WO2024078544A1 - 氢气吸入干预早产儿促进发育 - Google Patents

氢气吸入干预早产儿促进发育 Download PDF

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Publication number
WO2024078544A1
WO2024078544A1 PCT/CN2023/124066 CN2023124066W WO2024078544A1 WO 2024078544 A1 WO2024078544 A1 WO 2024078544A1 CN 2023124066 W CN2023124066 W CN 2023124066W WO 2024078544 A1 WO2024078544 A1 WO 2024078544A1
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hydrogen
subject
complications
premature
pharmaceutical composition
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PCT/CN2023/124066
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English (en)
French (fr)
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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 WO2024078544A1 publication Critical patent/WO2024078544A1/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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61M13/00—Insufflators for therapeutic or disinfectant purposes, i.e. devices for blowing a gas, powder or vapour into the body
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the field of biomedicine, and in particular to the use of hydrogen for treating complications of premature birth.
  • Inflammation is a determinant of adverse outcomes after preterm birth. Inflammation is important for the development of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP), and is particularly important for intracerebral hemorrhage (ICH) and periventricular leukoaraiosis (PVL). Acute inflammatory processes, especially in survivors of sepsis or NEC, may not resolve well, resulting in persistent inflammation (SI). The main intrinsic risk factors for SI are small gestational age, low birth weight, and sex (male). SI can lead to long-term complications in multiple organ systems including the central nervous system (e.g., cerebral palsy, neurobehavioral disorders), lungs (chronic pulmonary insufficiency of prematurity, CPIP), and the intestine.
  • BPD bronchopulmonary dysplasia
  • NEC necrotizing enterocolitis
  • ROP retinopathy of prematurity
  • Persistent inflammation is associated with prematurity.
  • the immune regulatory system of premature infants is significantly different from that of full-term infants and adults.
  • Preterm infants rely on nonspecific innate immunity, and T cell responses, including T helper cells that negatively regulate inflammation, such as regulatory T cells (Tregs), are weak.
  • proinflammatory cytokines such as (IL-1, IL-6, IL-8, TNF-a) and other inflammation-related proteins (such as C-reactive protein (CRP), intercellular adhesion molecule (ICAM)-1, erythropoietin, ferritin
  • CRP C-reactive protein
  • ICM intercellular adhesion molecule
  • erythropoietin ferritin
  • immunosuppressive elements such as IL-10, S100A8/9, myeloid-derived suppressor cells, Tregs, CD71+ cells.
  • Inflammation is associated with brain diseases in premature infants.
  • the brain of premature infants responds to injury differently from that of full-term newborns or children, and extremely premature infants are highly susceptible to neurodevelopmental disorders and cerebral palsy.
  • Moderately and late preterm infants show a risk of developmental delay at 2 years of age, most notably in the language area, and behavioral problems at 7 years of age.
  • Neuroinflammation in the human brain is mainly caused by three types of cells: microglia, astrocytes, and immune cells from the peripheral system migrate into the brain tissue after blood-brain barrier dysfunction. They produce proinflammatory cytokines, which further induce the activation, migration and proliferation of cytotoxic T cells and natural killer cells, and brain tissue, especially white matter damage, occurs.
  • microglia show abundant cytokine and chemokine receptors, as well as damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs) and extracellular matrix factors.
  • DAMPs damage-associated molecular patterns
  • PAMPs pathogen-associated molecular patterns
  • Activated microglia have the ability to phagocytose, proliferate and migrate to the injured area.
  • DAMPs damage-associated molecular patterns
  • PAMPs pathogen-associated molecular patterns
  • Activated microglia have the ability to phagocytose, proliferate and migrate to the injured area.
  • DAMPs damage-associated molecular patterns
  • PAMPs pathogen-associated molecular patterns
  • extracellular matrix factors extracellular matrix factors.
  • Activated microglia have the ability to phagocytose, proliferate and migrate to the injured area.
  • the concentration of microglia around cystic lesions is increased, indicating that the inflammatory process is not yet complete.
  • Preterm infants with SI have adverse neurodevelopmental outcomes at 18-22 months, including cerebral palsy, reduced Bayley Scales of Infant Development II test scores, reduced intellectual and psychomotor developmental indices, and impaired vision.12 Sustained elevations of acute inflammatory proteins in the first 4 weeks of life increase impairments in various IQ and executive function measures by 2-5 times.
  • Inflammation is associated with lung disease in preterm infants. Continuous prenatal lung tissue development and differentiation of lung architecture sufficient for gas exchange make survival possible for preterm infants. Interruptions in lung development (especially during early development) may interfere with lung maturation, leading to impairment of lung function and structure. Therefore, extremely preterm infants are at high risk for chronic lung disease (CLD), which may be characterized by a BPD “phenotype”. Prematurity is associated with an increased risk of asthma and school-age asthma. Compared with term infants, preterm infants are more likely to be exposed to multiple risk factors for the “asthma phenotype” (cesarean section, infection, and antibiotic use), all of which are associated with a higher risk of SI.
  • CLD chronic lung disease
  • Pulmonary SI is triggered by mechanical ventilation, oxygen inhalation, and infection. Concentrations of proinflammatory cytokines (IL-1 ⁇ , IL-6, IL-8, TNF- ⁇ ) are higher in tracheal aspirates of mechanically ventilated infants. Intraamniotic injection of lipopolysaccharide (LPS) can lead to changes in pulmonary vascular markers and changes in lung structure in preterm infants. In particular, intraamniotic inflammation causes smooth muscle hypertrophy, a decrease in the number of alveoli, and an increase in alveolar volume.
  • LPS lipopolysaccharide
  • VEGF vascular endothelial growth factor
  • IL-1 ⁇ , IL-6, IL-17A elevated levels of inflammatory markers
  • Intrauterine infection enhances the expression of Th17, leading to an uncontrolled inflammatory response.
  • Umbilical cord blood samples from extremely premature infants with BPD have increased levels of Th17 and IL-17+Treg lymphocytes compared with controls.
  • the purpose of the present invention is to provide a therapeutic drug and method for preventing or treating premature complications and improving the development of premature infants.
  • hypoxia inducible factor-1a HIF-1a
  • IL-1a interleukin 1a
  • the pharmaceutical composition is a gaseous composition.
  • the volume concentration of hydrogen in the gas composition is 1-70%, preferably 1-45%, more preferably 1-42%, and more preferably 1-4% (for example, 1%, 1.5%, 2%, 2.5%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.99% or 4%).
