Disease ameliorating drug for treating alzheimer's disease containing hydrogen

Abstract

Provided is a drug for treating Alzheimer's disease, which is capable of maintaining an improvement in cognitive function and an improvement in nerve quality for a specific period of time even after the completion of the treatment. This drug (disease ameliorating drug) for the etiological treatment of Alzheimer's disease contains hydrogen as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a composition for etiological treatment of the progressive form of Alzheimer's disease. Background Art

[0002] 1. Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. It causes significant cognitive decline, leading to memory loss and impairment of daily activities. In the final stage of the disease, affected patients lose the ability to respond to their environment, carry on a conversation, and control movement, leading to the death of the patient.

[0003] As memory and cognitive function continue to deteriorate, severe personality changes may occur, and the individual requires extensive care. Urinary and fecal incontinence are accompanying symptoms of the inevitable decline in the quality of life in the progressive form of Alzheimer's disease. Currently developed treatments for Alzheimer's disease use improvement in memory function as an indicator of improvement, but do not evaluate improvement in other Alzheimer's disease-related difficulties as determinants of quality of life.

[0004] 2. Molecular hydrogen (formula H 2 , hereinafter referred to as "hydrogen") was initially described as an antioxidant with medicinal value. Subsequent studies have shown that hydrogen has multiple functions that are effective in different disease models. Hydrogen has been shown to be beneficial for elderly patients with stroke, heart attack, chronic obstructive pulmonary disease, cancer, and COVID-19. Importantly, the safety of hydrogen inhalation has been confirmed in phase I clinical trials. Subgroup analysis of randomized clinical trials indicates that hydrogen improved the condition of subjects with the apolipoprotein E4 (APOE4) genotype who exhibited mild cognitive impairment (MCI) (see Patent Document 1).

[0005] 3. To objectively evaluate Alzheimer's disease (AD), we chose to use advanced magnetic resonance imaging techniques and evaluate the neural quality of patients with Alzheimer's disease using a modified diffusion tensor imaging (DTI) procedure.

[0006] For the sake of explanation, we note that the brain MRI was performed in the radiology department of Nishijima Hospital, and the results were sent to the doctor through the electronic chart system. Digital tractography imaging was performed using Neuro3D and GRAPPA techniques, and five starting points were set at the positions where the nerve bundles passed through the entire hippocampus. DTI was obtained at fractional anisotropy (FA) values of 0.1 and 0.2. The size of the tract (trajectory) was calculated based on the number of pixels in the tract (trajectory) display, and the number of pixels was calculated using Image J software. The DTI with an FA value of 0.1 reflects the visualization of the overall neurons, and the DTI with an FA value of 0.2 reflects the highly visualized nerve mass. This is because, if the nerve mass is maintained, DTI shows that water molecules diffuse only in one direction along the nerve fibers (see Patent Document 2).

[0007] Patent Document 1: JP2019209018 Patent Document 2: W02018 / 012596 SUMMARY OF THE INVENTION

[0008] An object of the present invention is to develop a drug / therapeutic agent that maintains cognitive improvement and nerve improvement / enhancement even after the completion of treatment for a limited period of time. In other words, it is the development of cause-oriented treatment. In addition, it is the development of an improved drug / therapy aimed at improving the quality of life.

[0009] The number of Alzheimer's disease patients is increasing rapidly worldwide. Currently available drugs and medications for treating Alzheimer's disease show moderate efficacy and only temporarily relieve clinical problems (symptomatic therapy). Drugs and medications that slow down the progression of the disease have no significant effect, and their side effects cannot be ignored. In the past 30 years, regardless of how much resources and efforts have been invested in the drug development of Alzheimer's disease, no drug that can slow down or stop the progression of the disease or can effectively improve symptoms (disease improvement therapy) has been developed. Etiological treatment means that the treatment effect persists for a specified period of time after the treatment is stopped. Etiological treatment is also called etiological therapy, root-oriented treatment, etc.

