JP2024072231A - Composition and method for preventing or improving amyotrophic lateral sclerosis (als) and/or als-related symptom - Google Patents

Abstract

To provide a composition for preventing or improving amyotrophic lateral sclerosis (ALS) and/or ALS-related symptoms.SOLUTION: The present invention provides a composition for preventing or improving amyotrophic lateral sclerosis (ALS) and/or ALS-related symptoms in human, comprising hydrogen gas-containing gas as an active ingredient, and a method for preventing or improving ALS and/or ALS-related symptoms by administering this composition to humans who have newly developed ALS.

Description

The present invention relates to compositions for preventing or ameliorating amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS.
The present invention also relates to methods of preventing or ameliorating amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease, a neurodegenerative disease in which the cell bodies of both upper and lower motor neurons are degenerated and lost sporadically and progressively. The cause of sporadic ALS is unknown. The clinical symptoms of ALS are known to be lower motor neuron symptoms, upper motor neuron symptoms, bulbar paralysis symptoms, cognitive dysfunction, and negative signs. Dissociated small hand atrophy is also known as a characteristic symptom.
ALS is always progressive, and once you have the disease, the symptoms never get any better. No matter which part of the body's muscles are affected, the disease will eventually affect all the muscles in the body, and eventually the respiratory muscles will stop working, causing respiratory failure in most people. If you do not use a ventilator, the period from onset of the disease to death is approximately 2 to 5 years.
In recent years, it has been proposed that hydrogen molecules may suppress chronic inflammation by eliminating hydroxyl radicals generated within cells and mitochondria of cells, and may be effective against many diseases caused by chronic inflammation (Non-Patent Document 1). However, there have been no reports of the prevention or improvement of ALS and/or symptoms associated with ALS.

An object of the present invention is to provide a composition for preventing or ameliorating amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS.

As a result of intensive research, the present inventors have unexpectedly found that a gas containing hydrogen gas prevents or improves amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS.
Thus, the present invention includes the following features.
(1) A composition for preventing or ameliorating amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS in humans, comprising hydrogen as an active ingredient.
(2) The composition according to (1), wherein the symptoms associated with ALS are selected from one or more of lower motor neuron symptoms, upper motor neuron symptoms, bulbar symptoms, cognitive impairment, negative signs, dissociated hand atrophy, and reduced quality of life associated with these symptoms.
(3) The composition according to (1) or (2), characterized in that the lower motor neuron symptoms are one or more selected from the group consisting of decreased power, muscle atrophy, and muscle fasciculations; the upper motor neuron symptoms are one or more selected from the group consisting of increased jaw reflex, pointing reflex, pseudobulbar palsy, forced crying/laughing, pathological increased tendon reflex, increased tendon reflex, Hoffmann reflex, spasticity, preserved atrophic muscle tendon reflex, absent abdominal reflex, absent abdominal reflex, and Babinski sign; the cognitive dysfunction is one or more selected from the group consisting of personality change, behavioral disorder (abnormality), language disorder, and executive dysfunction; and the negative symptoms are one or more selected from the group consisting of sensory disorder, eye movement disorder, bladder-rectal disorder, bedsores, cerebellar symptoms, extrapyramidal symptoms, and autonomic nervous symptoms.
(4) The composition according to any one of (1) to (3), wherein the concentration of hydrogen is greater than 0 and less than or equal to 18.5 volume percent.
(5) The composition according to any one of (1) to (4), wherein the hydrogen concentration is 0.5 volume % or more and 18.5 volume % or less.
(6) The composition according to any one of (1) to (5), wherein the composition is administered to the human by inhalation.
(7) A method for producing the composition according to any one of (1) to (6) above, characterized in that the composition is produced using a hydrogen gas generator.

According to the present invention, amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS can be prevented or ameliorated by hydrogen gas.

The present invention will now be described in further detail.
1. Amyotrophic lateral sclerosis (ALS)
Symptoms associated with ALS include lower motor neuron symptoms, upper motor neuron symptoms, bulbar symptoms, cognitive impairment, negative symptoms, dissociated wrist atrophy, and reduced quality of life associated with these symptoms.

The lower motor neuron symptoms associated with ALS in the present invention include one or more symptoms selected from the group consisting of reduced power, muscle atrophy, and muscle fasciculations.

