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WO2019154220A1 - Utilisation de bêta-nicotinamide mononucléotide ou d'un précurseur de ce dernier dans la préparation d'un médicament ou d'un produit de soins de santé destiné au traitement ou au soulagement d'un trouble respiratoire ou d'une maladie respiratoire - Google Patents

Utilisation de bêta-nicotinamide mononucléotide ou d'un précurseur de ce dernier dans la préparation d'un médicament ou d'un produit de soins de santé destiné au traitement ou au soulagement d'un trouble respiratoire ou d'une maladie respiratoire Download PDF

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WO2019154220A1
WO2019154220A1 PCT/CN2019/073917 CN2019073917W WO2019154220A1 WO 2019154220 A1 WO2019154220 A1 WO 2019154220A1 CN 2019073917 W CN2019073917 W CN 2019073917W WO 2019154220 A1 WO2019154220 A1 WO 2019154220A1
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disease
lung
preparation
particles
precursor
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魏霞蔚
魏于全
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Sichuan University
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Sichuan University
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to the use of ⁇ -nicotinamide mononucleotide or a precursor thereof for preparing a medicament or a health care product for treating or alleviating respiratory disorders or diseases.
  • Nicotinamide nucleotides are also called ⁇ -Nicotinamide Mononucleotide ( ⁇ -NMN or NMN) or nicotinamide mononucleotide or nicotinamide nucleotides.
  • ⁇ -NMN or NMN ⁇ -Nicotinamide Mononucleotide
  • nicotinamide mononucleotide or nicotinamide nucleotides The molecular formula is as follows:
  • Nicotinamide nucleotides are important products of nicotinamide phosphoribosyltransferase (NAMPT) regulation reaction, and key intermediates in NAD+ synthesis process play an important role in cell energy metabolism.
  • Nicotinamide Riboside (NR) is a precursor of ⁇ -nicotinamide mononucleotide (NMN).
  • NAD+ nicotinamide adenine dinucleotide
  • NAD+ nicotinamide adenine dinucleotide
  • NR NR
  • NPN ⁇ -Nicotinamide Mononucleotide
  • NAMPT nicotinamide phosphoribosyltransferase
  • NAD+ NAD+ precursors
  • NMN NAD+ precursors
  • NMN NAD+ levels in tissues and delay physiological function decline: including inhibition of weight gain, enhancement of energy metabolism, improvement of sensitivity to insulin, improvement of vision, etc.
  • NMN was found to improve aging Causes impaired glucose tolerance in type 2 diabetes; prevents glaucoma in the elderly; NR increases the number of muscle stem cells and exercise capacity.
  • Chronic obstructive pulmonary disease is a chronic progressive disease caused by chronic inflammation and destruction of the airways and lung parenchyma, and is usually associated with smoking or prolonged exposure to other harmful microparticles and gases. Chronic obstructive pulmonary disease is blocked by airways and comes from The reduction in maximum expiratory flow of the lungs is a major feature. The disease is characterized by a progressive airflow block that is sometimes partially reversed by administration of a bronchodilator. Typical symptoms are coughing, excessive spasm, and difficulty breathing.
  • the term chronic obstructive pulmonary disease encompasses a series of pulmonary activity processes and is a chronic bronchitis and/or emphysema characterized by airflow obstruction.
  • chronic obstructive pulmonary disease is very limited, and more frequent symptomatic treatment, often using bronchodilators. There are no measures to fundamentally alleviate the progression of chronic obstructive pulmonary disease. Therefore, there is an urgent need to develop new drugs for the treatment of chronic obstructive pulmonary disease.
  • the current therapeutic drugs for chronic obstructive pulmonary disease are mainly used for symptomatic treatment, and there are no drugs or treatments that can change the underlying inflammation or change the progression of the disease.
  • Particulate matter refers to a general term for solid and liquid particulate matter floating in the air, and has a particle size ranging from about 0.1 to 100 micrometers. Inhalable particulate matter can be inhaled by the human body and deposited in the respiratory tract, alveoli, etc. to cause disease. Particles with a particle size below 10 microns are often referred to as respirable particles, also known as PM10. The smaller the diameter of the particles, the deeper the area into the respiratory tract. Particles of 10 micron diameter are usually deposited in the upper respiratory tract, 5 micron in diameter can enter the deep part of the respiratory tract, and below 2 microns can penetrate 100% into the bronchioles and alveoli.
  • respirable particulates Common chemical constituents in respirable particulates are particulate elemental carbon (PEC, sometimes referred to as carbon black), inorganic ions, trace elements, and organic compounds, and sometimes inhalable particulate matter also adsorbs pathogenic microorganisms (viruses and bacteria).