[0010] Fecal incontinence causes confusion for patients and increases the burden on caregivers. At this stage, caregivers hope to use palliative care or other support services that focus on providing comfort and dignity in the final stage of life. However, with the increase in the number of patients, the lack of institutions providing such appropriate care has become a serious problem. Incontinence, especially fecal incontinence, is the most common reason for placing these patients in institutions. It is hoped that if a new treatment method can improve fecal incontinence in patients with progressive Alzheimer's disease, it will be possible to care for them in their home environment.

[0011] The present inventors found that hydrogen enables cause - oriented treatment of Alzheimer's disease and that it can solve problems related to fecal incontinence, etc., which led them to complete the present invention.

[0012] The present invention is as follows: (1) A cause - acting drug containing hydrogen as an active substance, which is used for treating Alzheimer's disease (disease - improving drug). (2) A cause - acting drug (1) that has a continuous therapeutic effect for at least 6 months after the end of treatment. (3) A cause - acting drug (1) that has a continuous therapeutic effect one year after treatment compared to the pre - treatment state. (4) A reinforcing drug containing hydrogen as an active ingredient, which improves the quality of life of patients with Alzheimer's disease. (5) A reinforcing drug containing hydrogen as an active substance, which improves nerve function and has a therapeutic effect even in patients with severe forms of Alzheimer's disease. (6) A reinforcing drug containing hydrogen as an active ingredient, which is used to improve fecal incontinence in patients with Alzheimer's disease. (7) A reinforcing drug containing hydrogen as an active ingredient, which is used to improve urinary incontinence in patients with Alzheimer's disease. This description includes the disclosure of Japanese Patent Application No. 2022 - 122081, which gives priority to the present application.

[0013] Hydrogen enables cause - oriented treatment of Alzheimer's disease. In addition, it can improve fecal incontinence and urinary incontinence in patients with Alzheimer's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shows the average change over time in the clinical symptoms of eight patients with Alzheimer's disease evaluated by ADAS - cog. Hydrogen inhalation was carried out for 0 to 6 months and then stopped. Monitoring of this process showed that after stopping inhalation, the improvement continued for 6 months or even 1 year. Figure 2 Is a graph comparing the change in ADAS - cog scores after the start of hydrogen inhalation with patients in a control group who did not inhale hydrogen. Follow - up showed that the improvement continued for 6 months after stopping hydrogen inhalation and that even one year after stopping treatment, the improvement continued compared to the pre - treatment state. Figure 3The average change over time in the neural mass of 8 patients with Alzheimer's disease was shown by DTI. Hydrogen inhalation was carried out for 0 to 6 months, after which inhalation was stopped and the process was monitored. At 6 months, the DTI area of the neural pathway increased and the neural mass improved. After stopping inhalation, the effect continued for another 6 months, and even 1 year after stopping, the improvement continued compared to the pre-treatment state. Figure 4 The figure showing the statistical analysis is presented, where for statistical analysis reasons, the variance of each measurement was improved to obtain more accurate values, and the value of FA = 0.2 was normalized to FA = 0.1 (FA = 0.2 / FA = 0.1). Hydrogen inhalation showed a significant effect after 6 months, and this significant effect continued for 6 months after the end of treatment, and compared to the pre-treatment condition, the beneficial effect continued after 1 year. Figure 5 The change over time in DTI of a patient with Alzheimer's disease is shown. In this patient, no effect was observed after 6 months of hydrogen inhalation, so hydrogen inhalation was continued. After 2 years, the area of the nerve fibers visualized in DTI increased at FA = 0.2. The axial view shows the front view and the lateral view shows the side view. Figure 6 Quantified the area of the nerve fiber bundle from Figure 5 and showed the change over time. Figure 7 Shows the difference between the disease improvement therapy and the symptomatic therapy. Figure 8 Shows a schematic diagram of a device designed to administer hydrogen to a patient. Detailed Description of the Invention

