WO2024078545A1 - 氢气吸入治疗自闭症 - Google Patents

氢气吸入治疗自闭症 Download PDF

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Publication number
WO2024078545A1
WO2024078545A1 PCT/CN2023/124070 CN2023124070W WO2024078545A1 WO 2024078545 A1 WO2024078545 A1 WO 2024078545A1 CN 2023124070 W CN2023124070 W CN 2023124070W WO 2024078545 A1 WO2024078545 A1 WO 2024078545A1
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Prior art keywords
hydrogen
autism
subject
pharmaceutical composition
gas
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PCT/CN2023/124070
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English (en)
French (fr)
Inventor
魏佑震
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上海氢医医疗科技有限公司
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Publication of WO2024078545A1 publication Critical patent/WO2024078545A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/10—Preparation of respiratory gases or vapours
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/10—Preparation of respiratory gases or vapours
    • A61M16/12—Preparation of respiratory gases or vapours by mixing different gases

Definitions

  • the present invention relates to the field of biomedicine. Specifically, the present invention relates to the use of hydrogen for treating autism.
  • Autism also known as autism, is a type of pervasive developmental disorder (PDD) and was first described by Leo Kanner in 1943.
  • Autism Asperger's disorder and PDD-not otherwise specified (PDD-NOS) are often collectively referred to as autism spectrum disorders (ASDs).
  • Autism often manifests as communication disorders and compulsive behaviors.
  • the patient's cognitive characteristics are abnormal, such as impaired social cognition and social perception, executive dysfunction, and perceptual and information processing disorders. Its clinical manifestations include: language and communication disorders, impaired social interaction, narrowed interests, stereotyped behaviors, often accompanied by mental retardation, emotional instability, frequent crying, sleep disorders, etc.
  • the purpose of the present invention is to provide the use of hydrogen for treating autism.
  • a device for treating autism comprising:
  • the hydrogen supply module is configured to provide hydrogen or a mixed gas containing hydrogen. body.
  • the volume concentration of hydrogen in the mixed gas is 2-99.9%, preferably 20-70%, and more preferably 40-70%.
  • the mixed gas further contains a gas selected from the following group: oxygen, nitrogen, helium, or a combination thereof.
  • the volume concentration of oxygen in the mixed gas is 0.1-21%, preferably 4-15%, and more preferably 8-10%.
  • the drug delivery module is configured to deliver the drug by inhalation, preferably by nasal catheter inhalation.
  • the drug administration module is configured to administer hydrogen to the subject at a flow rate of 1-3 L/min, preferably 1-2 L/min, and more preferably 1.5-2 L/min.
  • control module is configured to administer hydrogen to the subject in the form of intermittent administration.
  • control module is configured to administer hydrogen to the subject for a duration of ⁇ 30 min each time, preferably ⁇ 45 min, more preferably ⁇ 60 min, and more preferably ⁇ 120 min.
  • control module is configured to administer hydrogen to the subject for a total duration of ⁇ 60 min per day, preferably ⁇ 90 min, more preferably ⁇ 120 min, and more preferably ⁇ 240 min. In another preferred embodiment, the control module is configured to administer hydrogen to the subject at a frequency of at least 4 days per week, preferably at least 5 days, and more preferably at least 6 days.
  • the device is used to treat symptoms selected from the following group: sleep disorders, communication difficulties, poor language development, inattention, poor sitting, poor comprehension, and refusal to follow instructions.
  • the device is used to improve developmental abilities selected from the group consisting of sensory perception, gross motor skills, fine motor skills, language and communication, cognition, social interaction, self-care, and emotional behavior.
  • the emotional behavior includes: attachment emotional behavior, emotional understanding, emotional expression and regulation, relationships and emotions, interest in objects, sensory preferences, and special behaviors.
  • the autism is childhood autism.
  • the subject is a human or non-human mammal.
  • the subject is an adult or a child, preferably a child aged 2-12 years old.
  • the device further comprises a rehabilitation module, and the rehabilitation module performs rehabilitation training on the subject through artificial intelligence.
  • the device further comprises an evaluation module, and the evaluation module is used to evaluate the disease condition of the subject.
  • a device as described in the first aspect of the present invention for use in treating a subject suffering from autism.
  • the use of hydrogen for preparing a pharmaceutical composition for treating autism wherein the pharmaceutical composition is a gas composition, and the volume concentration of hydrogen in the gas composition is 2-99.9%, preferably 20-70%, and more preferably 40-70%.
  • a pharmaceutical composition in a fourth aspect of the present invention, characterized in that the pharmaceutical composition contains hydrogen at a concentration of 2-99.9%.
  • the pharmaceutical composition is a gas composition, a liquid composition, or a combination thereof.
  • the pharmaceutical composition is a gas composition
  • the gas composition contains:
  • the volume concentration of the hydrogen is 20-70%, more preferably 40-70%.
  • the volume concentration of oxygen in the pharmaceutical composition is 0.1-21%, preferably 4-15%, and more preferably 8-10%.
  • hydrogen or a pharmaceutical composition as described in the fourth aspect of the present invention is provided for use in treating autism in a subject in need thereof.
  • the pharmaceutical composition is administered by inhalation, oral administration, or transdermal administration.
  • the pharmaceutical composition is a gas composition for inhalation administration, preferably inhalation via a nasal catheter.
  • hydrogen is administered to the subject at a flow rate of 1-3 L/min, preferably 1-2 L/min, more preferably 1.5-2 L/min.
  • hydrogen is administered to the subject for a period of ⁇ 30 min each time, preferably ⁇ 45 min, more preferably ⁇ 60 min, and more preferably ⁇ 120 min.
  • hydrogen is administered to the subject for a total duration of ⁇ 60 min per day, preferably ⁇ 90 min, more preferably ⁇ 120 min, and more preferably ⁇ 240 min.
  • hydrogen is administered to the subject at a frequency of at least 4 days per week, preferably at least 5 days, and more preferably at least 6 days per week.
  • the treatment lasts for at least 120 days, preferably at least 180 days, more preferably at least 240 days.
  • the treatment of autism includes treating symptoms selected from the following group: sleep disorders, communication difficulties, poor language development, inattention, poor sitting, poor comprehension, and refusal to follow instructions.
  • the treatment of autism includes improving developmental abilities selected from the group consisting of sensory perception, gross motor skills, fine motor skills, language and communication, cognition, social interaction, self-care, and emotional behavior.
  • the emotional behavior includes: attachment emotional behavior, emotional understanding, emotional expression and regulation, relationships and emotions, interest in objects, sensory preferences, and special behaviors.
  • the subject is a human or non-human mammal.
  • the subject is an adult or a child, preferably a child aged 2-12 years old.
  • a method for treating autism in a subject in need thereof comprising the steps of administering hydrogen to the subject in need thereof.
  • the administration is by inhalation, oral administration, or transdermal administration.
  • the inhalation administration is nasal catheter inhalation.
  • the method comprises the step of administering hydrogen or a mixed gas containing hydrogen to a subject in need thereof.
  • the volume concentration of hydrogen in the mixed gas is 2-99.9%, preferably 20-70%, and more preferably 40-70%.
  • the mixed gas further contains a gas selected from the following group: oxygen, nitrogen, helium, or a combination thereof.
  • the volume concentration of oxygen in the mixed gas is 0.1-21%, preferably 4-15%, and more preferably 8-10%.
  • the administration includes: administering hydrogen to the subject at a flow rate of 1-3 L/min, preferably 1-2 L/min, and more preferably 1.5-2 L/min.
  • the administration comprises: administering hydrogen to the subject for a period of ⁇ 30 min each time, preferably ⁇ 45 min, more preferably ⁇ 60 min, and more preferably ⁇ 120 min.