  • the gas composition further contains a gas selected from the following group: oxygen, nitrogen, helium, or a combination thereof.
  • the volume concentration of oxygen in the gas composition is 18-21%, preferably 19-20%, and more preferably 20%.
  • the premature birth complications are selected from the following group: developmental failure, respiratory system complications, cardiovascular system complications, digestive system complications, immune system complications or infectious diseases, central nervous system complications, or a combination thereof.
  • the dysplasia includes: bronchial or pulmonary dysplasia, cardiac or vascular dysplasia, esophageal, gastric or intestinal dysplasia, immune function dysplasia, brain or central nervous system dysplasia, peripheral nerve dysplasia, or a combination thereof.
  • the respiratory complication is selected from the group consisting of respiratory distress syndrome, transient tachypnea, pneumonia, apnea and bradycardia, pulmonary interstitial emphysema, or a combination thereof;
  • cardiovascular system complications are selected from the following group: patent ductus arteriosus.
  • the digestive system complications are selected from the group consisting of jaundice, feeding intolerance, necrotizing enterocolitis, or a combination thereof.
  • the immune system complication or infectious disease is selected from the group consisting of infection, sepsis, meningitis, or a combination thereof.
  • the central nervous system complications are selected from the following group: retinopathy of prematurity, intraventricular hemorrhage and post-hemorrhagic hydrocephalus, periventricular cerebral embolism, cerebral palsy, or a combination thereof.
  • the complications of premature birth include: abnormal temperature regulation, anemia, or a combination thereof.
  • the pharmaceutical composition prevents and/or treats premature birth complications by inhibiting HIF-1a and/or inhibiting IL-1a.
  • the subject is a human or non-human mammal.
  • the subject is a non-human mammal, preferably including mice and rats.
  • a device for treating complications of premature birth comprising:
  • the hydrogen supply module is configured to provide hydrogen or a gas composition containing hydrogen.
  • the volume concentration of hydrogen in the gas composition is 1-70%, preferably 1-45%, more preferably 1-42%, and more preferably 1-4% (for example, 1%, 1.5%, 2%, 2.5%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.99% or 4%).
  • the gas composition further contains a gas selected from the following group: oxygen, nitrogen, helium, or a combination thereof.
  • the volume concentration of oxygen in the gas composition is 18-21%, preferably 19-20%, and more preferably 20%.
  • the drug delivery module is configured to deliver the drug by inhalation.
  • the drug administration module is configured to administer hydrogen to the subject at a flow rate of 0.3-1.0 L/min, preferably 0.3-0.6 L/min, and more preferably 0.3 L/min.
  • control module is configured to administer hydrogen to the subject in the form of intermittent administration or continuous administration.
  • control module is configured to administer hydrogen to the subject for a duration of ⁇ 30 min each time, preferably ⁇ 60 min, more preferably ⁇ 120 min, and more preferably ⁇ 180 min or more.
  • 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.
  • a pharmaceutical composition in a third 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 1-70%, preferably 1-45%, more preferably 1-42%, and more preferably 1-4% (e.g. 1%, 1.5%, 2%, 2.5%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.99% or 4%).
  • hydrogen or a pharmaceutical composition as described in the fourth aspect of the present invention is provided for preventing and/or treating complications of premature birth in a subject in need thereof.
  • the pharmaceutical composition is administered by inhalation, oral administration, or transdermal administration.
  • 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.
  • a method for preventing and/or treating complications of premature birth in a subject in need thereof comprising the steps of administering hydrogen to a subject in need thereof.
  • the administration is by inhalation, oral administration, or transdermal administration.
  • the method comprises the step of administering hydrogen or a gas composition containing hydrogen to a subject in need thereof.
  • the volume concentration of hydrogen in the gas composition is 1-70%, preferably 1-45%, more preferably 1-42%, and more preferably 1-4% (for example, 1%, 1.5%, 2%, 2.5%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 3.99% or 4%).
  • the gas composition further contains a gas selected from the following group: oxygen, nitrogen, helium, or a combination thereof.
  • the volume concentration of oxygen in the gas composition is 18-21%, preferably 19-20%, and more preferably 20%.
  • the administration includes: administering hydrogen to the subject at a flow rate of 0.3-1.0 L/min, preferably 0.3-0.6 L/min, more preferably 0.3 L/min.
  • the administration comprises: administering hydrogen to the subject for a period of ⁇ 30 min each time, preferably ⁇ 60 min, more preferably ⁇ 120 min, more preferably ⁇ 180 min or more.
  • 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 comprises administering 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 per week.
  • the method lasts for at least 120 days, preferably at least 180 days, more preferably at least 240 days.
  • FIG1 shows that in an in vitro experiment, in the presence of hydrogen, hypoxia-inducible factor-1a (HIF-1a) in macrophages stimulated by lipopolysaccharide (LPS) is inhibited.
  • HIF-1a hypoxia-inducible factor-1a
  • FIG. 2 shows that in an in vitro experiment, in the presence of hydrogen, interleukin 1a (IL-1a) in macrophages stimulated by lipopolysaccharide (LPS) is inhibited.
  • IL-1a interleukin 1a
  • LPS lipopolysaccharide
  • FIG. 3 shows that in an in vitro experiment, in the presence of hydrogen, HIF-1a in macrophages stimulated by H 2 O 2 is inhibited.
  • FIG. 4 shows that in an in vitro experiment, in the presence of hydrogen, IL-1a in macrophages stimulated by H 2 O 2 was inhibited.
  • FIG5 shows that in an in vivo experiment, hydrogen inhalation can reduce elevated IL-1a and numerous chemokines in the blood of rats after intraperitoneal injection of LPS.
  • FIG6 shows the experimental results of the protective effect of hydrogen on neurological damage in hypoxic rats.
  • Figure 7 shows the behavioral tests of hypoxic rats under hydrogen intervention, the left picture is the water maze test, and the right picture is the space exploration experiment.
  • Figure 8 shows the results of behavioral tests, where Figure 8A shows the escape latency time results of the water maze test; Figure 8B shows the time the rats stayed in the quadrant where the platform was located in the spatial exploration experiment; and Figure 8C shows the movement path of the rats in the spatial exploration experiment, where the lower left quadrant is the quadrant where the platform is located.
  • FIG. 9 shows the morphological structure image of rat neuron synapse.
  • the inventors After extensive and in-depth research, the inventors have developed for the first time a use of hydrogen for the prevention and/or treatment of premature complications.