[0015] The following is a detailed description of the present invention. The present invention is an etiological action drug for treating Alzheimer's disease. Etiological treatment refers to the basic treatment, that is, the treatment effect that continues after the treatment is completed. For example, the improvement of Alzheimer's disease continues for 3 months, or 6 months, or 1 year after the end of treatment, or the improvement continues after 2 years. Figure 7 Shows the difference between etiological / cause-oriented treatment and symptomatic treatment. Figure 7 The horizontal axis of the figure in shows the duration of treatment, and the vertical axis shows the improvement achieved by the patient (the higher the number, the greater the effect). As Figure 7 shown, in the case of symptomatic treatment, even if the treatment is continued, the effect will decline and it will also deteriorate after treatment compared to the pre-treatment state. In contrast, etiological treatment produces a continuous effect through continuous treatment, which continues after the treatment is stopped, or at least shows an improvement compared to the pre-treatment state.

[0016] With this etiological / causal drug according to the present invention, it is possible to improve fecal incontinence and urinary incontinence in patients with Alzheimer's disease. In other words, patients with Alzheimer's disease are unable to control defecation and urination. For example, they find it difficult to use the toilet independently and thus experience fecal incontinence and urinary incontinence. However, through treatment with a causal drug containing hydrogen as an active agent, they can use the toilet and defecate. In other words, the etiological drug according to the present invention improves fecal incontinence and urinary incontinence in patients with Alzheimer's disease. The etiological drug for treating Alzheimer's disease according to the present invention can also improve the quality of life of patients with Alzheimer's disease. The etiological drug for treating Alzheimer's disease according to the present invention is also effective for patients with severe forms of Alzheimer's disease. Patients with severe forms of Alzheimer's disease are, for example, patients with a high degree of progression (grades 7a to 7f) of Alzheimer's disease (FAST, Sclan SG et al., Int Psychogeriatr, 1992; 4 Suppl 1: 55-69). 1

[0017] The concentration of hydrogen contained in the etiological drug for treating Alzheimer's disease, which contains hydrogen as an active substance, is 1% to 4% (v / v) or 2.5% to 3.5% (v / v) or about 3%. For safety reasons, the hydrogen content should not exceed about 4% (v / v). However, under sealed conditions, a higher hydrogen content can be present to avoid the generation of static electricity. The etiological drug for treating Alzheimer's disease according to the present invention, which contains hydrogen as an active ingredient, can contain oxygen and / or other inert gases. The oxygen composition contains a mixture of hydrogen and oxygen. Gaseous oxygen is consumed during respiration. The concentrations of gaseous oxygen are 10% to 30% (v / v), 15% to 25% (v / v), and 21% (v / v), respectively. Among the inert gases, nitrogen, helium, argon, etc. can be used; inexpensive nitrogen is suitable. The volume of such an inert gas can be determined by those skilled in the art within a not-too-high range. In terms of the concentration of gaseous oxygen for respiration, it is preferably up to 80% (v / v) or lower. For the etiological active drug product for treating Alzheimer's disease according to the present invention, which contains hydrogen as an active substance, a mixture of hydrogen and air can also be used. Such a gas mixture can be easily produced by thoroughly mixing air and hydrogen. In addition, gases used for anesthesia can be used for possible applications. In this case, the etiological drug for treating Alzheimer's disease according to the present invention, which contains hydrogen as an active agent, will be a mixed gas containing hydrogen and an anesthetic gas. The anesthetic gas can be, for example, nitrous oxide.

[0018] The etiological agent drug for treating Alzheimer's disease according to the present invention, which contains hydrogen as an active agent, can be stored in a pressurized container, such as a gas cylinder. In addition, a device for generating hydrogen by electrolyzing water can be used. The present invention also includes a container of the etiological agent drug for treating Alzheimer's disease containing hydrogen as an active agent and a device / equipment capable of generating hydrogen.

