a schematic diagram illustrating an example of an apparatus for preventing or treating arrhythmia. [Figure 2] 1 is a schematic diagram illustrating an example of an apparatus for preventing or treating arrhythmia. [Figure 3]1 is a graph showing the results of Experimental Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0010] Hereinafter, embodiments of the present invention will be described in detail, with reference to the drawings where necessary. In the drawings, identical or corresponding parts are designated by identical or corresponding reference numerals, and redundant explanations will be omitted. The dimensional ratios in the drawings may be exaggerated for the purpose of explanation, and do not necessarily correspond to the actual dimensional ratios.

[0011] [Anti-arrhythmic or therapeutic agent] In one embodiment, the present invention provides an agent for preventing or treating arrhythmia, characterized by containing hydrogen. The agent for preventing or treating arrhythmia of this embodiment contains hydrogen as an active ingredient. Hydrogen is also recognized as a food additive, and the safety of hydrogen dissolved in water has been confirmed. Furthermore, gaseous hydrogen has also been used as a diving gas, and it has been confirmed that there are no side effects even when high concentrations of hydrogen are inhaled. At present, there are no papers reporting on the side effects of dissolved hydrogen or hydrogen gas, and hydrogen has an extremely low risk of side effects.

[0012] As will be described later in the Examples, the inventors have found that administering hydrogen can prevent or treat arrhythmia. The preventive or therapeutic agent of this embodiment has little risk of side effects and can establish a simple technique for preventing or treating arrhythmia.

[0013] The arrhythmia preventive or therapeutic agent of this embodiment may be in the form of a gas or a liquid. When the preventive or therapeutic agent of this embodiment is in the form of a gas, for example, a patient with myocardial infarction can inhale the preventive or therapeutic agent of this embodiment in an ambulance to prevent arrhythmia. Furthermore, for example, in cardiac rehabilitation, exercise therapy can be performed while preventing arrhythmia by inhaling the preventive or therapeutic agent of this embodiment.

[0014] When the preventive or therapeutic agent of this embodiment is a gas, the hydrogen concentration is preferably 1 to 10% (v / v), more preferably 1 to 6% (v / v), and particularly preferably 1.5 to 4% (v / v). Components other than hydrogen in the gas include inert gases, oxygen, additives, and the like. Examples of inert gases include nitrogen. Examples of additives include nitric oxide and fragrances, which will be described later. When the preventive or therapeutic agent of this embodiment is a gas, it may be inhaled and administered through the patient's mouth, nose, etc., or into the patient's lungs via an artificial respirator.

[0015] The preventive or therapeutic agent of this embodiment may be a liquid in which hydrogen is dissolved. Examples of the liquid include water, physiological saline, and buffer solutions. For example, the maximum hydrogen saturation level in hydrogen water at 1 atmosphere is 1.57 ppm, and the hydrogen concentration in the liquid preventive or therapeutic agent is preferably 1 ppm or higher, more preferably 1.2 ppm or higher, and particularly preferably 1.5 ppm or higher.

[0016] When the preventive or therapeutic agent of this embodiment is a liquid, the liquid may further contain pharmaceutically acceptable additives such as stabilizers, preservatives, pH adjusters, colorants, and fragrances. Examples of stabilizers include parahydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol; and phenols such as phenol and cresol. Examples of pH adjusters include phthalic acid, phosphoric acid, citric acid, succinic acid, acetic acid, fumaric acid, malic acid, carbonic acid, and their potassium, sodium, or ammonium salts; and sodium hydroxide.

[0017] When the preventive or therapeutic agent of this embodiment is in liquid form, it may be administered to a patient orally, or by intraarterial injection, intravenous injection, subcutaneous injection, or the like.

[0018] The preventive or therapeutic agent of this embodiment may further contain nitric oxide. In infarction diseases such as myocardial infarction, cerebral infarction, and mesenteric vascular occlusion, ischemia-reperfusion therapy may be performed to restore blood flow to ischemic tissues that have been cut off by mechanically dilating the infarcted area or dissolving thrombi. Similarly, after organ transplantation, blood flow is restored to tissues that have been cut off. When blood flow is restored, oxygen is suddenly added to the ischemic tissues, causing various physiological reactions, including the production of reactive oxygen species and free radicals, neutrophil infiltration, and platelet activation. These reactions are known to exacerbate organ damage, a condition known as ischemia-reperfusion injury.

[0019] Nitric oxide has the effect of dilating blood vessels and is known to alleviate ischemia-reperfusion injury through its administration. However, nitric oxide reacts with superoxide anions produced inside and outside the cells to produce peroxynitrite, which is highly tissue-damaging and has a high risk of side effects. In contrast, hydrogen is known to react with peroxynitrite and reactive oxygen species, reducing and eliminating them.