  • PEC particulate elemental carbon
  • Inhalable particulate matter enters the body primarily through the respiratory tract, and a small portion can enter the body through the digestive tract or skin. After the inhalable particles are deposited in the human respiratory tract, their clearance, retention and transfer are related to their particle size and deposition location. In general, the smaller the particle size and the further the deposition site, the longer the removal time required, and the easier it is to stay in the human body, the easier it is to transfer toxic substances to other parts of the body.
  • Carbon black is one of the main air pollutants in China. It is harmful to humans after inhalation. Combustion is the main source of this particulate matter. Due to huge energy consumption, eastern and northern China is the most serious in the world. One of the aerosol contaminated sites. Carbon black is also an important and typical component of respirable particulate matter in many areas. After CB enters the respiratory tract, most of the particles are cleared by mucociliary movement. However, ultrafine particles are able to penetrate the blood gas barrier and shift to the lungs and systemic circulation.
  • CB reactive oxygen species
  • ⁇ -Nicotinamide Mononucleotide NPN
  • NR ⁇ -nicotinamide Riboside
  • the technical problem to be solved by the present invention is to provide a new alternative for preparing drugs or health care products for treating or alleviating respiratory disorders or diseases.
  • the technical solution of the present invention to solve the above technical problems is to provide a use of a ⁇ -nicotinamide mononucleotide or a precursor thereof for the preparation of a medicament or a health care product for treating or alleviating a respiratory disorder or disease.
  • the ⁇ -nicotinamide mononucleotide precursor is ⁇ -nicotinamide ribose.
  • the respiratory disorder or disease is a pulmonary disease.
  • the lung disease is a chronic obstructive pulmonary disease.
  • the lung disease is a lung disease caused by inhalable particles in the air.
  • the lung disease caused by the inhalable particles in the air is lung damage caused by inhalable particles in the air.
  • the lung injury is aging of pulmonary macrophages.
  • the air inhalable particles are at least one of PM10 particles, PM2.5 particles or carbon black particles.
  • the drug is prepared by adding a pharmaceutically acceptable excipient or an auxiliary component to the ⁇ -nicotinamide mononucleotide or a precursor thereof as an active ingredient.
  • the preparation is an oral preparation.
  • the oral preparation per unit contains ⁇ -nicotinamide mononucleotide or a precursor thereof of 25-1000 mg.
  • the oral preparation includes a solid preparation, a liquid preparation or a suspension preparation.
  • the solid preparation includes a capsule, a tablet, a pill, a powder or a granule.
  • the liquid preparation includes an emulsion, a solution, a suspension, a syrup or an elixir.
  • the invention also provides a method of treating or ameliorating a respiratory disorder or disease comprising the step of administering to a subject having a respiratory disorder or disease an effective amount of a beta-nicotinamide mononucleotide or a precursor thereof.
  • the ⁇ -nicotinamide mononucleotide precursor is ⁇ -nicotinamide ribose.
  • the respiratory disorder or disease is a pulmonary disease.
  • the lung disease is chronic obstructive pulmonary disease.
  • the lung disease is a lung disease caused by inhalable particles in the air.
  • the lung disease caused by the inhalable particles in the air is lung damage caused by inhalable particles in the air.
  • the lung injury caused by the inhalable particles in the air is aging of the pulmonary macrophage.
  • the inhalable particles are at least one of PM10 particles, PM2.5 particles or carbon black particles.
  • the administration route in the method is oral administration.
  • the effective amount of the ⁇ -nicotinamide mononucleotide or a precursor thereof is 50 to 1000 mg/d.
  • the oral administration dosage form comprises a solid preparation, a liquid preparation or a suspension preparation.
  • the solid preparation includes a capsule, a tablet, a pill, a powder or a granule.
  • the liquid preparation includes an emulsion, a solution, a suspension, a syrup or an elixir.
  • the present invention creatively provides the use of a beta-nicotinamide mononucleotide and its precursor beta-nicotinamide ribose in the manufacture of a medicament or nutraceutical for treating or ameliorating a respiratory disorder or disease.
  • ⁇ -nicotinamide mononucleotide and its precursor can effectively treat or alleviate respiratory disorders or diseases, such as chronic obstructive pulmonary disease, and reduce the occurrence of PM10 particles, PM2.5 particles or carbon black particles.
  • the aging of lung macrophages which provides a clinical drug for the relief and recovery of lung injury caused by chronic obstructive pulmonary disease as a representative of lung diseases and respirable particles represented by nanocarbon particles. New effective options.
  • Figure 1 shows the results of PPE-induced chronic obstructive pulmonary disease in mice.
  • Figures 2A and 2B show the therapeutic effects of PPE on chronic obstructive pulmonary disease in mice.
  • Figure 3 shows the results of mouse lung weight.