[0019] A subject can use such an etiological active drug for treating Alzheimer's disease according to the present invention, which contains hydrogen as an active ingredient, and can inhale it. Inhalation can be accomplished by an inhalation device that utilizes a delivery tube from a container containing the etiological active drug for treating Alzheimer's disease according to the present invention, which contains hydrogen as an active agent. The method of inhalation is not limited. For example, an inhalation mask can be provided, and it is desired that such a mask covers the patient's mouth and nose simultaneously. A nasal tube can also be used for inhaling hydrogen. A sealed chamber having a sufficient size to accommodate the patient can also be used for the patient to inhale hydrogen, and when in the chamber, the patient can inhale the etiological agent drug for treating Alzheimer's disease according to the present invention, which contains hydrogen as an active agent, into the chamber. Such a chamber is an example where the patient can inhale the etiological agent drug for treating Alzheimer's disease according to the present invention, which contains hydrogen as an active substance, while lying down or sitting.

[0020] The present invention also includes a device for administering to a patient suffering from Alzheimer's disease the etiological agent drug for treating Alzheimer's disease according to the present invention, [i.e.] a container containing the etiological agent drug for treating Alzheimer's disease, which contains hydrogen as an active agent, a gas inhalation device, and the above-mentioned container equipped with a delivery tube for delivering the gas to be inhaled. Such a container can be, for example, a hydrogen gas cylinder. Any method can be used to obtain hydrogen. Hydrogen can be generated by electrolysis of water, photocatalytic decomposition of water, extracted from hydrogen generation materials, hydrogen storage / absorption alloys, etc. Similarly, as described above, an inhalation mask, a nasal tube can be used to inhale the gas, and a sealed chamber is mentioned. The method of hydrogen inhalation can be any method. The device is preferably equipped with a container that contains at least one gas from the gas group of oxygen, inert gas, air, anesthetic gas. In this case, it is advantageous to provide the etiological agent drug containing hydrogen as an active agent, together with at least one selected gas from the gas group of oxygen, inert gas, air, used alone or in combination, for treating Alzheimer's disease. A nebulizer can also be used. For example, a suction bag can be attached to the inhalation mask, and hydrogen can be supplied from a hydrogen gas cylinder containing hydrogen into the suction bag. A schematic diagram of the device according to the present invention is shown in Figure 8Among them. This figure shows an inhalation device (1), a container (2) containing a medicinal substance with hydrogen as an active ingredient, a container (3) containing at least one gas from the group of oxygen, inert gas, air, and anesthetic gas, and a supply pipe (4). Through this supply pipe, the gas is sent into the inhalation device and administered to the patient. In the case of nasal tube inhalation, it is not necessary to pre-dilute hydrogen with other gases; hydrogen can also be diluted with air during breathing.

[0021] The administration of the etiological active drug containing hydrogen as an active agent for the treatment of Alzheimer's disease is preferably administered once for 0.1 hour to 5 hours, more preferably 0.3 hour to 2 hours, or administered 1 hour 1× to 5×, or 1× to 3×, or 2× respectively within a time period of 1 day to 30 days, or 5 days to 20 days, or 6 days to 10 days. The inhalation rate when administering hydrogen depends on the vital capacity of the individual, for example, several liters per minute, or about 8 liters.

[0022] The effect of the etiological action drug containing hydrogen as an active agent for the treatment of Alzheimer's disease according to the present invention can be evaluated by the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) cognitive assessment tool (Rosen WG, Mohs RC, Davis KL (1984), A new rating scale for Alzheimer's disease, American Journal of Psychiatry 141, 1356 - 1364). ADAS-cog evaluates and scores the word list device, speaking ability, speech comprehension, speech difficulties in spontaneous speech, command completion, object and finger naming, construction tasks, ideomotor skills, orientation, word recognition, and the ability to reproduce test instructions. The scoring range is from 0 to 70, and the higher the score, the greater the cognitive impairment (normal → several).