  • the present invention has experimentally confirmed that hydrogen can inhibit the inflammatory factor IL-1a by inhibiting hypoxia-inducible factor-1a (HIF-1a), thereby inhibiting the occurrence of inflammation, improving premature complications, and promoting the development of premature infants.
  • HIF-1a hypoxia-inducible factor-1a
  • In vivo experiments have confirmed that hydrogen has a significant therapeutic effect on hypoxia-induced neuronal damage commonly seen in premature infants.
  • Clinical trials have confirmed that hydrogen can significantly improve bronchopulmonary dysplasia in premature infants. Based on this, the present invention provides uses, specific devices and methods for treating premature complications with hydrogen. On this basis, the present invention is completed.
  • premature birth used in this application refers to delivery before 37 weeks of gestation.
  • the World Health Organization's definition of premature birth before 37 weeks of gestation includes very premature birth and extreme premature birth (28 weeks of gestation).
  • Preterm infants are at increased risk of death, complications, and neurodevelopmental sequelae.
  • the mortality and morbidity rates of extremely premature infants are very high. Immaturity for gestational age can affect multiple organ systems, and extremely premature infants are at risk of long-term morbidity and adverse neurodevelopmental outcomes, including motor, neurosensory, cognitive, and behavioral deficits.
  • respiratory respiratory distress syndrome, transient tachypnea, bronchopulmonary dysplasia, pneumonia, apnea and bradycardia, pulmonary interstitial emphysema
  • cardiovascular patent ductus arteriosus
  • digestive system jaundice, feeding intolerance, necrotizing enterocolitis
  • immune/infectious infection, sepsis, meningitis
  • central nervous system retinopathy of prematurity, intraventricular hemorrhage, post-hemorrhagic hydrocephalus, periventricular cerebral embolism, cerebral palsy
  • general lesions inability to regulate body temperature, anemia, etc.
  • H 2 Molecular hydrogen
  • H2 As a diatomic molecule with a certain reducing property, H2 has a very strong free diffusion ability and selectively has anti-oxidation, anti-inflammatory, anti-apoptosis and other effects in the body. Hydrogen is not only a gaseous drug with therapeutic effects, but also has certain therapeutic effects as a liquid drug taken orally, intravenously or topically.
  • 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 treatment device 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 gas composition 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
  • compositions and drug delivery modules are provided.
  • the present invention provides a pharmaceutical composition containing hydrogen.
  • the pharmaceutical composition of the present invention can be administered through the drug administration module of the present invention.
  • drug module used in the present invention refers to a module in the therapeutic device 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 pharmaceutical composition may be a gas composition
  • the drug delivery module may be: hydrogen is guided to the nose and mouth in the form of gas through a nasal catheter or a mask, or supplied to the nose and mouth in a non-contact manner, inhaled through natural breathing, enters the lungs through the trachea and bronchi, and enters the blood through 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 vary according to factors such as the patient's physiological state and the area where the device is used, and the specific air pressure value can be reasonably adjusted by a skilled person in the field or a skilled physician according to the above actual situation.
  • 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 administration module is configured to allow the pharmaceutical composition of the present invention to be present in the space where the premature infant is located (typically such as an incubator).
  • the hydrogen-containing pharmaceutical composition of the present invention can be filled in the incubator.
  • the hydrogen concentration in the pharmaceutical composition is preferably ⁇ 4%, subject to the risk of explosion.
  • the drug administration module is configured to directly “spray” the gas to the nose and mouth at a certain pressure that the patient can tolerate, the purpose of which is to solve the problems of contact sensitivity, contact infection, and contact injury of some patients; more importantly, by "direct blowing", a local high-concentration "hydrogen environment” limited to the nose and mouth is created, without having to make the environment where the baby is located, such as the "incubator” as a whole, at a relatively high hydrogen concentration for safety.
  • the hydrogen concentration can be arbitrary (e.g., 1-70%).
  • the pharmaceutical composition of the present invention may contain oxygen, and the concentration of oxygen can be reasonably adjusted by a skilled person or physician according to actual conditions.
  • the conventional oxygen concentration in air may cause oxygen damage, and the concentration of oxygen in the pharmaceutical composition is preferably lower than the oxygen concentration in conventional air (21%), for example, 18%-20%.
  • the pharmaceutical composition and/or drug module may be: hydrogen in the form of a solution (e.g., hydrogen-containing water or a hydrogen-containing beverage, or a hydrogen-containing ion component), which is drunk orally into the gastrointestinal tract and absorbed into the blood through the digestive tract.
  • the hydrogen in the hydrogen-containing beverage may exist 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 consumed 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 pharmaceutical composition and/or drug module may be: hydrogen is in a gas bath or water bath, through a gas medium or liquid medium containing hydrogen (hydrogen molecules, hydrogen ions, etc.), including a liquid medium containing hydrogen ions, including any proportion (for example, ⁇ 1%, ⁇ 20%, ⁇ 40%, ⁇ 60%, or ⁇ 70%, or higher), through forming a hydrogen-containing gas environment (gas bath) or a hydrogen-containing liquid environment (water bath) covering the body, through an area of any size (for example, ⁇ 0.1%, ⁇ 20%, ⁇ 40%, ⁇ 60%, or ⁇ 70%, or higher).
  • Hydrogen is absorbed by the skin of any part of the body (including the head, hands, arms, feet, legs, buttocks, perineum, etc.) and enters the blood through the skin barrier.
  • Water baths and/or gas baths can be used for any length of time and at any gas pressure.
  • the pharmaceutical composition and/or drug module can be: injecting hydrogen or a gas composition containing hydrogen (hydrogen molecules, hydrogen ions, etc.) into the subject's body, including injecting pure hydrogen or a mixed gas composed of other gases in any proportion (e.g., ⁇ 40%, ⁇ 30%, ⁇ 20%, ⁇ 10%, ⁇ 5%, or lower), or injecting a solution of hydrogen or any mixed gas mixed with hydrogen, directly injecting into the body including any part or organ (such as the chest 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 the gas composition can be any volume and any flow rate that does not exceed the subject's tolerance and maximum volume.
  • the pharmaceutical composition and/or drug module may be: mucosal administration to a subject via drops containing hydrogen gas components or hydrogen ion components, including but not limited to via the conjunctiva, nasal mucosa, or a combination thereof.
  • the drops may be formulated as eye drops or nasal drops, but are not limited thereto.
  • the hydrogen concentration in the drops may be ⁇ 0.5ppm, ⁇ 1.0ppm, ⁇ 1.6ppm or higher, or its maximum solubility, but is not limited thereto.