In the present invention, the upper motor neuron symptoms associated with ALS include one or more symptoms selected from increased jaw reflex, pointing reflex, pseudobulbar palsy, forced crying/laughing, pathological increased tendon reflex, increased tendon reflex, Hoffmann reflex, spasticity, preserved atrophic tendon reflex, loss of abdominal cutaneous reflex, loss of abdominal reflex, and Babinski sign.

The cognitive dysfunction, which is a symptom associated with ALS in the present invention, includes one or more symptoms selected from personality change, behavioral disorder (abnormality), language disorder, and executive dysfunction.

In the present invention, the negative symptoms associated with ALS include one or more symptoms selected from sensory disturbances, eye movement disorders, bladder and rectum disorders, bedsores, cerebellar symptoms, extrapyramidal symptoms, and autonomic symptoms.

In the present specification, the "hydrogen" which is an active ingredient of the composition of the present invention is molecular hydrogen (i.e., gaseous hydrogen), and is simply referred to as "hydrogen" or "hydrogen gas" unless otherwise specified. In addition, the term "hydrogen" used in the present specification refers to _H2 , _D2 (deuterium), HD (hydrogen deuteride), or a mixed gas thereof in terms of molecular formula. _D2 is expensive, but is known to have a stronger superoxide scavenging effect than _H2 . The hydrogen usable in the present invention is _H2 , _D2 (deuterium), HD (hydrogen deuteride), or a mixed gas thereof, preferably _H2 , or _D2 and/or HD may be used instead of _H2 or mixed with _H2 .

The hydrogen gas-containing gas is preferably air containing hydrogen gas or a mixed gas containing hydrogen gas and oxygen gas. The hydrogen gas concentration of the hydrogen gas-containing gas is greater than zero (0) and less than 18.5 vol%, more preferably greater than zero (0) and less than 10.0 vol%. In actual use, any hydrogen concentration of 18.5 vol% or less can be selected and used, for example, 0.5 vol% to 18.5 vol%, 0.5 vol% to 18.5 vol%, 1 vol% to 18.5 vol%, 1 vol% to 10 vol%, 1 vol% to 5 vol%, etc. In the present invention, the higher the hydrogen gas concentration is below the explosion limit, the greater the effect of preventing or improving amyotrophic lateral sclerosis (ALS) and/or symptoms related to ALS. Since hydrogen is a flammable and explosive gas, it is preferable to contain hydrogen in the composition of the present invention under safe conditions and administer it to patients who have developed amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS in order to prevent or improve amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS. Even if the hydrogen concentration is extremely low, such as 0.5% by volume, it is expected that amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS can be prevented and/or improved by inhaling the hydrogen for a long period of time.

When the gas other than hydrogen gas is air, the air concentration is, for example, in the range of 81.5 to 99.5% by volume. When the gas other than hydrogen gas is a gas containing oxygen gas, the oxygen gas concentration is, for example, in the range of 21 to 99.5% by volume.
As another main gas, nitrogen gas may be contained. Gases such as carbon dioxide, which are contained in air, may be contained in amounts similar to those present in air.
In the present invention, if necessary, a hydrogen-dissolved liquid can be administered or ingested by a patient suffering from amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS in combination with administration of a hydrogen-containing gas. Generally, among various methods of hydrogen intake, the amount of hydrogen that can be taken is greater by inhaling hydrogen gas than by drinking hydrogen water, so inhaling hydrogen is the primary intake method, and taking hydrogen through a liquid containing hydrogen, such as drinking hydrogen water, is a supplementary intake method.

When administered in combination with a hydrogen-dissolved liquid, the composition of the present invention may be administered prior to, simultaneously with, or after administration of the hydrogen-dissolved liquid.
The hydrogen-dissolved liquid is specifically an aqueous liquid having hydrogen gas dissolved therein, and examples of the aqueous liquid include, but are not limited to, water (e.g., sterilized water, purified water), physiological saline, buffer solutions (e.g., buffer solutions having a pH of 4 to 7.4), ethanol-containing water (e.g., an ethanol content of 0.1 to 2% by volume), drip infusions, infusions, injection solutions, beverages, etc. The hydrogen concentration of the hydrogen-dissolved liquid is, for example, 1 to 10 ppm, e.g., 2 to 8 ppm, 3 to 7 ppm, 3 to 6 ppm, 4 to 6 ppm, 4 to 5 ppm, 5 to 10 ppm, 5 to 8 ppm, 6 to 8 ppm, 6 to 7 ppm, etc.