[0023] For example, if a subject is diagnosed with Alzheimer's disease, especially progressive Alzheimer's disease, or is administered the etiological active drug containing hydrogen as an active agent for the treatment of Alzheimer's disease according to the present invention, the overall score on the ADAS-cog tool will be improved. For example, the score of the word list device [in the subscale] will be improved by one point or more, or two points or more (the value of the achieved score will decrease).

[0024] The effect of the etiological action drug can also be evaluated by neural quality. In this case, the neural quality can be evaluated based on regional images obtained by advanced magnetic resonance imaging of the brain using diffusion tensor imaging (DTI) technology.

[0025] For example, diffusion tensor imaging [DTI] can be used to monitor the progression of nerve fibers in the hippocampal region of the temporal lobe of a subject's brain, and the procedures described below can be used to analyze the area of the monitored nerve fibers. i) A process for generating diffusion tensor imaging [DTI] images extracted from the routes of nerve fibers in the hippocampal region of the temporal lobe of a subject's brain; ii) A process of setting five control inputs at regular intervals such that the nerve fiber pathways extracted by process (i) pass through them; iii) A process of setting the fractional anisotropy (FA) to 0.2 and obtaining an image of the nerve fibers extracted in the hippocampal region; iv) A process of calculating the area of the nerve fiber pathway based on the number of pixels in the image obtained during process iii); v) A process of detecting manifestations of dementia or pre-dementia based on the measured value of the area of the nerve fiber pathway.

[0026] In the above method, the hippocampal region refers to the hippocampal region and the parahippocampal gyrus region; the extracted images of the nerve fibers in the hippocampal region are from the lateral view and the axial view.

[0027] When the fractional anisotropy (FA) value is set to 0.1, an extracted image of the nerve fibers in the hippocampal region is obtained, and in the process of calculating the area of the nerve fiber pathway based on the number of pixels in a given image, the area of the nerve pathway at FA 0.2 is divided by the area of the nerve pathway at FA 0.1 to calculate the FA ratio (normalized). Based on the FA ratio, the nerve quality can be evaluated.

[0028] In the above (ii), 5 connected regions of interest (ROIs) can be created on the diffusion tensor representation.

[0029] Details of the method are described in International Application WO2018 / 012596. Examples

[0030] The present invention will be specifically described with reference to the following examples, but the present invention is not limited to these examples.

[0031] [Example 1] Hydrogen inhalation according to the World Medical Association Code of Ethics 2(Conducted in accordance with the Declaration of Helsinki). The clinical trial protocol was approved by the Nishijima Hospital Ethics Committee (2935-7, Ooka, Numazu Municipality, Shizuoka Prefecture) and registered in the database URL: http: / / www.jmacct.or.jp under JMACCT ID: JMAIIA00308. These families also signed written informed consent forms.

[0032] The inclusion criteria for patients with Alzheimer's disease were as follows: (1) Patients diagnosed with Alzheimer's disease according to the recommended criteria of the National Institute on Aging (NIA) 3 and the Alzheimer's Association (AA). 4 (2) Patients with an ADAS-cog tool score greater than 10 and less than 50, or patients with a corresponding score recalculated using the formula 70 - (MMSE × 2.33) with the MMSE tool. (3) Patients were retested every six months with the ADAS-cog / MMSE instrument as part of their regular treatment at the Neurodementia Clinic. (4) Patients without severe respiratory diseases that were expected to prevent effective inhalation of H (4) Patients without severe respiratory diseases that were expected to prevent effective inhalation of H, such as chronic obstructive pulmonary disease (COPD), pneumonia, airway inflammation, asthma, etc. 2 (6) Patients with experience of magnetic resonance imaging (MRI) of the brain. (6) Patients with experience of magnetic resonance imaging (MRI) of the brain. The total number of patients was 8, the female ratio was 87.5%, the age was 79.4 ± 6.1 years (standard deviation), and the average total ADAS-cog score was 229.7 ± 8.0 (standard deviation).