  • the administration comprises: administering hydrogen to the subject for a total duration of ⁇ 60 min per day, preferably ⁇ 90 min, more preferably ⁇ 120 min, and more preferably ⁇ 240 min.
  • the method administers hydrogen to the subject at a frequency of at least 4 days per week, preferably at least 5 days, more preferably at least 6 days. In another preferred embodiment, the method lasts for at least 120 days, preferably at least 180 days, more preferably at least 240 days.
  • the treatment of autism includes treating symptoms selected from the following group: sleep disorders, communication difficulties, poor language development, inattention, poor sitting, poor comprehension, and refusal to follow instructions.
  • the treatment of autism includes improving developmental abilities selected from the group consisting of sensory perception, gross motor skills, fine motor skills, language and communication, cognition, social interaction, self-care, and emotional behavior.
  • the emotional behavior includes: attachment emotional behavior, emotional understanding, emotional expression and regulation, relationships and emotions, interest in objects, sensory preferences, and special behaviors.
  • the subject is a human or non-human mammal.
  • the subject is an adult or a child, preferably a child aged 2-12 years old.
  • the method further comprises the step of: performing rehabilitation training on the subject.
  • the method further comprises the step of: evaluating the disease condition of the subject.
  • Figure 1 shows the experimental results of hydrogen improving the social interaction ability and fine motor skills of children with autism.
  • Figure 2 shows the experimental results of hydrogen improving the interpersonal relationships and emotions, special behaviors, and interest in objects in children with autism.
  • Figure 3 shows the changes in facial expressions of autistic children in their natural state before and after hydrogen inhalation for half a year.
  • FIG 4 shows the comparison results of the Childhood Autism Rating Scale (CARS) before and after hydrogen inhalation.
  • CARS Childhood Autism Rating Scale
  • Figure 5 shows the results of the Children's Sleep Habits Questionnaire (CSHQ) assessment before and after hydrogen inhalation.
  • CSHQ Children's Sleep Habits Questionnaire
  • Figure 6 shows the comparison of developmental ability assessment of autistic children in the hydrogen inhalation group and the control group.
  • Figure 7 shows the comparison of emotional behavior scores of autistic children in the hydrogen inhalation group and the control group.
  • the present invention provides a specific device and method for treating autism with hydrogen, wherein hydrogen is administered at a specific concentration and for a specific duration, which significantly improves the behavior, movement, and emotional symptoms of children with autism. On this basis, the present invention was completed.
  • Autism also known as autism, has a complex pathogenesis, and there is no clear unified understanding in this field.
  • the existing pathogenesis theories are: generalized brain lesions, dopamine theory, oxidative stress theory, developmental theory, and immune-inflammatory theory.
  • the immune-inflammatory theory predicts that stress and environmental stimuli trigger unique mast cells (MCs), which in turn trigger microglia, leading to abnormal synaptic pruning and dysfunctional neuronal connections. This process may change the "fear threshold" in the amygdala and lead to an exaggerated "fight or flight” response.
  • the combination of corticotropin releasing hormone (CRH) secreted under stress conditions and environmental stimuli may be the main cause of ASD.
  • stress and environmental stimuli trigger mast cells, which in turn activate microglia, produce oxidative stress, initiate inflammatory immune responses, trigger synaptic pruning, and cause neuronal synaptic abnormalities.
  • Hydrogen is a new type of anti-inflammatory and antioxidant agent. Both human and animal studies have shown that inhaled hydrogen has a protective effect in the prevention and treatment of various diseases.
  • the mechanism of action of hydrogen in treating ASD may be mainly manifested in the following two aspects: (1) eliminating free radicals; (2) preventing the activation of mast cells and/or microglia; and (3) preventing the activation of neuronal dendrites.
  • the functional and morphological plasticity of spines changes, re-establishing and restoring synaptic connections.
  • the term "hydrogen supply module” used in the present invention refers to a module used to deliver hydrogen to the drug delivery module in the device for treating autism of the present invention.
  • the hydrogen supply module may include a hydrogen generator, typically, it may include a device for electrolyzing water to generate hydrogen, and deliver the generated hydrogen to the drug delivery module; or, the hydrogen supply module may not include a hydrogen generator, typically, it may be connected to a hydrogen storage container (such as a gas storage tank, or a high-density hydrogen storage slow-release device, but not limited thereto) and directly deliver hydrogen or a mixed gas containing hydrogen to the drug delivery module.
  • a hydrogen storage container such as a gas storage tank, or a high-density hydrogen storage slow-release device, but not limited thereto
  • the term "dosage module" used in the present invention refers to a module in the device for treating autism of the present invention for administering hydrogen to a subject in need thereof.
  • methods of hydrogen administration include but are not limited to inhalation administration, oral administration, transdermal administration, subcutaneous administration, injection administration, ocular and nasal mucosal administration, and enema administration.
  • the drug delivery module is configured to: guide hydrogen in the form of gas to the nose and mouth through a nasal catheter or mask, or supply gas to the nose and mouth in a non-contact manner (i.e., directly "spray" the gas to the nose and mouth at a certain pressure that the patient can tolerate, the purpose of doing so is to solve the contact sensitivity problem of some patients), inhaled through natural breathing, enter the lungs through the trachea and bronchi, and enter the blood from the lungs through the air-blood barrier.
  • the air pressure setting for administering hydrogen to the subject by inhalation in the drug delivery module can be changed according to factors such as the patient's physiological state and the area where the device is used.
  • the drug delivery module can be configured to administer hydrogen to the subject at an air pressure of 0.1Mpa (i.e., one atmosphere) or higher; in high-altitude areas, the drug delivery module can be configured to administer hydrogen to the subject at an air pressure lower than 0.1Mpa (i.e., one atmosphere), but is not limited thereto.
  • the drug delivery module is configured as follows: hydrogen is taken orally into the gastrointestinal tract in the form of a solution (e.g., hydrogen-containing water or a hydrogen-containing beverage, or a hydrogen-containing ion component), and is absorbed into the blood through the digestive tract.
  • a solution e.g., hydrogen-containing water or a hydrogen-containing beverage, or a hydrogen-containing ion component
  • the hydrogen in the hydrogen-containing beverage may be present in a form selected from the following group: hydrogen molecules, hydrogen ions, hydrogen anions, or a combination thereof.
  • the hydrogen concentration in the hydrogen-containing beverage may be ⁇ 0.5ppm, ⁇ 1.0ppm, ⁇ 1.6ppm or higher, or its maximum solubility, but is not limited thereto.
  • the amount of hydrogen, hydrogen ions, or hydrogen-containing beverage taken each time may vary according to factors such as the patient's age, weight, course of disease, severity of disease, physiological state, etc., and may be reasonably adjusted by a skilled physician based on the above actual conditions.
  • the drug delivery module is configured as follows: hydrogen gas is passed through a hydrogen-containing gas medium or a liquid medium in a gas bath or a water bath, including a liquid medium containing hydrogen ions, including any proportion (e.g., ⁇ 2%, ⁇ 20%, ⁇ 40%, ⁇ 60%, or ⁇ 70%, or higher), to form a hydrogen-containing gas environment (gas bath) or a hydrogen-containing liquid environment (water bath) covering the body, and then passed through any
  • the hydrogen is absorbed into the blood through the skin barrier over any area (e.g., ⁇ 0.1%, ⁇ 20%, ⁇ 40%, ⁇ 60%, or ⁇ 80%, or higher) of any part of the body (including the head, hands, arms, feet, legs, buttocks, perineum, etc.).