A medicine for preventing or ameliorating amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS may be added to the hydrogen-dissolved liquid, or the medicine may be administered separately from the administration of the hydrogen-dissolved liquid or hydrogen gas-containing gas.

The hydrogen gas-containing gas or hydrogen-dissolved liquid is mixed to a predetermined hydrogen gas concentration and then filled into, for example, a pressure-resistant container (for example, a stainless steel cylinder, an aluminum can, a pressure-resistant plastic bottle (for example, a pressure-resistant PET bottle) and a plastic bag, an aluminum bag, etc., preferably with an aluminum film laminated on the inside). Aluminum has the property of being difficult to permeate hydrogen molecules. Alternatively, the hydrogen gas-containing gas or hydrogen-dissolved liquid may be prepared on the spot at the time of administration using a device such as a hydrogen gas generating device, a hydrogen water generating device, or a hydrogen gas adding device, for example, a known or commercially available hydrogen gas supply device (a device for generating hydrogen gas-containing gas), a hydrogen adding device (a device for generating hydrogen water), or a non-destructive hydrogen containing device (for example, a device for non-destructively adding hydrogen gas to the inside of a bag of a biologically applicable liquid such as an intravenous drip liquid).

The hydrogen gas supply device makes it possible to mix hydrogen gas generated by the reaction of a hydrogen generating agent (e.g., aluminum metal, magnesium hydride, etc.) with a dilution gas (e.g., air, oxygen, etc.) in a predetermined ratio (Japanese Patent No. 5228142, etc.). Alternatively, hydrogen gas generated by electrolysis of water is mixed with a dilution gas such as oxygen or air (Japanese Patent No. 5502973, Japanese Patent No. 5900688, etc.). This makes it possible to prepare a hydrogen gas-containing gas with a hydrogen concentration in the range of 0.5 to 18.5% by volume.

The hydrogen addition device is a device that generates hydrogen using a hydrogen generating agent and a pH adjuster and dissolves it in a biologically applicable liquid such as water (Japanese Patent No. 4756102, Japanese Patent No. 4652479, Japanese Patent No. 4950352, Japanese Patent No. 6159462, Japanese Patent No. 6170605, JP 2017-104842, Japanese Patent No. 6159462, etc.). Combinations of hydrogen generating agents and pH adjusters include, for example, metallic magnesium and strongly acidic ion exchange resin or organic acid (e.g., malic acid, citric acid, etc.), metallic aluminum powder and calcium hydroxide powder, etc. This allows the preparation of a hydrogen-dissolved liquid with a dissolved hydrogen concentration of about 1 to 10 ppm (for example, the product name "Seven Water" (MiZ Corporation), etc.).

The non-destructive hydrogen-containing device is a device or instrument that adds hydrogen molecules to a commercially available biologically applicable liquid such as an infusion liquid (e.g., enclosed in a hydrogen-permeable plastic bag such as a polyethylene bag) from the outside of the package, and is commercially available, for example, from MiZ Co., Ltd. (http://www.e-miz.co.jp/technology.html). This device can aseptically dissolve hydrogen in a biologically applicable liquid by immersing a bag containing the biologically applicable liquid in saturated hydrogen water, thereby permeating hydrogen into the bag and dissolving hydrogen in the biologically applicable liquid until a concentration equilibrium is reached. The device is composed of, for example, an electrolytic cell and a water tank, and the water in the water tank circulates between the electrolytic cell and the water tank to generate hydrogen by electrolysis. Alternatively, a simple disposable device can be used for the same purpose (JP Patent Publication No. 2016-112562, etc.). This device contains a plastic bag (hydrogen permeable bag, for example, a polyethylene bag) containing a biologically applicable fluid and a hydrogen generating agent (for example, metallic calcium, metallic magnesium/cation exchange resin, etc.) inside an aluminum bag, and the hydrogen generating agent is wrapped in, for example, a nonwoven fabric (for example, a water vapor permeable nonwoven fabric). The hydrogen generated by wetting the hydrogen generating agent wrapped in the nonwoven fabric with a small amount of water such as water vapor permeates the plastic bag and is dissolved in the biologically applicable fluid nondestructively and aseptically.

