COMPOSITION FOR TREATING AND/OR PREVENTING COGNITIVE IMPAIRMENT OR DEMENTIA

Abstract

Provided is a composition for treating and/or preventing cognitive impairment or dementia. The composition for treating and/or preventing cognitive impairment or dementia containing hydrogen gas, wherein the composition is used to allow the hydrogen gas to be inhaled by a subject. The concentration of the hydrogen gas to be inhaled is, for example, 0.5 to 18.3 vol %. The concentration of the hydrogen gas to be inhaled is, for example, 1 to 10 vol %. For example, the time of inhalation of the hydrogen gas is at least 10 minutes or longer per inhalation, and the frequency of inhalation of the hydrogen gas is once or more per day.

Claims

1.-4. (canceled)

5. A method for treating and/or preventing cognitive impairment or dementia, the method comprising administering to a subject a pharmaceutically effective amount of hydrogen gas by inhalation.

6.-7. (canceled)

8. The method according to claim 5, wherein a composition comprising hydrogen gas is inhaled by the subject, and the concentration of the hydrogen gas in the composition is 0.5 to 18.3 vol %.

9. The method according to claim 5, wherein a composition comprising hydrogen gas is inhaled by the subject, and the concentration of the hydrogen gas in the composition is 1 to 10 vol %.

10. The method according to claim 5, wherein the time of inhalation of the hydrogen gas is at least 10 minutes or longer per inhalation.

11. The method according to claim 5, wherein the frequency of inhalation of the hydrogen gas is once or more per day.

12. The method according to claim 5, wherein the time of inhalation of the hydrogen gas is at least 10 minutes or longer per inhalation, and the frequency of inhalation of the hydrogen gas is once or more per day.

13. The method according to claim 5, wherein the hydrogen gas is produced in situ by using a hydrogen gas feeder.

14. The method according to claim 5, wherein the hydrogen gas is provided from a pressure-resistant container.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Now, embodiments of the present invention will be described in more detail.

[0032] The present invention provides a composition containing hydrogen gas for treating and/or preventing cognitive impairment or dementia, wherein the composition is used to allow the hydrogen gas to be inhaled by a subject.

[0033] Mild cognitive impairment (MCI) is a transitional condition that involves memory impairment but it cannot be said that it is an intellectually healthy condition (cannot regarded as dementia). It takes typically 5 to 10 years (6 to 7 years on average) for MCI to progress to be diagnosed as dementia. Ten to fifteen percent of MCI cases diagnosed in consultation in a medical institution progresses to dementia per year. Although lifestyle and genetic factors, as well as aging, involves in the pathogenesis of MCI, age-related cognitive function decline is a major factor among them. Age-related cognitive function decline is not regarded as pathological condition. MCI is a condition causing a problem to one of cognitive functions (e.g., memory, decision, reasoning, execution) but not interfering with daily living, and the definition of MCI includes the following five items: [1] an individual suspected of MCI or his or her family member complains about memory impairment; [2] activities of daily living are normal; [3] general cognitive functions are normal; [4] memory impairment which cannot be explained only by influences of aging and the education level is present; and [5] not dementia. Accordingly, a process is contemplated that age-related cognitive function decline, in combination with the influences of lifestyle and genetic factors, progresses to MCI, and further to dementia. Hence, it is extremely important to provide proper treatment in the stage of age-related cognitive function decline to prevent the progression to MCI.

[0034] On the other hand, dementia is a condition that normally developed intellectual and mental functions chronically decline in an acquired manner because of some causes or diseases, resulting in difficulty in daily living and social living. The definition of dementia includes the following symptoms. [0035] A. The development of multiple cognitive deficits manifested by both: [0036] 1) memory impairment (impaired ability to learn new information or to recall previously learned information) [0037] 2) one or more of the following cognitive disturbances: [0038] a. aphasia (language disturbance) [0039] b. apraxia (impaired ability to carry out motor activities despite intact motor function) [0040] C. agnosia (failure to recognize or identify objects despite intact sensory function) [0041] d. disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting) [0042] B. The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. [0043] C. The deficits do not occur exclusively during the course of a delirium. [0044] D. The disturbance is not better accounted for by another Axis I disorder (e.g., Major Depressive Disorder, Schizophrenia).