[0033] A control group of Alzheimer's disease patients who did not inhale hydrogen was collected from the past data of patients at Nishijima Hospital. The initial scores of ADAS-cog ranged from 10 to 50, and data of patients who had been evaluated by the ADAS-cog instrument at Nishijima Hospital for at least one and a half years were used. The average initial score of 19 patients together with the standard deviation was 27.8 ± 3.5 (standard deviation).

[0034] A mixture of 3% (v / v) hydrogen and 21% (v / v) oxygen was administered to 8 patients with Alzheimer's disease for 1 hour per day, 2 times a day. Inhalation continued for 6 months, after which hydrogen inhalation was stopped and the progress was monitored.

[0035] The therapeutic efficacy was evaluated by clinical assessment using ADAS-cog, and the nerve quality (integrity) was evaluated by DTI using MRI.

[0036] Figure 1 The average change over time in the clinical symptoms of eight patients with Alzheimer's disease evaluated by ADAS-cog is shown (the lower the score, the greater the improvement). Continuous inhalation of hydrogen for 6 months produced an initial deterioration, but soon showed improvement in cognitive function. Six months or one year after stopping hydrogen inhalation, there was a significant improvement in cognitive impairment compared to before treatment, and the effect of hydrogen inhalation was persistent. In other words, the therapeutic effect was continuous and sustainable.

[0037] Figure 2 A graph showing the difference compared to a control group not inhaling hydrogen for each patient inhaling hydrogen is shown. The graph shows the ADAS-cog scores at the start of inhalation and scores at approximately 6 months and 12 months apart. Statistical significance was evaluated by the student t-test, with * indicating an output of p < 0.05 and ** indicating an output of p < 0.01, thus indicating significant statistical significance.

[0038] Figure 3 The evolution of the DTI area over time at an FA value of 0.2 in 9 patients with Alzheimer's disease is shown. By DTI, it is shown that after 6 months of continuous hydrogen inhalation, the nerve quality was improved. In addition, the effect of hydrogen inhalation persisted even 6 months after stopping hydrogen inhalation. Although the effect of hydrogen inhalation one year after the end of inhalation was weaker, a good result could be maintained compared to the condition at the start of inhalation.

[0039] For more accurate quantitative analysis, each measurement was normalized. The data variability was corrected by dividing the F = 0.2 value by the simultaneous F = 0.1 value. The number of pixels in the corresponding neuronal tract pathway at FA = 0.2 was normalized (divided) by the number of pixels at FA = 0.1, and the mean and standard error were obtained from the normalized values of 4 transverse and axial images from the right and left hemispheres of each patient. Statistical significance was evaluated by the student t-test, with * indicating an output of p < 0.05 and ** indicating an output of p < 0.01, thus indicating significant statistical significance of the results.

[0040] In other words, as Figure 1 and Figure 3 shown, the effect of hydrogen inhalation persisted not only after stopping inhalation but also during the 6-month delay period after stopping inhalation, both in the clinical graph and objective DTI, and the results showed an improvement compared to the baseline even 12 months after stopping inhalation. In addition, as Figure 2 and Figure 4As shown, there were statistically significant effects not only after hydrogen inhalation, but even 6 months after stopping inhalation, the effect remained statistically significant, and even 12 months later, the improvement persisted compared to the baseline at the start of hydrogen inhalation.

[0041] [Example 2] A patient with fecal and urinary incontinence suffering from a severe form of Alzheimer's disease was given an inhalation gas mixture containing 3% (v / v) hydrogen and 21% (v / v) oxygen 2× per day for one hour. Clinical symptoms were monitored, and the improvement of nerve pathways over time was monitored by DTI. After two years of hydrogen inhalation, the patient was able to urinate and defecate on her own.

[0042] More specifically, the patient was a 79-year-old female who was diagnosed with typical Alzheimer's disease in 2011 and was administered Alzheimer's drugs such as Donepezil, Galantamine, Lithium, etc. The condition gradually deteriorated, and the ADAS-cog score was 48 / 70, which is a severe form of Alzheimer's disease.