The hydrogen gas-containing gas or hydrogen-saturated biologically applicable liquid (e.g., sterile water, saline, infusion liquid, etc.) prepared using the above-mentioned device or apparatus can be administered orally or parenterally to patients who have developed amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS.
Another embodiment of the composition of the present invention includes a dosage form (e.g., tablet, capsule, etc.) containing a hydrogen generating agent that enables hydrogen generation in the digestive tract, which is prepared for oral administration (or ingestion) to a patient suffering from amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS. The hydrogen generating agent is preferably composed of an ingredient approved as, for example, a food or food additive.

3. Prevention or Improvement of Amyotrophic Lateral Sclerosis (ALS) and/or ALS-Related Symptoms According to a second aspect, the present invention provides a method for improving and/or suppressing the worsening of symptoms, including a decrease in activity level associated with symptoms caused by a patient who has developed amyotrophic lateral sclerosis (ALS) and/or ALS-related symptoms, comprising administering a composition of the present invention to the patient who has developed amyotrophic lateral sclerosis (ALS) and/or ALS-related symptoms.

The compositions of the present invention allow for an improvement in the patient's quality of life.
When hydrogen gas is used as an active ingredient, the composition of the present invention is preferably administered to a patient suffering from amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS via pulmonary administration, for example, by inhalation, aspiration, etc. When inhaling the gas, the gas can be inhaled from the mouth or nose via a nasal cannula or a mask-type device covering the mouth and nose, and then delivered to the lungs, and then delivered to the entire body via the blood.

In addition, when the hydrogen-dissolved liquid is administered to a patient, it is preferable to administer it orally, intravenously, or intraarterially (including drip infusion). The hydrogen-dissolved liquid to be administered orally is preferably stored at a low temperature, and the cooled liquid or the liquid stored at room temperature may be administered to a patient suffering from amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS. It is known that hydrogen dissolves in water at a concentration of about 1.6 ppm (1.6 mg/L) at room temperature and normal pressure, and the difference in solubility due to temperature is relatively small. Alternatively, when the hydrogen-dissolved liquid is in the form of a drip infusion or injection solution containing hydrogen gas prepared using the above-mentioned non-destructive hydrogen-containing device, it may be administered to a patient suffering from amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS by a parenteral administration route such as intravenous administration or intraarterial administration.

A hydrogen gas-containing gas having the above hydrogen concentration or a hydrogen-dissolved liquid having the above dissolved hydrogen concentration can be administered once or multiple times (e.g., 2 to 3 times) per day for a period of 1 week to 3 months or more, for example, 1 week to 6 months or more, to the body of a patient who has developed amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS. When the hydrogen gas-containing gas is administered, it can be administered for, for example, 10 minutes to 2 hours or more, preferably 20 minutes to 40 minutes or more, and more preferably 30 minutes to 2 hours per administration. In addition, when hydrogen gas-containing gas is administered through the lungs by inhalation, aspiration, etc., the gas can be administered to a patient suffering from amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS under an atmospheric pressure environment or under a high pressure environment, for example, above standard atmospheric pressure (approximately 1.013 atm) and below 7.0 atm, for example, 1.02 to 7.0 atm, preferably 1.02 to 5.0 atm, more preferably 1.02 to 4.0 atm, and even more preferably 1.02 to 1.35 atm. Administration under a high pressure environment can promote absorption of hydrogen into the body of a patient suffering from amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS.

The high pressure environment can be created by using a high pressure housing (e.g., a capsule-shaped housing) designed to have sufficient strength, which can form a high pressure inside that exceeds standard atmospheric pressure and is 7.0 atmospheres or less by pressurizing the hydrogen gas-containing gas (e.g., hydrogen-containing oxygen or air). The shape of the high pressure housing is preferably rounded overall without corners because it is pressure-resistant. In addition, the material of the high pressure housing is preferably lightweight and high strength, such as reinforced plastic, carbon fiber composite, titanium alloy, aluminum alloy, etc. Patients who have developed symptoms related to amyotrophic lateral sclerosis (ALS) and/or ALS can receive a composition for preventing or improving symptoms related to amyotrophic lateral sclerosis (ALS) and/or ALS, which contains hydrogen gas together with oxygen gas or air, in the high pressure housing.