[0045] It should be noted that dementia in the present invention includes dementia of the Alzheimer's type, dementia with Lewy bodies, and vascular dementia.

[0046] The composition according to the present invention contains hydrogen gas as an active ingredient. A preferred form of hydrogen gas is the form of hydrogen gas-containing gas.

[0047] Specifically, the hydrogen gas-containing gas can be air containing hydrogen gas, or a mixed gas containing hydrogen gas and oxygen gas. The concentration of the hydrogen gas in the hydrogen gas-containing gas is 18.3 vol % or lower, which is lower than the lower limit concentration for detonation of hydrogen gas, for example, 0.5 to 18.3 vol % or lower, preferably 1 to 10 vol %, for example, 2 to 8 vol %, 3 to 6 vol %, and more preferably 4 to 6 vol %, for example, 4 to 5 vol %. If the gas other than the hydrogen gas is air, the concentration of the air is, for example, in the range of 81.7 to 99.5 vol %. If the gas other than the hydrogen gas is a gas containing oxygen gas, the concentration of the oxygen gas is, for example, in the range of 21 to 99.5 vol %. Nitrogen gas can be contained as another primary gas in the hydrogen gas-containing gas, and, in addition, a gas such as carbon dioxide, which is a gas contained in the air, in an amount close to the abundance in the air may be contained in the hydrogen gas-containing gas. In any case, hydrogen gas is a flammable and explosive gas, and should be contained in the composition to a concentration safe for subjects such as humans for administration. Thus, it is recommended to reduce the concentration of hydrogen gas below the explosion limit of hydrogen gas (below 10%) for safe feeding.

[0048] The flow rate of hydrogen gas diluted to a safe concentration for inhalation is suitably 1 to 10 liter/min, and preferably 6 to 8 liter/min for patients with hyperpnoea.

[0049] The hydrogen gas-containing gas is blended to a given hydrogen gas concentration, and then a pressure-resistant container (e.g., an aluminum can, a plastic bottle) is filled therewith. Alternatively, the hydrogen gas-containing gas may be produced in situ by using a known hydrogen gas feeder.

[0050] The hydrogen gas feeder enables mixing of hydrogen gas generated from reaction between a hydrogen-generating agent (e.g., metal aluminum) and water and diluting gas (e.g., air, oxygen) with a given ratio (e.g., Japanese Patent No. 5228142), or enables mixing of hydrogen gas generated through electrolysis of water and diluting gas (e.g., Japanese Patent No. 5502973, Japanese Patent No. 5900688). Thereby, a hydrogen gas-containing gas with a hydrogen concentration in the range of 0.5 to 18.5 vol % can be prepared.

[0051] To administer the composition according to the present invention to a subject, for example, pulmonary administration through inhalation or the like is preferred. In inhalation of gas, the gas is sent to the lung through inhalation from the mouth or nose via a mask-type device covering the mouth and nose or a nasal cannula to achieve systemic delivery by diffusion from the lung or via the blood, though the administration method is not limited thereto. Since patients with severe dementia may feel discomfort for wearing a mask-type device or nasal cannula, however, it is recommended to perform pulmonary administration with such an instrument or device for patients with cognitive impairment or mild or moderate dementia allowing use of such an instrument or device. Inhaled hydrogen gas distributes much in the brain, lung, and muscle, and the accumulation of hydrogen (AUC) is larger than those in other routes of administration such as oral administration, intraperitoneal administration, and intravenous administration. Here, comparison is made between drinking of hydrogen water by a human and inhalation of hydrogen gas by a human. In drinking of hydrogen water, most of the hydrogen molecules distribute in tissues and organs in the abdominal portion through diffusion from the stomach and digestive tract, and a part of the hydrogen molecules is absorbed from the intestinal wall and distributes in tissues and organs in the body through the blood circulation. In inhalation of hydrogen gas, on the other hand, the hydrogen molecules are transferred through the following pathways: [1] the hydrogen molecules are mixed with inhaled air and transferred to the lung tissue, and distributed to the surrounding tissues through diffusion; [2] the hydrogen molecules are dissolved in the blood through pulmonary gas exchange and systemically transferred; and [3] the hydrogen molecules are directly transferred to the brain tissue via the nasal mucosa without passing through the blood-brain barrier (BBB). Although hydrogen molecules easily pass through the BBB, we consider that inhalation of hydrogen gas is characterized particularly in that the hydrogen molecules in hydrogen gas are quickly transferred into the brain through the pathway [3].