  • a water bath and/or gas bath at any time length and any gas pressure can be used.
  • the drug delivery module is configured to inject hydrogen or a hydrogen-containing gas mixture into the subject, including injecting pure hydrogen or a gas mixture composed of other gases in any proportion (e.g., ⁇ 40%, ⁇ 30%, ⁇ 20%, ⁇ 10%, ⁇ 5%, or lower), or injecting a solution of hydrogen or any gas mixture mixed with hydrogen, directly into the body including any part or organ (such as the thoracic cavity, abdominal cavity, pelvic cavity, cranial cavity, spinal canal, subcutaneous, trachea and bronchus, alveoli, gastrointestinal tract, hollow organs, etc.).
  • the injection volume and injection rate of hydrogen or gas mixture can be any volume and any flow rate that does not exceed the subject's tolerance and maximum volume.
  • the drug delivery module is configured to: administer the drug to the subject through a drop of a hydrogen gas component or a hydrogen ion component, including but not limited to the conjunctiva, the nasal mucosa, or a combination thereof.
  • the drop can be formulated as eye drops or nasal drops, but is not limited thereto.
  • the hydrogen concentration in the drop can be ⁇ 0.5ppm, ⁇ 1.0ppm, ⁇ 1.6ppm or higher, or its maximum solubility, but is not limited thereto.
  • the drug delivery module is configured to: perform lavage administration to the subject through a wash or lavage fluid containing hydrogen gas or hydrogen ion components, including but not limited to: using hand soap, face wash, bath liquid, perineal wash to wash the body, or using gastrointestinal lavage fluid, anorectal lavage fluid for lavage.
  • the hydrogen concentration in the wash or lavage fluid may be ⁇ 0.5ppm, ⁇ 1.0ppm, ⁇ 1.6ppm or higher, or its maximum solubility, but is not limited thereto.
  • control module used in the present invention refers to a module used in the device for treating autism of the present invention to control the time, duration, interval, and course of administration of hydrogen to a subject in need thereof.
  • administration is in the form of a gas composition, it also includes controlling the gas flow, content, and composition.
  • the gas flow rate, content, composition, time and dosing interval of hydrogen administration to the subject can vary according to factors such as the patient's age, disease severity, physiological state, compliance, work and rest time, and can be reasonably adjusted by a skilled person in the field or a skilled physician according to the above actual situation.
  • Administration can be performed at any time of the day, during the day, at night, or during the day and at night. Taking into account the subject's compliance and work and rest time, hydrogen administration is preferably performed at night or when the subject is resting.
  • the duration of each administration can be arbitrary, and the dosing interval can also be arbitrary. Longer administration duration and shorter dosing interval are expected to obtain better therapeutic effects.
  • the preferred administration duration is ⁇ 30 minutes, ⁇ 45 minutes, ⁇ 60 minutes, ⁇ 90 minutes, ⁇ 120 minutes, or longer, but not limited thereto; the preferred dosing interval is 8-12 hours.
  • the course of administration of hydrogen to the subject can be in any range, such as a few days to a few years, and can be determined based on the symptoms to be treated, the mode of administration, the patient's age, course of disease, severity of disease, physiological The condition and other factors change, which can be reasonably adjusted by a skilled technician or a skilled physician based on the actual situation mentioned above.
  • rehabilitation module used in the present invention refers to a module in the device for treating autism of the present invention that is used to perform rehabilitation training on a subject while undergoing hydrogen treatment.
  • the rehabilitation module used in the present invention is guided by the basic principles of the communication training system PECS developed by the Denavarra Autism Learning Program in the United States, integrating multiple artificial intelligence technologies including NLP, image recognition, and human-computer interaction, and assisting autistic patients or other patients with social communication disorders to observe and experience the process of communication through gradual training stages, classified pictures and sentence strips.
  • the intervention based on knowledge and language levels mainly includes picture stimulation, interactive games, and gesture language assistance.
  • the intervention programs such as turn-based manipulation teaching method (DTT), key response training (PRT), and perspective selection intervention (PTI) are used to activate the knowledge schema of children. Pragmatic intervention is carried out from the perspectives of improving children's pragmatic narrative, discourse comprehension, and conversation maintenance.
  • the task of children learning new knowledge is integrated into the conversation task set based on the children's existing knowledge to improve the children's verbal social ability.
  • Semi-autonomous social assistance intelligent training with human participation can provide reaction training for the facial expressions, gestures and eyes of children during the conversation, and the intervention of objects, body movements, oral-facial imitation, sound imitation, meaningful scenes and sounds can have a positive effect on the behavior of children. It can also imitate the communication between humans and children with the help of natural language processing and semantic understanding technologies, set language tasks in specific contexts and identify the communication purpose of children, and implement the intervention of children at the language level such as turn-taking, rhetorical discourse, and pre-set understanding.
  • the system can integrate the feedback information of human educators into its own decision-making mechanism, provide better training programs, and form an artificial intelligence self-cocooning training system for autistic patients.
  • assertment module used in the present invention refers to a module in the device for treating autism of the present invention for performing symptom assessment on a subject before or after hydrogen treatment.
  • the assessment module can be based on the following assessment methods, but is not limited to them:
  • WISC-IV Wechsler Preschool Intelligence Scale, Fourth Edition (WPPIS-IV), LMDunn, USA, 1965
  • VABS Vineland Adaptability Scale
  • AAP American Academy of Pediatrics
  • primary care screening includes screening using warning indicator screening, video analysis methods, and child psychological development problem warning sign screening forms
  • primary screening includes screening using the CHAT, M-CHAT, CHAT-23, Early Screening Questionnaire for Autism Characteristics (ESAT), and Autism Behavior Checklist (ABC)
  • secondary screening includes screening using the Childhood Autism Rating Scale (CARS); and diagnosis of autism using ASD diagnostic scales (including the Autism Diagnostic Observation Schedule-G (ADOS-G) and the Autism Diagnostic Interview-Revised (ADI-R));
  • AETC Autism Evaluation of Treatment Checklist
  • Methods and tools that can be used for other assessment purposes including the Six Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP) developed by Mark L. Sandberg of the United States for assessing children's language and social abilities, and the Children's Sensory Integration Ability Development Rating Scale (Sensory Integration Checklist) designed by Anna Jean Ayres of the United States and compiled by Zheng Xinxiong of Taiwan for assessing children's sensory integration.
  • VB-MAPP Six Verbal Behavior Milestones Assessment and Placement Program
  • the present invention has found that the intake of hydrogen at a specific concentration and duration can improve the symptoms of autism, with significant effects, strong timeliness, and no toxic side effects.
  • the present invention provides a variety of hydrogen intake methods without affecting normal course training.
  • the device or method of the present invention can be combined with artificial intelligence technology, coordinated with teaching and rehabilitation courses, and even preschool/primary school teaching content, so as to integrate education into the teaching process without delaying the normal course progress. At the same time, it saves manpower and realizes the standardization of teaching and training.
  • the registration number of the China Clinical Trial Registry is ChiCTR2100048006.
  • the hydrogen supply module used in this embodiment includes a machine for electrolyzing water to generate hydrogen.
  • the generated hydrogen has a purity of 100% and can be supplied to the patient alone or mixed with oxygen (the concentration of hydrogen varies from 66.6% to 33.3% of oxygen.
  • the gas flow rate is adjustable. The adjustment range depends on the weight of the child patient and is generally controlled at 1-3 liters/minute; the drug delivery module is configured to deliver the drug by inhalation through a nasal catheter; the control module is configured to deliver the drug 1-2 times a day, each time for 40-90 minutes, and the course of treatment varies from 3 to 6 months; some may require year-round medication (hydrogen, hydrogen ions or other effective hydrogen components).