When treating amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS with the composition of the present invention, it is desirable to use a hydrogen gas generator, hydrogen water generator, or hydrogen gas addition device (e.g., the above-mentioned hydrogen gas supply device (or gaseous hydrogen inhalation device), hydrogen addition instrument (or hydrogen water generator), non-destructive hydrogen containing device (device that non-destructively dissolves hydrogen gas in a biologically applicable liquid such as an infusion liquid sealed in a hydrogen-permeable bag)) that has been confirmed to have sufficient therapeutic effect and safety.

The present invention will be described in more detail with reference to the following examples, but the technical scope of the present invention is not limited to these examples.

Suppression of amyotrophic lateral sclerosis (ALS) and/or ALS-related symptoms by hydrogen gas inhalation A 64-year-old Japanese man felt something was wrong with his left calf in the spring of 2021, and when he went to the hospital in August of the same year, he was diagnosed with ALS, and the doctor said that there was no treatment and that he had 3 to 4 years left to live. The paralysis of his left calf progressed, and the calf of his left leg became noticeably thinner than his right leg just by looking at it. He also had difficulty walking, and could not walk straight without using a cane.
The patient began inhaling hydrogen gas in October 2022. The hydrogen gas inhaler used was Jobs-α (trademark registered as Jobs) manufactured by MiZ Corporation (Kamakura, Kanagawa Prefecture, Japan). The hydrogen concentration of Jobs-α is approximately 4% to 5%, and the amount of hydrogen generated is 200 ml/min as 100% hydrogen generation. The inhalation time was 7 to 8 hours per day, mainly while sleeping.
On November 10, 2022, the tone of the calf muscles had returned to a level that was visible to the naked eye.
I went on a business trip to Europe in early December 2022. My family was worried about whether I could go on a business trip despite having ALS, but I decided to go because by inhaling hydrogen gas, my condition did not worsen and I was able to work energetically despite my busy schedule. Although there was a cold wave in Europe and the temperature was low, I had no problems walking. Although I cannot do without a cane for safety, my walking ability has definitely improved. Other symptoms include increased appetite and easier bowel movements, and improvements have been confirmed in blood pressure, blood sugar levels, and liver function values.

The present invention makes it possible to prevent or improve amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS simply by administering hydrogen to ALS patients. Since hydrogen itself has no known side effects, it can improve the patient's quality of life.

Claims (7)

A composition for preventing or ameliorating amyotrophic lateral sclerosis (ALS) and/or symptoms associated with ALS in a human, comprising hydrogen as an active ingredient. 2. The composition of claim 1, wherein the symptoms associated with ALS are selected from one or more of the following: lower motor neuron symptoms, upper motor neuron symptoms, bulbar symptoms, cognitive impairment, negative symptoms, dissociated wrist atrophy, and reduced quality of life associated with these symptoms. The composition according to claim 1 or 2, characterized in that the lower motor neuron symptoms are one or more symptoms selected from decreased power, muscle atrophy, and muscle fasciculations, the upper motor neuron symptoms are one or more symptoms selected from increased jaw reflex, pointing reflex, pseudobulbar palsy, forced crying/laughing, pathological increased tendon reflex, increased tendon reflex, Hoffmann reflex, spasticity, preserved atrophic muscle tendon reflex, lost abdominal reflex, lost abdominal reflex, and Babinski sign, the cognitive dysfunction is one or more symptoms selected from personality change, behavioral disorder (abnormality), language disorder, and executive dysfunction, and the negative symptoms are one or more symptoms selected from sensory disorder, ocular motility disorder, bladder-rectal disorder, bedsores, cerebellar symptoms, extrapyramidal symptoms, and autonomic nervous symptoms. 4. The composition of claim 2 or 3, wherein the concentration of hydrogen is greater than 0 and not greater than 18.5% by volume. The composition according to claim 2 or 3, wherein the concentration of hydrogen is from 0.5% by volume to 18.5% by volume. The composition of claim 2 or 3, wherein the composition is administered to the human by inhalation. 4. A method of making the composition of claim 2 or 3, wherein the composition is made using a hydrogen gas generator.