[0052] The hydrogen gas-containing gas in the above hydrogen concentration can be administered to a subject once or a plurality of times (e.g., twice or three times) per day over a period of 1 week to 6 months or longer (e.g., 4 weeks or longer), preferably of 2 weeks to 3 months. The hydrogen gas-containing gas can be administered, for example, over 10 minutes to 2 hours or longer, preferably over 10 minutes to 40 minutes in one administration. In pulmonary administration of the hydrogen gas-containing gas through inhalation, the gas can be administered to a subject under the atmospheric pressure, or under a high-pressure environment in the range of higher than the standard atmospheric pressure (means approximately 1.013 atm) and 7.0 atm or lower, for example, 1.02 to 7.0 atm, preferably 1.02 to 5.0 atm, more preferably 1.02 to 4.0 atm, even more preferably 1.02 to 1.35 atm. Administration under such a high-pressure environment promotes the body absorption of hydrogen in a subject.

[0053] The high-pressure environment can be produced, for example, by using a high-pressure capsule designed to have a sufficient strength and allowing formation of a high pressure higher than the standard atmospheric pressure and 7.0 atm or lower in the inside through injection of air into the inside. The shape of the high-pressure capsule is preferably generally round without any corner for pressure resistance. The material of the high-pressure capsule is preferably lightweight with high strength, and examples thereof include fiber-reinforced plastics, carbon fiber composites, titanium alloys, and aluminum alloys. A Subject can receive administration of the composition containing hydrogen gas together with oxygen gas or air in the high-pressure capsule.

[0054] The term “subject” herein encompasses mammals, for example, primates including humans, rodents such as mice and rats, pet animals such as dogs and cats, and ornamental animals in zoos or the like. Humans are preferred subjects.

EXAMPLE

[0055] Hereinafter, the present invention will be described in detail based on Examples. However, the present invention is not limited to these Examples.

Example 1

1. Introduction

[0056] One of the causes for cognitive function decline is senility, a feature which is the most remarkable and difficult to control in the course of aging. Aging includes various clinical symptoms, and a wide variety of pharmacological and non-pharmacological approaches have been used for improving age-related cognitive impairment. However, no satisfactory result has been obtained. The hydrogen molecule (H.sub.2) is a novel biological and medical gas having multifunctional and therapeutic characteristics. While H.sub.2 has been recently reported to improve cognitive impairment and neurodegeneration in some animal models, the efficacy in a clinical study has not been evaluated in previous studies. We analyzed the efficacy of 4-week inhalation of H.sub.2 on the cognitive functions of women aged 65 years or more in the present open-label preliminary experiment.

2. Material and Method

[0057] Elderly women living in a community (n=13, 68.0±3.0 years old, body weight: 66.9±10.3 kg, height: 161.1±5.8 cm) volunteered for participants for the present open-label preliminary experiment (registered in ClinicalTrials.gov, NCT02830854). Individuals with a serious disease or a mental disease had been excluded as they met the exclusion criteria. This study was conducted according to the guideline of the Declaration of Helsinki, and the local ethics committee approved the protocol of the present clinical study. The participants all gave informed consent, and were each asked to keep her usual lifestyle and take meals as usual during the study. The participants inhaled H.sub.2 for 15 minutes per day over 4 weeks. The H.sub.2 gas (4%) was provided from a hydrogen gas feeder (MiZ Company Limited, Kanagawa Prefecture, Japan), and research inspectors monitored daily inhalation of H.sub.2 during the study. Mini Mental State Examination (MMSE) scores before the initiation of the study and 4 weeks thereafter were used to evaluate the therapeutic effect. In addition, assessment of other cognitive ability markers and evaluation of side effects were conducted based on the results before the initiation of the study and 4 weeks thereafter. The cognitive functions of the participants were evaluated by using the MMSE and the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). The MMSE is a 30-point questionnaire widely used in clinical practice to determine the degree of cognitive impairment of an elderly individual. The ADAS-Cog is a method, consisting of 11 tasks, of assessing cognitive abilities, and determines memory impairment, language impairment, praxis impairment, attention deficits, and other cognitive abilities to test for dementia. In addition to the assessments, the participants were asked to report adverse events during the study through self-assessment or an open-ended questionnaire on side effects (e.g., queasy feeling, headache). Statistical significance was determined by using a Wilcoxon signed-rank test (before the initiation of the study vs. 4 weeks thereafter). If p≤0.05 was satisfied, the result was considered statistically significant.