  • the pharmaceutical composition and/or drug module may be: administering the drug to a subject by lavage through a wash or lavage fluid containing hydrogen gas or hydrogen ion components, including but not limited to: washing the body with hand soap, face wash, bath liquid, perineal wash, or lavage with gastrointestinal lavage fluid or anorectal lavage fluid.
  • 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 in the treatment device of the present invention for controlling the time, duration, interval, and course of administration of hydrogen to a subject in need.
  • administration is in the form of a gas composition, it also includes automatic control of the gas flow, content, composition, and flow direction of the gas, and automatic tracking and changing the direction of the patient's mouth and nose to achieve real-time direct blowing.
  • the gas flow rate, content, composition, time and dosing interval of hydrogen administered to the subject can vary according to factors such as the patient's age, disease severity, physiological state, compliance, work and rest schedule, and can be reasonably adjusted by a skilled person in the field or a skilled physician according to the above actual conditions. Administration can be performed at any time of the day, during the day, at night, or during the day and at night. The duration of each administration can be adjusted according to the condition and doctor's advice, and the dosing interval can also be adjusted. Longer administration durations and shorter dosing intervals are expected to achieve better therapeutic effects.
  • the administration duration is ⁇ 30 minutes, ⁇ 45 minutes, ⁇ 60 minutes, ⁇ 90 minutes, ⁇ 120 minutes, ⁇ 180 minutes, or longer, but not limited thereto; the dosing interval is 5-8 hours.
  • hydrogen can be administered to the subject throughout the treatment period (such as placing the subject in an incubator containing hydrogen).
  • the course of hydrogen administration to the subject can be in any range, such as a few days to a few years, and varies according to factors such as the symptoms to be treated, the method of administration, the patient's age, course of disease, severity of disease, physiological state, etc., which can be reasonably adjusted by a skilled person in the field or a skilled physician based on the above actual situation.
  • the present invention has discovered the use of hydrogen in treating premature complications such as bronchopulmonary dysplasia and nervous system dysplasia in premature infants, and provides a method for treating premature complications and improving dysplasia in premature infants;
  • the method of the present invention has no toxic side effects, is highly safe, and has a simple administration method and low cost. It can be flexibly used in conjunction with existing treatment measures and devices such as incubators.
  • Intervention method Add LPS or H 2 O 2 to the cell culture medium, or irradiate with ultraviolet light for toxic stimulation. After a certain period of toxic stimulation, the indicators HIF-1a and IL-1a are detected; after the control group experiences toxic stimulation, a certain amount of hydrogen is introduced into the incubator, and then the corresponding indicators are detected.
  • results As shown in Figure 1-2, in the presence of hydrogen, the hypoxia-inducible factor-1a (HIF-1a) and interleukin-1a (IL-1a) of macrophages stimulated by lipopolysaccharide (LPS) were inhibited. As shown in Figure 3-4, in the presence of hydrogen, the HIF-1a and IL-1a of macrophages stimulated by H 2 O 2 were inhibited.
  • HIF-1a hypoxia-inducible factor-1a
  • IL-1a interleukin-1a
  • mice Normal adult rats were used to construct an inflammatory or immune animal model by intraperitoneal injection of newly prepared LPS saline solution (medical grade) according to a certain ratio based on body weight in a quiet state.
  • the rats were divided into a model group and a model hydrogen administration group; the rats in the model hydrogen administration group were immediately placed in a feeding box containing 42% hydrogen + 21% oxygen (residual nitrogen) after the model was established; blood was collected at set time intervals.
  • Examples 1 and 2 confirm that hydrogen terminates the activation and transcriptional translation of HIF-1a by annihilating intracellular free radicals caused by environmental pressure, thereby relieving the stress on cells, preventing IL-1a from being released and activated from the nucleus, avoiding the production and secretion of chemokines, inhibiting the migration and exudation of immune cells, and preventing the occurrence of tissue inflammation, and has the potential to improve premature symptoms.
  • the preventive and/or therapeutic effects of hydrogen on related diseases and symptoms are further verified.
  • hypoxia-inducible factor-1a HIF-1a
  • hypoxic environment stimulation interferes with the development of rat brain tissue, induces motor dysfunction as well as learning, cognition, visual integration, language processing, attention and social disorders, thereby verifying the role of hydrogen in improving the brain development of newborn rats.
  • Grouping and treatment methods As shown in Figure 6, within 10 hours after birth, the rat pups were divided into three groups: normal control group, hypoxia group, and hypoxia + hydrogen inhalation group. Hypoxia conditions: The oxygen concentration in the hypoxia box controlled by software was reduced from 15% to 3% in 30 minutes and lasted for 5 minutes; the rat pups in the hypoxia + hydrogen inhalation group were immediately put into a hydrogen feeding box, which contained 42% hydrogen + 21% oxygen + 37% nitrogen. After 2 hours, they were breastfed, and this rotation was repeated for 3 consecutive days.
  • the three groups of rats were raised normally, and after reaching adulthood (about 3 months), they underwent electrophysiological testing of brain slices. The results are shown in Figure 7.
  • the spontaneous discharge frequency and electrical signal amplitude of the rats in the hypoxia group were greatly reduced, which was significantly different from the normal control group; the spontaneous discharge frequency and electrical signal amplitude of the rats in the hypoxia + hydrogen inhalation group were greatly increased compared with the hypoxia group, and the difference between the groups was significant; compared with the normal group, there was no significant difference.
  • Golgi-Nissl staining technique shows the whole picture of rat brain tissue neurons.
  • the fine morphology and structure of brain neurons in the hypoxia group rats showed that the dendritic spines became smaller, shorter, sparsely distributed, and the density decreased; the morphology and distribution density of dendritic spines in the brain neurons of the hypoxia + hydrogen inhalation group rats were close to normal, and there was a significant difference compared with the hypoxia group.
  • hypoxia can cause neuronal dysplasia in newborn rats and further affect their behavioral functions.
  • Hydrogen inhalation has a significant improvement effect on neuronal development, which can basically reach normal levels. It is confirmed that hydrogen inhalation has a protective effect on hypoxia-induced neurological dysplasia in premature infants and can promote the development of premature infants.
  • hydrogen has a significant effect on improving bronchopulmonary dysplasia in premature infants.
  • the inventors mainly studied the group of children who were still unable to leave oxygen or ventilator 28 days after premature birth and whose chest X-rays showed bronchopulmonary dysplasia.