  • Figure 4 shows the results of lung tissue staining.
  • Figure 5 shows the effect of NMN on lung neutrophils in mice with chronic obstructive pulmonary disease.
  • Figure 6 shows the effect of NMN on the proportion of lung mononuclear cells in mice with chronic obstructive pulmonary disease.
  • Figure 7 shows a lung tissue-specific lipase staining pattern.
  • Figure 8 shows the levels of p16 and p21 proteins in lung lavage cells and lung tissues of PPE-induced chronic obstructive pulmonary disease model mice.
  • Figure 9 shows the effect of NMN on the expression of p16 and p21 protein in mice with chronic obstructive pulmonary disease; a is lung lavage cell protein, and b is lung tissue protein.
  • Figure 10 is a diagram showing the immunohistochemical staining of lung tissue in a mouse model of chronic obstructive pulmonary disease.
  • Figure 11 shows qPCR results in lung tissue of mice with chronic obstructive pulmonary disease.
  • Figure 12 shows the lung function of mice with chronic obstructive pulmonary disease model.
  • Figure A shows the statistical graph of quasi-static lung compliance (Cchord).
  • Cfvc50 is the lung compliance when 50% of the vital capacity is reached
  • CP0 is the pressure. Lung compliance at 0 o'clock.
  • Figure 13 shows the lung FEV100 values of mice in the chronic obstructive pulmonary disease model group.
  • Figures 14A-14E show the results of lung MMEF, PEF, IC, ERV, FVC values in mice with chronic obstructive pulmonary disease model group.
  • Figures 15A and 15B show the expression of ⁇ h2ax in alveolar macrophages, which is shown as the percentage (%) of stained cells (**p ⁇ 0.01).
  • FIG. 16A, 16B shows the lung cells The expression is shown as the percentage (%) of stained cells. (**p ⁇ 0.01).
  • 17A and 17B show changes in macrophage morphogenesis caused by CBNPs (Fig. is cell diameter um, *p ⁇ 0.05, **p ⁇ 0.01 compared with control group).
  • Figure 18 shows the changes in intracellular aging-related protein levels of macrophages treated with CBNPs.
  • Figure 19 shows the changes in intracellular ROS levels of macrophages treated with different concentrations of CBNPs. Treatment of peritoneal macrophages for 1 week) (****p ⁇ 0.0001).
  • the present invention provides a use of a ⁇ -nicotinamide mononucleotide or a precursor thereof for the preparation of a medicament or a health care product for treating or ameliorating a respiratory disorder or disease.
  • the ⁇ -nicotinamide mononucleotide precursor is ⁇ -nicotinamide ribose.
  • the respiratory disorder or disease is a pulmonary disease; further, the pulmonary disease is a chronic obstructive pulmonary disease.
  • the lung disease is a lung disease caused by inhalable particles in the air. Further, the lung disease caused by the inhalable particles in the air is lung damage caused by inhalable particles in the air.
  • the lung injury is aging of pulmonary macrophages.
  • the air inhalable particles are at least one of PM10 particles, PM2.5 particles or carbon black particles.
  • the PM10 particles refer to particulate matter having a particle size below 10 microns in air.
  • the PM2.5 particles refer to particulate matter having a particle size below 2.5 microns in air.
  • the drug is prepared by adding a pharmaceutically acceptable excipient or an auxiliary component to the ⁇ -nicotinamide mononucleotide or a precursor thereof as an active ingredient.
  • the preparation is an oral preparation.
  • the oral preparation per unit contains ⁇ -nicotinamide mononucleotide or a precursor thereof of 25-1000 mg.
  • the oral preparation includes a solid preparation, a liquid preparation or a suspension preparation.
  • the solid preparation includes a capsule, a tablet, a pill, a powder or a granule.
  • the liquid preparation includes an emulsion, a solution, a suspension, a syrup or an elixir.
  • the invention also provides a method of treating or ameliorating a respiratory disorder or disease comprising the step of administering to a subject having a respiratory disorder or disease an effective amount of a beta-nicotinamide mononucleotide or a precursor thereof.
  • the ⁇ -nicotinamide mononucleotide precursor is ⁇ -nicotinamide ribose.
  • the respiratory disorder or disease is a pulmonary disease.
  • the lung disease is chronic obstructive pulmonary disease.
  • the lung disease is a lung disease caused by inhalable particles in the air.
  • the lung disease caused by the inhalable particles in the air is lung damage caused by inhalable particles in the air.
  • the lung injury caused by the inhalable particles in the air is aging of the pulmonary macrophage.
  • the inhalable particles are at least one of PM10 particles, PM2.5 particles or carbon black particles.
  • the administration route in the method is oral administration.
  • the effective amount of the ⁇ -nicotinamide mononucleotide or a precursor thereof is 50 to 1000 mg/d.