  • sleep status can be sent to a variety of dedicated applications for smart phones (ios or android) with Bluetooth connections, so that sleep status can be visualized. These data can be used as a sign of sleep and health.
  • the CRAS scale and the children's sensory integration test questionnaire commonly used in this field can be used to objectively and accurately test the patient's learning ability and behavior.
  • Hydrogen inhalation significantly improved the sleep quality of the children, such as increasing the depth of sleep, prolonging quiet sleep, reducing the number of awakenings at night, and reducing the number of nighttime awakenings; greatly improved behavioral patterns, such as longer sitting time, cooperating with teachers, actively participating, improving behavioral imitation ability, and reducing abnormal behaviors (self-harm, crying, fighting, talking to oneself); improved communication ability and willingness, such as active communication, language content consistent with the context, language expression ability, imitation ability, and increased eye contact; significantly improved learning ability and level, such as comprehension ability, cognitive ability, and learning interest; improved emotional expression and level, such as emotional stabilization, enrichment, cheerful personality, and reduced aggressive behavior; improved eating habits, such as regular and diversified eating, and no longer picky or partial eating.
  • Figures 1 and 2 show the results of the child development ability and emotional behavior ability scale assessment of a case.
  • the child underwent a child development ability assessment before enrollment in September 2021, and a second assessment was conducted in January 2022, 5 months after hydrogen inhalation.
  • the comparison of the results before and after the two assessments showed that the child's behavior in daily life has improved significantly, showing that the child has made significant progress in social interaction skills, fine motor skills, relationships, and emotions.
  • the changes in the child's facial expressions before and after hydrogen inhalation for half a year are shown in Figure 3.
  • Control group 7 children who received conventional rehabilitation training in the hospital during the same period received conventional rehabilitation training but did not receive hydrogen inhalation
  • Hydrogen inhalation group 7 children enrolled in the group received hydrogen inhalation intervention while receiving conventional rehabilitation training. Among them, 4 children in the hydrogen inhalation group completed the treatment as required by the project, and 3 children dropped out midway.
  • Hydrogen inhalation method nasal cannula inhalation, nasal cannula use one person one tube, clear and eliminate in sequence.
  • Inhalation time each continuous uninterrupted inhalation is not less than 45 minutes, the cumulative inhalation is not less than 1.5 hours per day, 5 consecutive days per week (weekdays), weekends (two days) rest; 180 consecutive days.
  • Detection indicators and methods Subjective assessment tools were used, including the Child Autism Rating Scale (CARS), the Child Sensory Integration Ability Development Rating Scale, the Child Sleep Habits Questionnaire (CSHQ), and the Autism Children's Development Ability Assessment Form.
  • CARS Child Autism Rating Scale
  • CSHQ Child Sleep Habits Questionnaire
  • the developmental ability assessment of autistic children includes eight areas: sensory perception, gross motor skills, fine motor skills, language and communication, cognition, social interaction, self-care, and emotional behavior. The seven areas other than emotional behavior were analyzed and compared, and the analysis results are shown in Figure 6:
  • the improvement rate in the experimental group was 44%, and the improvement rate in the control group was 18%.
  • the improvement rate in the experimental group was 31%, and the improvement rate in the control group was 25%.
  • Emotional behavior assessment includes seven aspects, namely, attachment emotional behavior, emotional understanding, emotional expression and regulation, relationship and emotion, interest in objects, sensory preference, and special behavior.
  • the analysis results are shown in Figure 7:
  • the improvement rate in the experimental group was 63%, while the improvement rate in the control group was 50%.
  • the improvement rate of the experimental group was 56%, and the improvement rate of the control group was 45%.
  • the improvement rate of the experimental group was 31%, and the improvement rate of the control group was 13%.
  • the improvement rate in the experimental group was 41%, while the improvement rate in the control group was 29%.
  • the improvement rate was 29% in the experimental group and 19% in the control group.

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Abstract

一种氢气用于治疗自闭症的用途。使用氢气治疗自闭症的特定装置和方法，其中以特定浓度、特定时长给药氢气，能够显著地改善自闭症患者的行为、动作、情绪等症状，从而具有在自闭症治疗领域应用的前景。

Description

氢气吸入治疗自闭症 技术领域
本发明涉及生物医药领域。具体地说，本发明涉及氢气用于治疗孤独症(自闭症)的用途。
背景技术
孤独症也称为自闭症，属于广泛性发育障碍(pervasive developmental disorders,PDD)的一种，1943年最先由Leo Kanner描述。人们常将自闭症障碍、阿斯伯格障碍(Asperger's disorder)和未指定的广泛性发育障碍(PDD-not otherwise specified,PDD-NOS)统称为自闭症谱系障碍(Autism spectrum disorders,ASDs)。自闭症常表现为交流障碍和强迫性行为，患者认知特征呈现违越常规，如社会认知和社会知觉受损、执行功能障碍，知觉和信息处理障碍，其临床表现为：语言和交流障碍、社会交往受损、兴趣收窄、刻板行为，常伴有智力低下、情绪不稳定、经常哭闹，睡眠障碍等。通常开始于儿童早期，是一组异质性的神经发育障碍，伴有脑组织的炎症状态；其特征是早期即出现社交障碍、活动受限、重复的刻板行为和单一兴趣。患有ASD的儿童无法应对焦虑，即使是对良性诱因也会做出超常的反应，其核心症状是缺乏社会互动、刻板和限制行为，而相关症状包括易怒、焦虑、攻击和几种共病。由于自闭症患者表现出来的社会互动和交流障碍，与行为刻板重复和兴趣狭窄，是两大类不同的症状，各具特征，因此自闭症是一种综合征。
在全球范围内，即便是在发达国家，自闭症患者也没有达到比较理想的照护，丧失生产力的同时消耗了大量教育成本。早期全面和有针对性的行为干预可以改善社会交往，减少焦虑和攻击。药物可以减少症状，但不能直接改善社会交往。目前，针对自闭症尚无确切有效的治疗方法。
目前，本领域尚未有能够显著改善自闭症症状的治疗手段。
因此，本领域需要开发一种改善自闭症症状的治疗药物及方法。
发明内容
本发明的目的就是提供氢气用于治疗自闭症的用途。
在本发明的第一方面，提供了一种用于治疗自闭症的装置，所述装置包括：
1)供氢模块；
2)给药模块；
3)控制模块。
在另一优选例中，所述的供氢模块被配置为提供氢气、或含有氢气的混合气 体。
在另一优选例中，所述的混合气体中氢气的体积浓度为2-99.9％，优选为20-70％，更优选为40-70％。
在另一优选例中，所述的混合气体中进一步含有选自下组的气体：氧气、氮气、氦气、或其组合。
在另一优选例中，所述的混合气体中氧气的体积浓度为0.1-21％，优选为4-15％，更优选为8-10％。
在另一优选例中，所述的给药模块被配置为以吸入方式给药，优选以鼻导管吸入方式给药。
在另一优选例中，所述的给药模块被配置为，以流速1-3L/min向受试者给药氢气，优选1-2L/min，更优选1.5-2L/min。
在另一优选例中，所述的控制模块被配置为以间隔给药形式向受试者给予氢气。
在另一优选例中，所述的控制模块被配置为，以每次≥30min的时长向受试者给药氢气，优选≥45min，更优选≥60min，更优选≥120min。
在另一优选例中，所述的控制模块被配置为，以每日≥60min的总时长向受试者给药氢气，优选≥90min，更优选≥120min，更优选≥240min。在另一优选例中，所述的控制模块被配置为，以每周至少4天的频率向受试者给药氢气，优选至少5天，更优选至少6天。
在另一优选例中，所述的装置用于治疗选自下组的症状：睡眠障碍、交流困难、语言发育不良、注意力不集中、安坐不良、理解力差、不听指令。
在另一优选例中，所述的装置用于改善选自下组的发展能力：感官知觉、粗大运动、精细动作、语言与沟通、认知、社会交往、生活自理、情绪行为。
在另一优选例中，所述的情绪行为包括：依附情绪行为、情绪理解、情绪表达与调节、关系与情感、对物品的兴趣、感觉偏好、特殊行为。
在另一优选例中，所述的自闭症为儿童自闭症。
在另一优选例中，所述的受试者为人或非人哺乳动物。
在另一优选例中，所述的受试者为成人或儿童，优选为2-12周岁儿童。
在另一优选例中，所述的装置进一步包括康复模块，所述康复模块通过人工智能对受试者进行康复训练。
在另一优选例中，所述的装置进一步包括评估模块，所述评估模块用于对受试者的疾病状况进行评估。
在本发明的第二方面，提供了如本发明第一方面所述的装置，用于治疗患有自闭症的受试者。
在本发明的第三方面，提供了氢气的用途，用于制备治疗自闭症的药物组合物，所述的药物组合物为气体组合物，并且所述气体组合物中氢气的体积浓度为2-99.9％，优选为20-70％，更优选为40-70％。
在本发明的第四方面，提供了一种药物组合物，其特征在于，所述药物组合物含有浓度为2-99.9％的氢。
在另一优选例中，所述的药物组合物为气体组合物、液体组合物、或其组合。
在另一优选例中，所述药物组合物为气体组合物，并且所述气体组合物含有：
A)体积浓度为2-99.9％的氢气；
B)选自下组的其他气体：氧气、氮气、氦气、或其组合。
在另一优选例中，所述的氢气的体积浓度为20-70％，更优选为40-70％。
在另一优选例中，所述的药物组合物中氧气的体积浓度为0.1-21％，优选为4-15％，更优选为8-10％。
在本发明的第五方面，提供了氢气、或如本发明第四方面所述的药物组合物，其用于在有需要的受试者中治疗自闭症。
在另一优选例中，所述的药物组合物通过吸入给药、口服给药、或经皮给药。
在另一优选例中，所述的药物组合物为用于吸入给药的气体组合物，优选为鼻导管吸入。
在另一优选例中，以流速1-3L/min向受试者给药氢气，优选1-2L/min，更优选1.5-2L/min。
在另一优选例中，以每次≥30min的时长向受试者给药氢气，优选≥45min，更优选≥60min，更优选≥120min。
在另一优选例中，以每日≥60min的总时长向受试者给药氢气，优选≥90min，更优选≥120min，更优选≥240min。
在另一优选例中，以每周至少4天的频率向受试者给药氢气、优选至少5天、更优选至少6天。
在另一优选例中，所述的治疗持续至少120天、优选至少180天、更优选至少240天。