[0020] Therefore, by further comprising nitric oxide, nitrite, or a nitric oxide donor, the preventive or therapeutic agent of this embodiment can dilate blood vessels in the lungs and heart while suppressing side effects caused by nitric oxide, thereby enabling, for example, exercise therapy in rehabilitation to be performed more efficiently. Furthermore, arrhythmia can be suppressed, and unexpected deaths can be reduced. The concentration of nitric oxide in the preventive or therapeutic agent of this embodiment is preferably 1 to 100 ppm.

[0021] In addition to rehabilitation, administration of this drug during worsening heart failure, for example, may dilate blood vessels and reduce the risk of arrhythmia, which is thought to not only improve the condition but also reduce unexpected deaths.

[0022] [Devices for preventing or treating arrhythmias] (First embodiment) The device of the first embodiment comprises a hydrogen gas supply source, a pressure regulator and a flow meter connected to the hydrogen gas supply source, and a supply path for supplying the hydrogen gas from the supply source, and is used to prevent or treat arrhythmia by inhaling and administering to a patient a hydrogen-containing arrhythmia preventive or therapeutic agent, either directly or via an artificial respirator.

[0023] Fig. 1 is a schematic diagram showing an example of the apparatus of the first embodiment. As shown in Fig. 1, the apparatus 100 of the first embodiment includes a hydrogen gas supply source 110, a pressure regulator 120 and a flow meter 130 connected to the hydrogen gas supply source 110, and a supply path L1 for supplying hydrogen gas from the supply source 110. The supply path L1 is preferably provided with a valve (not shown) for controlling the amount of the arrhythmia preventive or therapeutic agent supplied.

[0024] The hydrogen gas supply source 110 may be configured to contain an inert gas such as nitrogen in addition to hydrogen gas, and to adjust the hydrogen concentration. Furthermore, for the patient's breathing, the device 100 preferably further includes an oxygen gas supply source 150, a pressure regulator 160 and a flow meter 170 connected to the oxygen gas supply source 150, and a supply path L2 for supplying oxygen gas from the supply source 150. The supply path L2 preferably includes a valve (not shown) for controlling the amount of oxygen supplied. The hydrogen gas supply source 110 and the oxygen gas supply source 150 may be, for example, cylinders.

[0025] According to the device 100, an arrhythmia preventive or therapeutic agent containing hydrogen as an active ingredient can be inhaled and administered into the patient's lungs via a mask or artificial respirator 140, thereby preventing or treating arrhythmia.

[0026] (Second embodiment) The device of the second embodiment comprises a hydrogen gas supply source and a nitric oxide gas supply source, a pressure regulator and a flow meter connected to the hydrogen gas supply source and the nitric oxide gas supply source, and supply paths for supplying each gas from the supply sources, with all gas supply paths being arranged to merge to form a mixed gas before administration, and is intended to prevent or treat arrhythmia by inhaling and administering to a patient an arrhythmia preventive or therapeutic agent containing nitric oxide, either directly or via an artificial respirator.

[0027] The device of the second embodiment differs from the device of the first embodiment mainly in that it includes a nitric oxide gas supply source, a pressure regulator and a flow meter connected to the nitric oxide gas supply source, and a supply path for supplying nitric oxide gas from the source.

[0028] Fig. 2 is a schematic diagram showing an example of an apparatus according to a second embodiment. As shown in Fig. 2, the apparatus 300 according to the second embodiment includes a hydrogen gas supply source 110 and a nitric oxide gas supply source 180, a pressure regulator 120 and a flow meter 130 connected to the hydrogen gas supply source 110, a pressure regulator 190 and a flow meter 200 connected to the nitric oxide gas supply source 180, a supply path L1 for supplying hydrogen gas from the supply source 110, and a supply path L3 for supplying nitric oxide gas from the supply source 180, where the supply paths L1 and L3 are arranged to merge to form a mixed gas before administration, and the apparatus is used to prevent or treat arrhythmia by inhaling and administering an arrhythmia preventive or therapeutic agent containing nitric oxide via a mask or an artificial respirator 140.

[0029] The supply paths L1 and L3 are preferably provided with valves (not shown) for controlling the supply amount of the arrhythmia preventive or therapeutic agent. The hydrogen gas supply source 110 may contain an inert gas such as nitrogen in addition to hydrogen gas, thereby adjusting the hydrogen concentration. The nitric oxide gas supply source 180 may contain an inert gas such as nitrogen in addition to nitric oxide gas, thereby adjusting the nitric oxide concentration.