  • Hydrogen was used as an auxiliary treatment in addition to conventional treatment. Premature infants were given hydrogen inhalation for 8-9 hours/day, for example, 3 times a day, 3 hours each time. After treatment, it was initially observed that hydrogen can reduce lung inflammatory exudation and reduce the oxygen dependence time of premature infants.

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Abstract

本发明提供了氢气用于预防和/或治疗早产并发症的用途。本发明提供了氢气治疗早产并发症的用途、特定装置和方法，能够通过抑制缺氧诱导因子-1a(HIF-1a)从而抑制炎症因子IL-1a，从而抑制炎症的发生，改善早产并发症，促进早产儿的发育。动物实验证实氢气对早产儿中常见的缺氧诱导的缺氧诱导的神经元损伤具有明显治疗作用，临床试验证实氢气能够显著改善早产儿支气管肺发育不良，从而具有在早产并发症治疗领域的应用前景。

Description

氢气吸入干预早产儿促进发育 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早产并发症的用途。
背景技术
早产后不良结局的决定因素是炎症。炎症对支气管肺发育不良(BPD)、坏死性小肠结肠炎(NEC)和早产儿视网膜病变(ROP)的发展，对脑出血(ICH)和室周白质疏松(PVL)尤为重要。急性炎症过程，特别是在败血症或NEC的幸存者中，可能无法很好地解决，从而导致持续的炎症(SI)。SI的主要内源性危险因素是胎龄小、低出生体重和性别(男)。SI可导致包括中枢神经系统(如脑瘫、神经行为障碍)、肺(慢性早产儿肺功能不全，CPIP)和肠道在内的多个器官系统的长期并发症。
持续性炎症与早产相关。早产儿免疫调节系统与足月婴儿和成人相比显著不同。早产儿依赖于非特异性先天免疫，而T细胞反应，包括负向调节炎症的T辅助细胞，如调节性T细胞(Treg)功能较弱。因此，促炎细胞因子(如(IL-1、IL-6、IL-8、TNF-a)和其他炎症相关蛋白(如c反应蛋白(CRP)、细胞间黏附分子(ICAM)-1、促红细胞生成素、铁蛋白)被免疫抑制元件(如IL-10、S100A8/9、髓源性抑制细胞、Treg、CD71+细胞)过度表达且不够平衡。炎症过程不能在早产儿中、也不能在新生儿脑病存活的足月婴儿中持续。
炎症和早产儿大脑疾病相关。早产儿大脑对损伤的反应不同于足月新生儿或儿童，极早产儿对神经发育障碍和脑瘫的高度易感。中度和晚期早产儿在2岁时表现出发育迟缓的风险，最明显的表现在语言领域，7岁时表现出行为问题。人类大脑中的神经炎症主要由三种细胞类型引起：小胶质细胞、星形胶质细胞和外周系统的免疫细胞在血脑屏障功能障碍后迁移到脑组织。它们产生促炎细胞因子，进一步诱导细胞毒性T细胞和自然杀伤细胞的活化、迁移和增殖，脑组织尤其是白质损伤发生。损伤的程度显然取决于发育阶段，炎症刺激物(如IL-1β)导致新生小鼠比成年小鼠更明显的中性粒细胞迁移、趋化因子产生和更紊乱的血脑屏障。在炎症功能方面，小胶质细胞表现出丰富的细胞因子及趋化因子受体，以及损伤相关分子模式(DAMPs)、病原体相关分子模式(PAMPs)和细胞外基质因子。活化的小胶质细胞具有吞噬、增殖和迁移到损伤区域的能力。在早产儿死后的大脑中，囊性病变周围的小胶质细胞浓度增加，表明炎症过程尚未完成。在围产期缺氧缺血性脑病新生儿的脑脊液中，发现小胶质细胞衍生的炎症标志物水平显著升高，并与新生儿白质损伤导致痉挛型脑瘫有因果关系。
SI早产儿在18-22个月时会出现不良的神经发育结果，包括脑瘫、Bayley婴儿发育量表II测试分数降低、智力和精神运动发育指数降低以及视力受损。在生命的前4周，急性炎症蛋白的持续升高，能增加各种智商(IQ)和执行功能2-5倍的受损。
炎症和早产儿肺疾病相关。持续的产前肺组织发育、肺结构的分化足以进行气体交换，使早产儿存活成为可能。肺的发育中断(特别是在早期发育阶段)可能会干扰肺的成熟，导致肺功能和结构的损害。因此，极早产儿是慢性肺疾病(CLD)的高危人群，其特征可能是BPD“表型”。早产与哮喘和学龄哮喘的风险增加相关。与足月婴儿相比，早产婴儿更有可能暴露于多种“哮喘表型”的危险因素(剖宫产、感染和使用抗生素)，所有这些危险因素都与SI的高风险相关。肺部SI是由机械通气、吸氧和感染触发的。机械通气婴儿气管抽吸物中促炎细胞因子(IL-1β、IL-6、IL-8、TNF-α)浓度较高。羊膜内注射脂多糖(LPS)可导致早产儿肺血管标志物的改变和肺结构的改变。特别是羊膜内炎症引起平滑肌肥大，肺泡数量减少，肺泡体积增加。对分娩前羊膜内注射LPS的胎羔进行的研究显示，LPS对肺血流动力学有影响，尤其是注射LPS到分娩的时间足够长，造成血管重构时，这表明母体免疫激活和肺动脉高压之间存在联系。宫内感染模型进一步显示，肺组织中血管内皮生长因子(VEGF)表达降低(对肺泡形成至关重要)，细胞外基质(胶原)合成增加，炎症标志物(IL-1β,IL-6,IL-17A)水平升高，导致肺炎症损伤。宫内感染增强了Th17的表达，导致无法控制的炎症反应。与对照组相比，患有BPD的极早产儿脐带血样本中Th17和IL-17+Treg淋巴细胞水平增加。
在CLD的发病机制中，炎症过程的早期发作发挥了重要作用，早期细胞因子风暴被证明影响慢性肺部疾病的进展。在一项对早产儿血清细胞因子的纵向分析中，晚期诊断为BPD的婴儿在出生后的最初几周内IL-6、IL-8和粒细胞集落刺激因子(G-CSF)水平升高。利用小鼠BPD模型，出生后第1天通过给予IL-1受体拮抗剂进行早期抗炎干预，在第6天开始治疗时对小鼠BPD有保护作用。
此外，炎症还与早产儿肠道疾病、心血管疾病密切相关。目前，本领域尚未有能够显著预防或治疗早产并发症的手段。因此，本领域需要开发一种预防或治疗早产并发症，改善早产儿发育的治疗药物及方法。
发明内容
本发明的目的就是提供一种预防或治疗早产并发症，改善早产儿发育的治疗药物及方法。
在本发明的第一方面，提供了氢气的用途，用于制备药物组合物，所述药物组合物用于：
1)制备缺氧诱导因子-1a(HIF-1a)抑制剂和/或白介素1a(IL-1a)抑制剂；
2)预防和/或治疗早产并发症。
在另一优选例中，所述的药物组合物为气体组合物。
在另一优选例中，所述的气体组合物中氢气的体积浓度为1-70％，优选为1-45％，更优选为1-42％，更优选为1-4％(例如1％、1.5％、2％、2.5％、3％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、3.8％、3.9％、3.99％或4％)。