在另一优选例中，所述的治疗自闭症包括治疗选自下组的症状：睡眠障碍、交流困难、语言发育不良、注意力不集中、安坐不良、理解力差、不听指令。
在另一优选例中，所述的治疗自闭症包括改善选自下组的发展能力：感官知觉、粗大运动、精细动作、语言与沟通、认知、社会交往、生活自理、情绪行为。
在另一优选例中，所述的情绪行为包括：依附情绪行为、情绪理解、情绪表达与调节、关系与情感、对物品的兴趣、感觉偏好、特殊行为。
在另一优选例中，所述的受试者为人或非人哺乳动物。
在另一优选例中，所述的受试者为成人或儿童，优选为2-12周岁儿童。
在本发明的第六方面，提供了一种在有需要的受试者中治疗自闭症的方法，包括步骤：向有需要的受试者给药氢气。
在另一优选例中，所述的给药为通过吸入给药、口服给药、经皮给药。
在另一优选例中，所述的吸入给药为鼻导管吸入。
在另一优选例中，所述的方法包括步骤：向有需要的受试者给药氢气、或含有氢气的混合气体。
在另一优选例中，所述的混合气体中氢气的体积浓度为2-99.9％，优选为20-70％，更优选为40-70％。
在另一优选例中，所述的混合气体中进一步含有选自下组的气体：氧气、氮气、氦气、或其组合。
在另一优选例中，所述的混合气体中氧气的体积浓度为0.1-21％，优选为4-15％，更优选为8-10％。
在另一优选例中，所述的给药包括：以流速1-3L/min向受试者给药氢气，优选1-2L/min，更优选1.5-2L/min。
在另一优选例中，所述的给药包括：以每次≥30min的时长向受试者给药氢气，优选≥45min，更优选≥60min，更优选≥120min。
在另一优选例中，所述的给药包括：以每日≥60min的总时长向受试者给药氢气，优选≥90min，更优选≥120min，更优选≥240min。
在另一优选例中，所述的方法以每周至少4天的频率向受试者给药氢气、优选至少5天、更优选至少6天。在另一优选例中，所述的方法持续至少120天、优选至少180天、更优选至少240天。
在另一优选例中，所述的治疗自闭症包括治疗选自下组的症状：睡眠障碍、交流困难、语言发育不良、注意力不集中、安坐不良、理解力差、不听指令。
在另一优选例中，所述的治疗自闭症包括改善选自下组的发展能力：感官知觉、粗大运动、精细动作、语言与沟通、认知、社会交往、生活自理、情绪行为。
在另一优选例中，所述的情绪行为包括：依附情绪行为、情绪理解、情绪表达与调节、关系与情感、对物品的兴趣、感觉偏好、特殊行为。
在另一优选例中，所述的受试者为人或非人哺乳动物。
在另一优选例中，所述的受试者为成人或儿童，优选为2-12周岁儿童。
在另一优选例中，所述的方法进一步包括步骤：对受试者进行康复训练。
在另一优选例中，所述的方法进一步包括步骤：对受试者的疾病状况进行评估。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例) 中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
下列附图用于说明本发明的具体实施方案，而不用于限定由权利要求书所界定的本发明范围。
图1显示了氢气对自闭症患儿社会交往能力和精细动作改善的实验结果。
图2显示了氢气对自闭症患儿人际关系与情感、特殊行为、对物品的兴趣改善的实验结果。
图3显示了自闭症患儿吸氢半年前后自然状态下面部表情变化。
图4显示了吸氢前后儿童孤独症评定量表(CARS)的比较结果。
图5显示了吸氢前后儿童睡眠习惯问卷(CSHQ)评估结果。
图6显示了吸氢组和对照组自闭症儿童发展能力评估比较。
图7显示了吸氢组和对照组自闭症儿童情绪行为评分比较。
具体实施方式
本发明人经过广泛而深入的研究，首次开发了一种氢气用于治疗自闭症的用途。本发明提供了氢气治疗自闭症的特定装置和方法，其中以特定浓度、特定时长给药氢气，显著地改善了自闭症患儿的行为、动作、情绪等方面症状。在此基础上，完成了本发明。
自闭症(孤独症)
自闭症也称孤独症，其发病机制复杂，本领域尚未有明确的统一认识。目前存在的发病机制学说有：广泛性脑病变、多巴胺学说、氧化应激学说、发育学说、和免疫炎症学说。其中免疫炎症学说测压力和环境刺激触发独特的肥大细胞(Mast Cells,MCs)，继而触发小胶质细胞，导致异常的突触修剪和功能失调的神经元连接。这一过程可能会改变杏仁核中的“恐惧阈值”，并导致一种夸张的“战或逃”反应。应激条件下分泌的促肾上腺皮质激素释放激素(corticotropin releasing hormone,CRH)与环境刺激的结合可能是ASD发病的主要原因。简明地说：压力和环境刺激触发肥大细胞，继而激活小胶质细胞，产生氧化应激，发动炎症免疫反应，触发突触修剪，造成神经元突触失常。
氢
氢是一种新型抗炎、抗氧化剂，人类和动物研究均表明吸入氢气在多种疾病的防治中具有保护作用。氢气治疗ASD的作用机制主要可能表现在以下两方面：(1)消除自由基；(2)防止肥大细胞和/或小胶质细胞的受激活化；神经元树突 棘功能及形态可塑性变化，重新建立和恢复突触联系。
供氢模块
本发明所用的术语“供氢模块”是指在本发明的治疗自闭症的装置中用于将氢气输送给给药模块的模块。供氢模块可以包含氢气发生装置，典型地，其可以包含电解水从而产生氢气的装置，并将产生的氢气输送给给药模块；或者，供氢模块可以不包含氢气发生装置，典型地，其可以连接储氢容器(例如储气罐，或高密度储氢缓释器材，但不限于此)并直接将氢气或含有氢气的混合气体输送给给药模块。
给药模块
本发明所用的术语“给药模块”是指在本发明的治疗自闭症的装置中用于将氢给药至有需要的受试者的模块。在本发明中，氢给药的方法包括但不限于吸入给药、口服给药、经皮给药、皮下给药、注射给药、眼鼻黏膜给药、灌肠给药。
在本发明的一种实施方式中，所述给药模块被配置为：将氢气以气体形式，经鼻导管或者面罩引导至口鼻处、或以非接触式供气到鼻口部(即以一定的患者能够耐受的压力直接将气体“喷向”鼻口部，这样做的目的是解决部分患者的接触敏感问题)，经过自然呼吸方式吸入，经气管、支气管进入肺，由肺过气血屏障进入血液。在该实施方式中，给药模块中以吸入方式向受试者给药氢气的气压设置可以根据患者生理状态、装置应用的地区等因素变化，具体的气压值是本领域技术人员或熟练的医师能够根据上述实际情况合理调整的。典型地，在低海拔地区，给药模块可以被配置为以0.1Mpa(即一个大气压)或更高的气压向受试者给药氢气；在高海拔地区，给药模块可以被配置为以低于0.1Mpa(即一个大气压)的气压向受试者给药氢气，但不限于此。
在本发明的另一种实施方式中，所述给药模块被配置为：氢以溶液方式(例如含氢水或含氢饮料，或含氢离子成分)，经口喝进胃肠道，经消化道吸收进入血液。在这种实施方式中，含氢饮料中的氢可以以选自下组的形式存在：氢分子、氢离子、氢负离子、或其组合。含氢饮料中的氢浓度可以是≥0.5ppm，≥1.0ppm，≥1.6ppm或更高、或其最大溶解度，但不限于此。在这种实施方式中，每次饮入的氢、氢离子、或含氢饮料的量可以根据患者的年龄、体重、病程、疾病严重程度、生理状态等因素变化，并且是或熟练的医师能够根据上述实际情况合理调整的。
在本发明的另一种实施方式中，所述给药模块被配置为：氢气以气浴或水浴方式，通过含氢的气体介质或液体介质，包括含有氢离子成分的液体介质，包括任意比例(例如≥2％、≥20％、≥40％、≥60％、或≥70％、或更高)构成，经过形成笼罩身体的含氢的气体环境(气浴)或含氢的液体环境(水浴)，通过任意 大小面积(例如≥0.1％、≥20％、≥40％、≥60％、或≥80％、或更高)的全身任何部位的皮肤(包括头、手、臂、足、腿、臀、会阴，等)吸收，氢气经过皮肤屏障吸收进入血液。可以使用任意时间长度、任何气体压力下的水浴和/或气浴。
在本发明的一种实施方式中，所述给药模块被配置为：将氢气或含氢的混合气体注射入受试者体内，包括注射单纯氢气或混合任意比例(例如≤40％、≤30％、≤20％、≤10％、≤5％、或更低)的其它气体构成的混合气，或注射以氢气或任何混有氢气的混合气的溶解液，直接注射进入体内包括任何部位或器官(如胸腔、腹腔、盆腔、颅腔、椎管、皮下、气管及支气管、肺泡、胃肠道、中空性器官，等)。在该实施方式中，氢气或混合气体的注射体积和注射速率可以是不超过受试者耐受量和最大容积的任意体积和任意流量。
在本发明的一种实施方式中，所述给药模块被配置为：通过含有氢气成分或氢离子成分的滴液向受试者进行黏膜给药，包括但不限于通过眼结膜、鼻腔黏膜、或其组合。在这种实施方式中，所述的滴液可以被配制为滴眼液、滴鼻液，但不限于此。滴液中的氢浓度可以是≥0.5ppm，≥1.0ppm，≥1.6ppm或更高、或其最大溶解度，但不限于此。
在本发明的一种实施方式中，所述给药模块被配置为：通过含有氢气成分或氢离子成分的洗液及灌洗液向受试者进行灌洗给药，包括但不限于：使用洗手液、洗脸液、浴液、会阴洗液清洗身体、或使用胃肠灌洗液、肛肠灌洗液灌洗。洗液或灌洗液中的氢浓度氢浓度可以是≥0.5ppm，≥1.0ppm，≥1.6ppm或更高、或其最大溶解度，但不限于此。