[0030] Preferably, the device 200 further comprises an oxygen gas supply source 150 for patient breathing, a pressure regulator 160 and a flow meter 170 connected to the oxygen gas supply source 150, and a supply path L2 for supplying oxygen gas from the supply source 150. In this case, the supply paths L1, L2, and L3 are arranged to merge to form a mixed gas before administration. The supply path L2 is preferably provided with a valve (not shown) for controlling the amount of oxygen supplied.

[0031] The hydrogen gas supply source 110, the nitric oxide gas supply source 180, and the oxygen gas supply source 150 may be, for example, cylinders. The device 200 allows an arrhythmia prevention or treatment agent containing hydrogen and nitric oxide as active ingredients to be inhaled and administered into the patient's lungs via a mask or artificial respirator 140, thereby preventing or treating arrhythmia.

[0032] Since drugs for preventing or treating arrhythmias are usually administered for a relatively short period of time, the devices of the first and second embodiments can be used in many places, such as the patient's home, an ambulance, or a rehabilitation room, by combining them with a small cylinder or an inhalation device, or with a device that directly generates hydrogen or nitric oxide.

[0033] [Other embodiments] In one embodiment, the present invention provides a method for preventing or treating arrhythmia, comprising administering an effective amount of hydrogen to a patient in need of such prevention or treatment.

[0034] In the treatment method of this embodiment, the hydrogen is the same as that described above. Nitric oxide may be further administered in addition to hydrogen. The nitric oxide is the same as that described above.

[0035] In one embodiment, the present invention provides hydrogen for the prevention or treatment of arrhythmia, as described above.

[0036] In one embodiment, the present invention provides use of hydrogen for producing an agent for preventing or treating arrhythmia. The agent for preventing or treating arrhythmia of this embodiment may further contain nitric oxide in addition to hydrogen. In the use of this embodiment, the hydrogen is the same as described above. Furthermore, the nitric oxide is the same as described above. [Example]

[0037] The present invention will be described below with reference to examples, but the present invention is not limited to the following examples.

[0038] [Experimental Example 1] The pigs were anesthetized with pentobarbital and electrocardiograms were taken. After tracheal intubation, they were connected to a ventilator and respiratory management was performed. A catheter was inserted into the inferior vena cava via the groin, and a balloon was placed in the left anterior descending coronary artery. The balloon was inflated to stop blood flow. After 40 minutes, electrocardiograms were taken without any intervention for 10 minutes, and the number of arrhythmias was counted. For the next 10 minutes, the pigs were divided into a control group, a hydrogen inhalation group, a nitric oxide inhalation group, or a combined group (hydrogen and nitric oxide inhalation group), and the number of arrhythmias was counted in the same way.

[0039] The gas inhaled by the control group was a mixture of oxygen and nitrogen (oxygen concentration 35%) without hydrogen or nitric oxide. The gas inhaled by the hydrogen inhalation group was a mixture of air and hydrogen with a hydrogen concentration of 1.3%. The gas inhaled by the nitric oxide inhalation group was a mixture of air and nitric oxide with a nitric oxide concentration of 80 ppm. The gas inhaled by the combination group was a mixture of air, hydrogen, and nitric oxide with a hydrogen concentration of 1.3% and a nitric oxide concentration of 80 ppm.

[0040] As shown in Figure 3, the number of arrhythmias increased in the control group, whereas the number of arrhythmias decreased in the hydrogen inhalation group. Furthermore, the combined use group showed that the increase in the number of arrhythmias in the nitric oxide inhalation group could be reduced by inhaling hydrogen. These results demonstrate that administering hydrogen can prevent or treat arrhythmias. [Industrial Applicability]

[0041] According to the present invention, it is possible to provide a technique for preventing or treating arrhythmia that has little risk of side effects and can be easily carried out. [Explanation of symbols]

[0042] 100, 300...apparatus, 110...hydrogen gas supply source, 120, 160, 190...pressure regulator, 130, 170, 200...flow meter, L1, L2, L3...supply path, 150...oxygen gas supply source, 140...mask or ventilator, 180...nitric oxide gas supply source.

Claims

1. An agent containing hydrogen as an active ingredient that reduces the increase in arrhythmia caused by inhalation of nitric oxide.

2. A composition comprising hydrogen and nitric oxide for administering nitric oxide while reducing an increase in the number of arrhythmias.

3. 10. An apparatus for administering the composition of claim 2 by inhalation to a patient directly or via a ventilator, the apparatus comprising: a hydrogen gas supply source; a nitric oxide gas supply source; a pressure regulator and a flow meter connected to the hydrogen gas supply source and the nitric oxide gas supply source; and supply paths for supplying each gas from the sources, wherein all gas supply paths are arranged to merge to form a mixed gas before administration.

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