在另一优选例中，所述的气体组合物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，所述的气体组合物中氧气的体积浓度为18-21％，优选为19-20％，更优选为20％。
在另一优选例中，所述的早产并发症选自下组：发育不良、呼吸系统并发症、心血管系统并发症、消化系统并发症、免疫系统并发症或传染性疾病、中枢神经系统并发症、或其组合。
在另一优选例中，所述的发育不良包括：支气管或肺发育不良、心脏或血管发育不良、食管，胃或肠道发育不良、免疫功能发育不良、脑或中枢神经发育不良、周围神经发育不良、或其组合。
在另一优选例中，所述的呼吸系统并发症选自下组：呼吸窘迫综合征、瞬态呼吸急促、肺炎、呼吸暂停和心动过缓、肺间质性肺气肿、或其组合；
在另一优选例中，所述的心血管系统并发症选自下组：动脉导管未闭。
在另一优选例中，所述的消化系统并发症选自下组：黄疸、喂养不耐受、坏死性小肠结肠炎、或其组合。
在另一优选例中，所述的免疫系统并发症或传染性疾病选自下组：感染、脓毒症、脑膜炎、或其组合。
在另一优选例中，所述的中枢神经系统并发症选自下组：早产儿视网膜病变、脑室内出血及出血后脑积水、脑室周的脑栓塞、脑瘫、或其组合。
在另一优选例中，所述的早产并发症包括：体温调节异常、贫血、或其组合。
在另一优选例中，所述的药物组合物通过抑制HIF-1a和/或抑制IL-1a预防和/或治疗早产并发症。
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，所述的受试者为非人哺乳动物，较佳地包括小鼠、大鼠。
在本发明的第二方面，提供了一种用于治疗早产并发症的装置，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、或含有氢气的气体组合物。
在另一优选例中，所述的气体组合物中氢气的体积浓度为1-70％，优选为1-45％，更优选为1-42％，更优选为1-4％(例如1％、1.5％、2％、2.5％、3％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、3.8％、3.9％、3.99％或4％)。
在另一优选例中，所述的气体组合物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，所述的气体组合物中氧气的体积浓度为18-21％，优选为19-20％，更优选为20％。
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。
在另一优选例中，所述的给药模块被配置为，以流速0.3-1.0L/min向受试者给药氢气，优选0.3-0.6L/min，更优选0.3L/min。
在另一优选例中，所述的控制模块被配置为以间隔给药、或持续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≥60min，更优选≥120min，更优选≥180min或以上。
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。
在本发明的第三方面，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1-70％，优选为1-45％，更优选为1-42％，更优选为1-4％(例如1％、1.5％、2％、2.5％、3％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、3.8％、3.9％、3.99％或4％)。
在本发明的第四方面，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预防和/或治疗早产并发症。
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，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。
在本发明的第五方面，提供了一种在有需要的受试者中预防和/或治疗早产并发症的方法，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，所述的方法包括步骤：向有需要的受试者给药氢气、或含有氢气的气体组合物。
在另一优选例中，所述的气体组合物中氢气的体积浓度为1-70％，优选为1-45％，更优选为1-42％，更优选为1-4％(例如1％、1.5％、2％、2.5％、3％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、3.8％、3.9％、3.99％或4％)。
在另一优选例中，所述的气体组合物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，所述的气体组合物中氧气的体积浓度为18-21％，优选为19-20％，更优选为20％。
在另一优选例中，所述的给药包括：以流速0.3-1.0L/min向受试者给药氢气，优选0.3-0.6L/min，更优选0.3L/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≥60min，更优选≥120min，更优选≥180min或以上。
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。
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显示了体外实验中，在氢气存在条件下，能够使巨噬细胞受脂多糖(LPS)激发的缺氧诱导因子-1a(HIF-1a)被抑制。
图2显示了体外实验中，在氢气存在条件下，能够使巨噬细胞受脂多糖(LPS)激发的白介素1a(IL-1a)被抑制。
图3显示了体外实验中，在氢气存在条件下，能够使巨噬细胞受H2O2激发的HIF-1a被抑制。
图4显示了体外实验中，在氢气存在条件下，能够使巨噬细胞受H2O2激发的IL-1a被抑制。
图5显示了体内实验中，吸氢能够降低大鼠腹腔注射LPS后血液中升高的IL-1a和众多趋化因子。
图6显示了氢气对缺氧大鼠神经损伤的保护作用的实验结果。
图7显示了氢气干预的缺氧大鼠行为学测试，左图为水迷宫测试，右图为空间探索实验。
图8显示了行为学测试结果，其中图8A显示了水迷宫测试的逃脱潜伏期时间结果；图8B显示了空间探索实验中大鼠在平台所在象限停留的时间；图8C显示了空间探索实验中大鼠的移动路径，其中左下象限为平台所在象限。
图9显示了大鼠神经元突触形态结构图像。
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预防和/或治疗早产并发症的用途。本发明通过实验证实，氢气能够通过抑制缺氧诱导因子-1a(HIF-1a)从而抑制炎症因子IL-1a，从而抑制炎症的发生，改善早产并发症，促进早产儿的发育。体内实验证实氢气对早产儿中常见的缺氧诱导的缺氧诱导的神经元损伤具有明显治疗作用。临床试验证实氢气能够显著改善早产儿支气管肺发育不良。基于此，本发明提供了氢气治疗早产并发症的用途、特定装置和方法。在此基础上，完成了本发明。