控制模块
本发明所用的术语“控制模块”是指在本发明的治疗自闭症的装置中用于控制将氢给药至有需要的受试者的时间、时长、间隔、疗程的模块。当以气体组合物形式给药时，还包括控制气体流量、含量、成分。
在本发明中，向受试者给药氢气的给药气体流量、含量、成分、时间和给药间隔可以根据患者的年龄、疾病严重程度、生理状态、依从性、作息时间等因素变化，并且是本领域技术人员或熟练的医师能够根据上述实际情况合理调整的。给药可以在一天的任意时间段进行，可以在白天、夜晚、或白天和夜晚进行。考虑到受试者配合度和作息时间，优选在夜间或受试者休息时进行氢气给药。每次给药的时长可以是任意的，给药间隔也可以是任意的，更长的给药时长和更短的给药间隔有望获得更佳的治疗效果。考虑到受试者配合度和作息时间，优选的给药时长≥30分钟、≥45分钟、≥60分钟、≥90分钟、≥120分钟、或更长时间，但不限于此；优选的给药间隔为8-12小时。
在本发明中，向受试者给药氢气的疗程可以在任意范围，例如几天到几年，并且根据需要治疗的症状、给药方式、患者的年龄、病程、疾病严重程度、生理 状态等因素变化，这是本领域技术人员或熟练的医师能够根据上述实际情况合理调整的。
康复模块
本发明所用的术语“康复模块”是指在本发明的治疗自闭症的装置中用于在氢气治疗同时对受试者进行康复训练的模块。
本发明所用的康复模块以美国德纳瓦州自闭症学习计划发展的沟通训练系统PECS的基本原理为理论指导，集成包括NLP、图像识别、人机交互等多重人工智能技术，藉着循序渐进的训练阶段、分门别类的图画及句子条协助自闭症患者或其他有社交沟通障碍的患者观察和体验沟通的过程。采用基于知识和语言层面的干预主要有图片刺激、互动游戏、手势语辅助等手段，采用回合式操作教学法(DTT)、关键反应训练(PRT)、观点采择干预(PTI)等干预方案激活患儿知识图式，从提高患儿语用叙事、话语理解、会话维持等角度进行语用干预，将患儿习得新知识的任务贯穿于基于患儿已有知识所设定的会话任务中，以改善患儿的言语社交能力。并基于人工参与下的半自主社交辅助智能训练可在会话过程中对患儿的面部表情、手势和眼神提供反应训练，物品模仿、肢体动作模仿、口腔-面部模仿、声音模仿、有意义的情景和声音的使用等对患儿行为的干预产生积极效果，并借助自然语言处理和语义理解等技术模仿人类与患儿进行交流，设置特定语境下的语言任务并识别患儿的交际目的，实现对患儿在话轮转换、修辞性话语、预设理解等语言层面的干预。所述系统可以将人类教育者的反馈信息融入到自身的决策机制中，提供更好的训练方案，形成自闭症患者人工智能自我破茧训练系统。
评估模块
本发明所用的术语“评估模块”是指在本发明的治疗自闭症的装置中用于在氢气治疗前、或治疗后对受试者进行症状评估的模块。
对孤独症儿童进行全面评定是有针对性地指导家长和专业机构对孤独症儿童进行干预和训练的依据。评估模块可基于下述评定方法进行评估，但不限于此：
(1)可用于5岁以下的婴幼儿发育评定的工具和方法，包括美国Cororado大学医学院佛兰肯堡(W.K.Frankkerburg)与多兹(J.B.D0dds)等提出的丹佛发育筛查测验(DDST)、美国Gesell等在1940年编制Gesell发展诊断量表(GDDS)及在此基础上发展出的Brazeton新生儿行为评定量表、美国加州柏克利婴儿研究所贝利等1969年修订版贝利婴儿发育量表(BSID)等；
(2)可用于心理学和智力评定的量表工具和方法，包括韦克斯勒于1955年编制、1981年修订的韦氏成人智力量表(WAIS)、韦氏儿童智力量表第四版
(WISC-IV)和韦氏幼儿智力量表第四版(WPPIS-IV)、美国L.M.Dunn 1965年 提出的皮勃迪图片词汇测试(PPVT)、斯坦福-比奈智力量表(SBIS)、英国瑞文(J.C.Raven)于1938年编制的瑞文测试(SPM)等；
(3)可用于适应能力评定的工具和方法，包括美国文兰训练学校道尔(E.A.Doll)1935年发表并于1984年修订的文兰适应能力量表(VABS)、日本三木安正于1980年修订并由北京大学等机构于1987年完成了国内的标准化工作的婴儿-初中生社会生活能力评定(S-M)、由原湖南医科大学姚树桥、龚耀先于1994年编制的儿童适应性行为评定量表等；
(4)可用于孤独症症状评定的工具和方法，包括美国儿科学会(AAP)早期筛查指南提出三级筛查程序：初级保健筛查、一级筛查和二级筛查；其中初级保健筛查包括使用警示指标筛查、录像分析方法、儿童心理发育问题预警征象筛查表进行筛查；一级筛查包括使用简易婴幼儿孤独症筛查量(CHAT)、简易婴幼儿孤独症筛查量表改良版(M-CHAT)、CHAT-23、孤独症特征早期筛问卷(ESAT)、孤独症行为量表(ABC)进行筛查；二级筛查包括使用儿童孤独症评定量表(CARS)进行筛查；以及使用ASD诊断量表(包括孤独症诊断观察量表(ADOS-G)和孤独症诊断访谈量表修订版(ADI-R))进行孤独症诊断等；
(5)可用于心理教育评定的方法和工具，包括由美国斯考普勒等人编制的心理教育量表(PEP)及经修订的C-PEP、中残联公布的孤独症儿童发展评估量表(试行)等；
(6)可用于评估孤独症治疗效果的方法和工具：包括孤独症治疗评估量表(AETC)等；
(7)可用于其他评估目的的方法和工具：包括用于评估儿童语言和社会能力的美国马克L·桑德伯格编制的(六)语言行为里程碑评估及安置程序(VB-MAPP)、用于儿童感觉统合评定的由美国Anna Jean Ayres设计、并由台湾郑信雄汇总编制的儿童感觉统合能力发展评定量表(感觉统合检核表)。
本发明的主要优点包括：
1)本发明发现，摄入特定浓度和时长的氢气能够使自闭症症状改善，效果显著，时效性强，没有任何毒副作用。
2)本发明提供了多种氢气摄入方式，不影响正常课程训练。
3)本发明的装置或方法可结合人工智能技术，配合教学和康复课程，甚至幼教/小学教学内容，寓教于其中，不耽误正常课业进程，同时，节省人工，并实现教学训练标准化。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold  Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
本发明人进行了氢气吸入干预儿童自闭症患者改善症状的多中心、非随机、开放式平行对照临床研究”项目。中国临床试验注册中心注册号：ChiCTR2100048006。该研究目前入组患儿110名，通过《青少年儿童睡眠习惯问卷》、《CRAS》、《儿童感觉统合测试问卷》、《青少年儿童饮食行为问卷》、《婴幼儿语言发育筛查量表》评估及现场研究人员观察分析治疗结果。
实施例1
本实施例中采用的供氢模块包括电解水产生氢气的机器设备，产生的氢气纯度100％，可以单独供应给患者，也可以混合氧气(氢气浓度在66.6％，氧气33.3％不等，气体流量可调节，调节范围根据儿童患者的体重而定，一般控制在1-3升/分钟；给药模块被配置为经过鼻导管吸入给药；控制模块被配置为每天给药1-2次、每次给药40-90分钟、疗程3-6个月不等；有的可能需要常年用药(氢气、氢离子或其他有效的氢成分)。
利用检测睡眠的“睡眠毯”或腕环、指环等穿戴设备，可以将睡眠状态等发送到各种设定蓝牙连接的智能手机(ios或android)的专用应用程序，从而将睡眠状态可视化，这些数据可以被用作睡眠和健康的标志。利用CRAS量表和本领域通常使用的儿童感觉统合测试问卷，可以客观准确地测试患者的学习能力及行为方式。
结果：氢气吸入显著改善患儿睡眠质量，如加大睡眠深度、安静睡眠延长、起夜次数减少、惊梦夜闹次数减少等；大幅改善行为方式，如安坐时长加长、与老师配合互动、主动参与、行为模仿能力提升、异常行为(自残、哭闹、打闹、自言自语)减少等；交流能力和意愿提高，如呈现主动交流、语言内容与语境相符、语言表达能力、仿说能力、眼神对视增加等；学习能力与水平显著提高，如理解能力、认知能力、学习兴趣等；情感表达和水平提升，如情绪稳定化、丰富化、性格开朗化、攻击行为减少等；饮食习惯改善，如进食规律和多样化，不再挑食、偏食。
图1、2为一病例的儿童发展能力即情绪行为能力量表评估结果。2021年9月该患儿在入组之前进行儿童发展能力评估，吸氢5个月后，2022年1月第二次评定，前后两次评估结果对比，说明该儿童日常生活中行为改善显著改善，显示该儿童在社会交往能力、精细动作和关系和情绪有明显进步。该患儿吸氢半年前后面部表情变化见图3。
实施例2
1.研究方法：
1)研究对象：为2021年11月至2022年2月期间，济南医院(济南市康复医院)康复医学科儿童康复门诊就诊的7+7名ASD的儿童。
2)入组标准：纳入本项临床研究的患儿均符合《精神疾病诊断和统计手册(第五版)》的诊断标准，诊断明确。本研究中所有被调查者的家长均知情同意。