[0043] The patient was unable to recall her date of birth at that time but was able to walk to the toilet by herself to urinate or defecate. Due to the rapid deterioration of her condition, other treatments were not possible, so hydrogen inhalation was started as an adjuvant / supplementary therapy on April 19, 2019.

[0044] The patient was unable to flush or use toilet paper at that time. In terms of fecal incontinence, there was no improvement in the frequency or severity in January 2020.

[0045] On November 18, 2020, the patient's husband noticed that the patient had gone to the toilet by herself and had defecated sufficiently by herself. Since then, in almost all cases, she has been able to go to defecate by herself.

[0046] Figure 5 The time course of DTI is shown. Figure 6 The change in DTI area over time is shown. Using advanced magnetic resonance imaging technology, the nerve quality was evaluated using a diffusion tensor imaging program. Figure 5 The front view and side view of the number of pixels in the nerve area are shown, Figure 6 showing the change over time. In Figure 5 and Figure 6 In both cases shown, the improvement in nerve quality in severe forms of Alzheimer's disease is obvious.

[0047] Reflecting the entire nerve with FA = 0.1, it can be clearly seen from the number of pixels that it gradually deteriorated during a period of time (5 months to 29 months) before hydrogen inhalation ( Figure 6 A and Figure 6B). The value of FA = 0.2 reflects the height of neural mass, while the decrease in pixel count indicates the decline of neural function. Figure 6 C to Figure 6 F).

[0048] After two years of inhalation, the pixel count increased slightly at F = 0.1 and F = 0.2, and the increase was more obvious at FA = 0.1 (from 29 months to 53 months) compared with FA = 0.2. Figure 6 ). These results indicate that the neural mass is improved after long-term hydrogen inhalation for about two years. Figure 5 The display at FA = 0.2 in D shows the emergence of new nerves, thus proving that there is not only quantitative improvement but also qualitative improvement in neural mass. Similar to Example 1, when the display changes at FA = 0.2, the change in neural mass is proved.

[0049] [Conclusion] The results show that inhalation of the hydrogen-containing mixed gas for 6 months improved the difficulties of Alzheimer's patients, and the therapeutic effect continued even 6 months to 1 year after stopping hydrogen inhalation. Continuous inhalation of hydrogen for 2 years has shown improvement in even severe forms of Alzheimer's disease. In addition, these inventions are only based on clinical trials, in which continuous clinical trials involve long-term administration of inhaled hydrogen to Alzheimer's patients; these results cannot be predicted from animal experiments, have not been described in the past, and cannot be easily inferred by experts in the field. Industrial Applicability

[0050] The drug containing hydrogen as an active agent according to the present invention can be used for etiological treatment of Alzheimer's disease. List of Reference Numerals

[0051] 1 Gas suction device 2 Container containing hydrogen 3 Container of gas containing an optional gas group of at least one from oxygen, inert gas or anesthetic gas gas 4 Tube All publications, patents and patent applications mentioned in this specification are hereby incorporated by reference directly herein.

Claims

1. An etiological drug containing hydrogen as an active ingredient, which is used for the treatment of Alzheimer's disease (disease-improving drug).

2. The etiological drug according to claim 1, wherein the improvement effect lasts for at least 6 months after treatment.

3. The etiological drug according to claim 1, wherein the improvement effect lasts for one year after the start of treatment as compared with the state before treatment.

4. A potentiating drug containing hydrogen as an active ingredient, which is used to improve the quality of life of patients with Alzheimer's disease.

5. A potentiating drug containing hydrogen as an active substance, which improves nerve function and has a therapeutic effect even in patients with severe forms of Alzheimer's disease.

6. A potentiating drug containing hydrogen as an active ingredient, which is used to improve fecal incontinence in patients with Alzheimer's disease.

7. A potentiating drug containing hydrogen as an active ingredient, which is used to improve urinary incontinence in patients with Alzheimer's disease.

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