早产及其并发症
本申请所用的术语“早产”是指不足37周分娩，世界卫生组织对妊娠37周前早产的定义包括非常早产和极端早产(妊娠28周)。早产婴儿死亡、并发症和神经发育后遗症的风险增加。极早产儿的死亡率与发病率非常高。胎龄不成熟会影响多种器官系统，极早产儿有长期发病和不良神经发育结果的风险，包括运动、神经感觉、认知和行为缺陷。
早产的并发症表现在多方面，呼吸方面：呼吸窘迫综合征、瞬态呼吸急促、支气管肺发育不良、肺炎、呼吸暂停和心动过缓、肺间质性肺气肿；心血管方面：动脉导管未闭；消化系统方面：黄疸、喂养不耐受、坏死性小肠结肠炎；免疫/传染性方面：感染、脓毒症、脑膜炎；中枢神经系统方面：早产儿视网膜病变、脑室内出血、出血后脑积水、室周的脑栓塞、脑瘫；一般性病变：不能调节体温、贫血等。
氢
分子氢(H2)是一种常见的、无色的、无味的、无毒的和非金属的室温气体，历来被认为是一种生物惰性气体。小分子大小使其快速扩散到目标组织和细胞，而生理变量不影响PH、血氧饱和度、温度、血压。
H2作为一种有一定还原性的双原子分子，其具有极强的自由扩散能力，在体内有选择性地抗氧化、抑制炎症反应、抗细胞凋亡等作用。氢不仅是一种有治疗作用的气体药物，而且作为口服、静脉注射或局部服用的液体药物也具有一定的治疗效果。
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气体组合物输送给给药模块。
药物组合物和给药模块
本发明提供了一种含有氢气的药物组合物。本发明的药物组合物可以通过本发明的给药模块给药。
本发明所用的术语“给药模块”是指在本发明的治疗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，所述药物组合物可以是气体组合物，所述给药模块可以是：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，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。
在一些实施方式中，给药模块被配置为使早产患儿所处的空间(典型地如保育箱)中存在本发明的药物组合物，例如可以在保育箱内填充本发明的含氢气的药物组合物。在此类实施方式中，出于安全目的考虑，药物组合物中氢气浓度优选≤4％，以无爆炸风险为准。在另一些实施方式中，所述给药模块被配置为以一定的患者能够耐受的压力直接将气体“喷向”鼻口部，其目的是解决部分患者的接触敏感、接触感染、接触损伤问题；更重要的是通过“直吹”营造一个只限于口鼻部的局部高浓度“氢环境”，而不必使婴儿所处环境比如“保育箱”整体都处于比较高的氢浓度，以策安全。在此类实施方式中，氢气浓度可以是任意的(例如1-70％)。
在本发明的药物组合物中可以含有氧气，氧气的浓度是是本领域技术人员或熟练的医师能够根据实际情况合理调整的。例如，对于极端早产儿，考虑到其器官发育程度非常低，常规的空气氧浓度可能造成氧损伤，氧气在药物组合物中的浓度优选为低于常规空气中氧浓度(21％)，例如18％-20％。
在本发明的另一种实施方式中，所述药物组合物和/或药模块可以是：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，所述药物组合物和/或药模块可以是：氢以气浴或水浴方式，通过含氢(氢分子、氢离子等)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≥1％、≥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，所述药物组合物和/或药模块可以是：将氢或含氢(氢分子、氢离子等)的气体组合物注射入受试者体内，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，氢气或气体组合物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，所述药物组合物和/或药模块可以是：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，所述药物组合物和/或药模块可以是：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，还包括自动控制气体流量、含量、成分、气体的流向、自动追踪并变向跟踪患者口鼻部实现实时直吹。
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。每次给药的时长可以是根据病情和医嘱进行调节的，给药间隔也可以是调节的，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。在一些实施方式中，给药时长≥30分钟、≥45分钟、≥60分钟、≥90分钟、≥120分钟、≥180分钟、 或更长时间，但不限于此；给药间隔为5-8小时。在另一些实施方式中，可以在治疗期间全程向受试者给药氢气(如使受试者处于含氢气的保育箱中)。
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。
本发明的主要优点包括：
1)本发明发现了氢气在治疗早产儿支气管肺发育不良、神经系统发育不良等早产并发症中的用途，提供了一种治疗早产并发症、改善早产儿发育不良的方法；
2)本发明的方法无毒副作用，安全性高，且给药方式简单、成本较低，可与现有治疗措施及保育箱等装置灵活配合使用。
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。
实施例1氢气的体外HIF-1a炎症通路抑制效果
既往研究已证实炎症与早产并发症密切相关。在本实施例中，炎症氢气对各种激发因素诱导的炎症反应的抑制效果。
实验方法：将RAW264.7细胞复苏，冻存细胞取出后37℃速溶，取15ml离心管，加入10ml含血清培养基，将冻存管中液体(通常为1.5ml)加入离心管中，混匀，1200转常温离心5min，去掉上清，加入5ml含血清培养基，轻吹制成细胞悬液，加入到培养瓶中。新复苏的细胞避免经常扰动。换液，把培养基吸出，再加入新的培养基。培养条件：DMEM-H 10％FBS；传代方法：1:3-1:6传代。2-3天换液1次。用细胞括刀将细胞括成单细胞后进行传代。
干预方法：在细胞培养液中加入LPS、或H2O2、或照射紫外线进行毒性刺激。经过一定时间的毒性刺激后，检测指标HIF-1a及IL-1a；对照组在经历毒性刺激后，在培养箱中通入一定量的氢气，再检测相应的指标。
结果：如图1-2所示，在氢气存在条件下，能够使巨噬细胞受脂多糖(LPS)激发的缺氧诱导因子-1a(HIF-1a)和白介素1a(IL-1a)被抑制。如图3-4所示，在氢气存在条件下，能够使巨噬细胞受H2O2激发的HIF-1a和IL-1a被抑制。
实施例2氢气的体内HIF-1a炎症通路抑制效果