3)分组方法：对照组：同期在院接受常规康复训练的患儿7名，接受常规康复训练，但不接受吸氢；吸氢组：7名入组的患儿，接受常规康复训练的同时，接受吸氢干预。其中吸氢组4名患儿按项目要求完成疗程，3名患儿中途退出。
吸氢方法：吸入方式：鼻导管吸入，鼻导管使用采取单人单管，依次清消。吸入时间：每次连续不间断吸入不小于45分钟，每天累积吸入不少于1.5小时，每周连续5天(工作日)，周末(两天)休息；连续180天。
4)检测指标及方法：采用主观评估工具，包括儿童孤独症评估量表(CARS)、儿童感觉统合能力发展评定量表、儿童睡眠习惯问卷(CSHQ)、孤独症儿童发展能力评估表。
2.研究结果：
1)完成研究周期的4名患儿评估指标前后比较
a)儿童孤独症评定量表(CARS)的结果显示改善率为12.75％(图4)。
b)根据儿童感觉统合能力发展评定量表，其中3名儿童存在感觉统合能力异常。评估结果显示，4项指标中前庭觉改善率为24％,触觉改善率为30％，本体觉改善率为30％，学习能力改善率为15％。
c)根据儿童睡眠习惯问卷(CSHQ)评估结果，睡眠评分大于41分时，说明存在睡眠障碍，根据评估结果，其中三名儿童存在睡眠障碍，干预后睡眠障碍评分下降率为22％(图5)。
2)与同期患儿对照组组间比较
a)孤独症儿童发展能力评估包含八个领域：感官知觉、粗大运动、精细动作、语言与沟通、认知、社会交往、生活自理、情绪行为。对于除情绪行为外的七个领域进行分析进行对照观察，分析结果如图6所示：
i.感官知觉方面：实验组改善率为18％，对照组改善率为16％。
ii.粗大运动方面：实验组改善率为36％，对照组改善率为27％。
iii.精细动作方面：实验组改善率为44％，对照组改善率为18％。
iv.语言与沟通方面：实验组改善率为25％，对照组改善率为14％。
v.认知方面：实验组改善率为22％，对照组改善率为19％。
vi.社会交往方面：实验组改善率为9％，对照组改善率为6％。
vii.生活自理方面：实验组改善率为31％，对照组改善率为25％。
结果显示：吸氢组在感官知觉、粗大运动、精细动作、语言与沟通、认知、社会交往、生活自理方面的改善率比对照组更高，其中精细动作改善最为明显。
b)情绪行为评估包括七个方面，即依附情绪行为、情绪理解、情绪表达与调节、关系与情感、对物品的兴趣、感觉偏好、特殊行为。分析结果如图7所示：
i.在依附情绪行为方面，实验组改善率为63％，对照组改善率为50％。
ii.在情绪理解方面，实验组改善率为56％，对照组改善率为45％。
iii.在情绪表达与调节方面，实验组改善率为31％，对照组改善率为13％。
iv.在关系与情感方面，实验组改善率为41％，对照组改善率为29％。
v.在对物品的兴趣方面，实验组改善率为29％，对照组改善率为19％。
vi.在感觉偏好方面，实验组改善率为49％，对照组改善率为33％。
vii.在特殊行为方面，实验组改善率为58％，对照组改善率为13％。
结果显示：吸氢组对自闭症儿童的情绪行为改善作用非常明显，尤其是在特殊行为方面。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (14)

  1. 一种用于治疗自闭症的装置，其特征在于，所述装置包括：
    1)供氢模块；
    2)给药模块；
    3)控制模块。
  2. 如权利要求1所述的装置，其特征在于，所述的供氢模块被配置为提供氢气、或含有氢气的混合气体。
  3. 如权利要求2所述的装置，其特征在于，所述的混合气体中氢气的体积浓度为2-99.9％，优选为20-70％，更优选为40-70％。
  4. 如权利要求1所述的装置，其特征在于，所述的控制模块被配置为以间隔给药形式向受试者给予氢气。
  5. 如权利要求1所述的装置，其特征在于，所述的控制模块被配置为，以每次≥30min的时长向受试者给药氢气，优选≥45min，更优选≥60min，更优选≥120min。
  6. 如权利要求1所述的装置，其特征在于，所述的装置用于治疗选自下组的症状：睡眠障碍、交流困难、语言发育不良、注意力不集中、安坐不良、理解力差、不听指令。
  7. 如权利要求1所述的装置，其特征在于，所述的装置用于改善选自下组的发展能力：感官知觉、粗大运动、精细动作、语言与沟通、认知、社会交往、生活自理、情绪行为。
  8. 如权利要求7所述的装置，其特征在于，所述的情绪行为包括：依附情绪行为、情绪理解、情绪表达与调节、关系与情感、对物品的兴趣、感觉偏好、特殊行为。
  9. 氢气的用途，其特征在于，用于制备治疗自闭症的药物组合物，所述的药物组合物为气体组合物，并且所述气体组合物中氢气的体积浓度为2-99.9％，优选为20-70％，更优选为40-70％。
  10. 一种药物组合物，其特征在于，所述药物组合物含有浓度为2-99.9％的氢。
  11. 如权利要求10所述的药物组合物，其特征在于，所述药物组合物为气体组合物，并且所述气体组合物含有：
    A)体积浓度为2-99.9％的氢气；
    B)选自下组的其他气体：氧气、氮气、氦气、或其组合。
  12. 如权利要求10所述的药物组合物，其特征在于，所述的氢气的体积浓度为20-70％，更优选为40-70％。
  13. 氢气、或如权利要求10所述的药物组合物，其特征在于，用于在有需要的受试者中治疗自闭症。
  14. 一种在有需要的受试者中治疗自闭症的方法，包括步骤：向有需要的受试者给药氢气。
PCT/CN2023/124070 2022-10-11 2023-10-11 氢气吸入治疗自闭症 WO2024078545A1 (zh)

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Citations (6)

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Publication number Priority date Publication date Assignee Title
CN104394873A (zh) * 2012-05-31 2015-03-04 丸石制药株式会社 全身麻醉药与氢组合而成的药品
JP2019108294A (ja) * 2017-12-19 2019-07-04 ＭｉＺ株式会社 腸内細菌叢の細菌種組成異常の予防又は改善のための組成物
US20200093856A1 (en) * 2018-09-03 2020-03-26 Miz Company Limited Hydrogen-containing composition for ameliorating depressive symptom
CN112004542A (zh) * 2018-02-23 2020-11-27 ＭｉＺ株式会社 用于治疗和/或预防认知障碍或痴呆症的组合物
US20210145865A1 (en) * 2018-06-07 2021-05-20 Osaka University Prophylactic or therapeutic agent for disease induced by oxidative stress
CN116077789A (zh) * 2023-04-07 2023-05-09 深圳尤尼智康医疗科技有限公司 一种兼有吸氢或氧及鼻脑途径给药的脑疾病综合干预系统

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104394873A (zh) * 2012-05-31 2015-03-04 丸石制药株式会社 全身麻醉药与氢组合而成的药品
JP2019108294A (ja) * 2017-12-19 2019-07-04 ＭｉＺ株式会社 腸内細菌叢の細菌種組成異常の予防又は改善のための組成物
CN112004542A (zh) * 2018-02-23 2020-11-27 ＭｉＺ株式会社 用于治疗和/或预防认知障碍或痴呆症的组合物
US20210145865A1 (en) * 2018-06-07 2021-05-20 Osaka University Prophylactic or therapeutic agent for disease induced by oxidative stress
US20200093856A1 (en) * 2018-09-03 2020-03-26 Miz Company Limited Hydrogen-containing composition for ameliorating depressive symptom
CN116077789A (zh) * 2023-04-07 2023-05-09 深圳尤尼智康医疗科技有限公司 一种兼有吸氢或氧及鼻脑途径给药的脑疾病综合干预系统

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