3. Results

[0058] A follow-up study was conducted for all of the participants, and some reported side effects. However, there was no participant excluded from the study because of any adverse event. The rate of adherence to lifestyle restrictions was 95.8%. Table I shows changes in cognitive functions during the study (study results at baseline vs. after 4 weeks).

TABLE-US-00001 TABLE 1 After % change Baseline 4 weeks (95% CI) P MMSE Total score 25.6 ± 1.6  29.1 ± 1.1  14.2 <0.001  (8.6-19.8) ADAS-Cog Language 3.6 ± 1.0 8.1 ± 1.2 140.0 <0.001 reproduction test  (94.4-185.6) Language 4.2 ± 3.2 1.1 ± 1.0 −40.1 0.01 recognition (−93.3-13.1) MMSE: Mini Mental State Examination ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale CI: the smaller the confidential interval is, the better the language recognition is

[0059] Inhalation of H.sub.2 gas resulted in remarkably increased MMSE total scores (mean: 13.7%, P<0.01); specifically, the cognitive functions improved from mild dementia at the baseline (score: 25.6 in 30) to normal cognitive abilities (score: higher than 27) at the end of the study. In addition, inhalation of H.sub.2 resulted in remarkably improved ADAS-Cog scores; specifically, improved performance was found in the word reproduction test (P<0.01) and the word recognition ability was improved after administration (P=0.01). The other 9 items in ADAS-Cog scoring (calling of names, instruction, structural execution, thinking and execution, direction, conversation ability, memory of test instructions, word finding impairment, understanding) were correctly executed (e.g., score=0) in both tests (not disclosed).

4. Discussion

[0060] In the open-label trial investigating the effectiveness of H.sub.2 on the cognitive performance of elderly individuals, the cognitive ability markers of the women aged 65 years or more who appeared healthy but had lowered cognitive functions improved through inhalation of H.sub.2 gas for 15 minutes every day over 4 weeks. After administration, the MMSE scores increased for 12 women (among 13 women), and increased word recognition ability was reported in the ADAS-Cog assessment after the H.sub.2 inhalation study. In addition, since no sign of side effects due to inhalation of H.sub.2, which had been subjectively reported, was found, inhalation of H.sub.2 was expected to have acceptable safety. The present preliminary experiment can be considered to verify the results of previous animal studies, thus H.sub.2 gas can be regarded as a pharmaceutical agent useful for health maintenance in terms of cognitive abilities, which are age-related. Cognitive impairment is believed to closely relate to oxidative stress in an elderly individual. Exogenous H.sub.2 acts as an antioxidant with selective action to help maintenance or recovery of redox reaction balance in the central nervous system, leading to improvement of cognitive abilities. Nagata et al. report that consumption of H.sub.2 lowered oxidative stress in the brain and hippocampus-dependent deterioration of learning and memory caused by oxidative stress was prevented in mice. Accordingly, it is a future task to demonstrate the effect of H.sub.2 gas to improve the cognitive abilities of humans through measurement of another cognitive function marker (e.g., functional brain imaging, biomarkers based on the cerebrospinal fluid and blood) in a randomized controlled study. If the efficacy and safety of H.sub.2 gas is further demonstrated in future clinical studies, H.sub.2 gas can be regarded as an innovative therapeutic drug for cognitive impairment such as amnesia, Alzheimer's disease, and vascular dementia.

[0061] All of the publications, patents, and patent applications cited herein are incorporated herein in their entirety by reference.

INDUSTRIAL APPLICABILITY

[0062] The present invention can be used for treating and/or preventing cognitive impairment or dementia.