实验方法：使用正常成年大鼠，在安静状态下根据体重按照一定配比腹腔注射新配置好的LPS生理盐水溶液(医用级)，构建大鼠炎症或免疫动物模型。分组为模型组及模型给氢组；模型给氢组大鼠在模型构成后立即投入含有42％氢气+21％氧气(余氮气)的饲养箱内；按照设定的时间间隔采血。
结果：大鼠腹腔注射LPS后，血液中IL-1a和趋化因子瞬时升高，吸氢后，这种变化受到抑制。
实施例1、2的结果证实，氢气通过湮灭环境压力造成的细胞内自由基，终止了HIF-1a的激活与转录翻译，从而解除了对细胞的胁迫，IL-1a不被从核内解脱和活化，避免了趋化因子的产生与分泌，抑制了免疫细胞的游走渗出，阻止了组织炎症的发生，具有改善早产症状的潜力。在以下实施例中，进一步验证氢气对相关疾病和症状的预防和/或治疗效果。
实施例3吸氢改善缺氧新生大鼠的脑部发育
除早产儿本身免疫条件易发生持续性炎症外，早产儿由于支气管肺发育不良，易产生缺氧，低氧也是造成组织中缺氧诱导因子-1a(HIF-1a)上调的重要刺激因素，进一步加重其炎症反应。
在本实施例中，通过缺氧环境刺激，干扰大鼠脑组织发育，诱导运动功能障碍以及学习、认知、视觉整合、语言处理、注意力和社交障碍，从而验证氢气改善新生大鼠脑部发育的作用。
分组及处理方法：如图6所示，大鼠仔鼠出生后10小时内，分成三组，正常对照组、缺氧组、缺氧+吸氢组。缺氧条件：软件控制的低氧箱内氧气浓度由15％下降并到3％控制在30分钟，并持续5分钟；缺氧+吸氢组大鼠仔鼠随即投入氢气饲养箱，此箱内氢气含量42％+氧气21％+37％氮气，2小时后，接受哺乳，如此轮转，连续3天。
3.1神经元放电频率测试
三组仔鼠正常饲养，至成年(3月左右)后，接受脑片电生理检测。结果如图7所示，缺氧组大鼠神经元自发放电频率大幅减少、电信号振幅大幅降低，与正常对照组差异显著；缺氧+吸氢组大鼠神经元自发放电频率、电信号振幅比较缺氧组大幅度提高，组间差异显著；与正常组之间比较，无显著差异。
3.2行为学测试
三组仔鼠正常饲养，至成年(3月左右)后，按常规方法进行MORRIS水迷宫学习记忆行为学测试和空间探索实验(图7)。结果如图8所示：定位航行实验中，缺氧组大鼠寻找逃生平台潜伏期延长，缺氧+吸氢组大鼠潜伏期缩短至接近正 常组，与缺氧组比较差异显著(图8A)；空间探索实验中，缺氧组大鼠平台所在象限探索时间占比显著减少，缺氧+吸氢组大鼠平台所在象限探索时间占比显著增加，与缺氧组相比差异显著(图8B、8C)。
3.3神经元形态结构比较
如图9所示，高尔基尼氏染色技术显示大鼠脑组织神经元全貌。缺氧组大鼠脑神经元微细形态结构比较正常组大鼠，树突棘形态变得细小、短缩，分布稀疏，密度降低；缺氧+吸氢组大鼠脑神经元树突棘形态及分布密度接近正常，与缺氧组比较，差异显著。
该实施例证实，缺氧能够在新生大鼠中导致神经元发育不良，并进一步影响其行为功能。吸氢对于神经元发育具有明显改善作用，基本能够达到正常水平。证实吸氢对于早产儿缺氧诱导的神经发育不良具有保护作用，能够促进早产儿发育。
实施例4临床研究
临床发现，氢气改善早产儿支气管肺发育不良具有显著效果。本发明人主要针对在早产出生后28天仍无法离开氧气或者呼吸机的、胸片提示支气管肺发育不良的患儿群体进行研究，将氢气作为常规治疗外的辅助治疗，对早产儿给予氢气吸入8-9小时/天，例如每天3次，每次3小时。治疗后初步观察到氢气可以减轻肺炎症渗出，减少早产儿赖氧时间。
为进一步确认氢气治疗早产并发症、促进发育的功效，本发明人于2021年1月，在充分的学术论证和知情同意的基础上，于山东省泰安市泰安中心医院开始针对部分早产儿进行预试验，在小范围小样本得到的安全性及有效性检验后，研究观察分析。
临床结果显示，吸氢后的早产儿，症状显著改善；住院日期缩短；脱离呼吸辅助机器的时间提前。呼吸浅快、呼吸暂停、呼吸窘迫病情减轻；心率、血压稳定；进奶量增加，溢奶、呕吐减轻；吸吮、觅食、握持、拥抱反射增强；体温调节功能提高。
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 (16)

  1. 氢气的用途，其特征在于，用于制备药物组合物，所述药物组合物用于：
    1)制备缺氧诱导因子-1a(HIF-1a)抑制剂和/或白介素1a(IL-1a)抑制剂；
    2)预防和/或治疗早产并发症。
  2. 如权利要求1所述的用途，其特征在于，所述的药物组合物为气体组合物。
  3. 如权利要求1所述的用途，其特征在于，所述的气体组合物中氢气的体积浓度为1-70％，优选为1-45％，更优选为1-42％，更优选为1-4％。
  4. 如权利要求1所述的用途，其特征在于，所述的气体组合物中进一步含有选自下组的气体：氧气、氮气、氦气、或其组合。
  5. 如权利要求1所述的用途，其特征在于，所述的气体组合物中氧气的体积浓度为18-21％，优选为19-20％，更优选为20％。
  6. 如权利要求1所述的用途，其特征在于，所述的早产并发症选自下组：支气管或肺发育不良、脑或中枢神经发育不良、心脏或血管发育不良、食管，胃或肠道发育不良、免疫功能发育不良、周围神经发育不良、或其组合。
  7. 如权利要求1所述的用途，其特征在于，所述的药物组合物通过抑制HIF-1a和/或抑制IL-1a预防和/或治疗早产并发症。
  8. 一种用于治疗早产并发症的装置，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。
  9. 如权利要求8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、或含有氢气的气体组合物，所述的气体组合物中氢气的体积浓度为1-70％，优选为1-45％，更优选为1-42％，更优选为1-4％。
  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. 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预防和/或治疗早产并发症。
  12. 一种在有需要的受试者中预防和/或治疗早产并发症的方法，其特征在于，包括步骤：向有需要的受试者给药氢气。
  13. 如权利要求12所述的方法，其特征在于，所述的给药包括：以流速0.3-1.0L/min向受试者给药氢气，优选0.3-0.6L/min，更优选0.3L/min。
  14. 如权利要求12所述的方法，其特征在于，所述的给药包括：以每次≥30min的时长向受试者给药氢气，优选≥60min，更优选≥120min，更优选≥180min或以上。
  15. 如权利要求12所述的方法，其特征在于，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。
  16. 如权利要求12所述的方法，其特征在于，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。
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