  • the oral administration dosage form comprises a solid preparation, a liquid preparation or a suspension preparation.
  • the solid preparation includes a capsule, a tablet, a pill, a powder or a granule.
  • the liquid preparation includes an emulsion, a solution, a suspension, a syrup or an elixir.
  • subject in the present invention means any organism to which a drug according to the present invention can be administered, for example, for the purpose of experimentation, diagnosis, prevention, and/or treatment.
  • Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans).
  • Subjects may seek treatment or necessary treatment, need treatment, receive treatment, receive treatment in the future, or be treated by a trained professional for a particular disease or condition.
  • treating means therapeutic treatment and prophylactic or preventative measures, the object of which is to prevent or delay (reduce) an unwanted physiological condition, disorder or disease, or to obtain a beneficial or desired clinical condition. result.
  • Clinical outcomes that are beneficial or desirable include, but are not limited to, relief of symptoms; amelioration of the extent of the condition, disorder, or disease; stability of the condition, disorder, or state of the disease (ie, no deterioration); condition, disorder, or Delay or slowing of the onset of disease progression; improvement or relief of a condition, disorder, or disease state (whether partial or total), whether detectable or undetectable; improvement of at least one measurable human physiological parameter The parameter need not be discernible by the patient; or an illness, an improvement, or an improvement in the condition, disorder, or disease. Treatment involves causing a clinically significant response without excessive levels of side effects.
  • ⁇ -nicotinamide mononucleotide of the present invention or a precursor thereof, such as ⁇ -nicotinamide ribose is not particularly limited in the treatment or relief of pulmonary diseases, and representative administration methods include, but are not limited to, oral administration, intravenous administration. Parenteral administration and topical administration, intramuscular or subcutaneous.
  • Solid preparations for the preparation of oral preparations include capsules, tablets, pills, powders or granules.
  • the ⁇ -nicotinamide mononucleotide or a precursor thereof is used as an active ingredient, and is mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or the following Ingredient mixing: (a) filler or compatibilizer, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binder, for example, hydroxymethylcellulose, alginate, gelatin, polyethylene (i) a humectant, for example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and carbonic acid (e) a slow solvent such as paraffin; (f) an absorption accelerator such as a quaternary amine compound; (a) fill
  • Solid preparations such as tablets, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner.
  • liquid preparations include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • liquid dosage forms may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfumes.
  • the suspending agent of the present invention may further comprise ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum methoxide or agar.
  • compositions for parenteral injection can also be prepared.
  • a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and sterile powder for reconstitution into a sterile injectable solution or dispersion may be employed.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the pharmaceutically acceptable excipient or auxiliary component of the present invention means a substance which is contained in a dosage form other than the active ingredient. It may refer to at least one of a carrier, carrier, diluent or adjuvant species that is generally chemically or physically compatible with the other components that make up a pharmaceutical dosage form and that is physiologically compatible with the receptor.
  • the pharmaceutically acceptable auxiliary component of the present invention has certain physiological activity, but the addition of the component does not change the dominant position of the above-mentioned pharmaceutical composition in the course of disease treatment, but only plays an auxiliary effect, and these auxiliary effects are only
  • the use of known activity of this component is an adjuvant treatment that is commonly used in the medical field. It is still within the scope of the present invention to use the above auxiliary ingredients in combination with the pharmaceutical composition of the present invention.
  • Example 1 Therapeutic effect of NMN and NR on chronic obstructive pulmonary disease
  • mice Observe for 5 to 10 minutes, pay attention to the recovery status and respiratory status of the mice.
  • NMN nicotinamide mononucleotide
  • PBS 0.10 g/mL
  • gavage 200 ⁇ L/only (20 mg/day*day).
  • the treatment group was given the above oral NMN drug, the control group and the model group were given an equal volume of PBS.
  • the administration time was 30 days.
  • mice were weighed and deeply anesthetized by intraperitoneal injection of pentobarbital (90 mg/kg) and pancuronium bromide (0.5 mg/kg).
  • the trachea was dissected, the trachea was inserted into the cannula, and the trachea was tied to the cannula with a suture.
  • the cannula was attached to a computer-controlled small animal ventilator, and the lung function related parameters of the mouse were determined, and each parameter was measured three times. After the assay was completed, the mice were removed and the lungs were removed for paraffin sectioning, protein extraction and qPCR.
  • mice in which PPE induces chronic obstructive pulmonary disease are treated with ⁇ -nicotinamide mononucleotide (NMN).
  • NNN ⁇ -nicotinamide mononucleotide
  • FIG. 3 shows that the PPE group of the chronic obstructive pulmonary disease model was significantly increased compared with the PBS control group, and the oral administration of NMN at the same time as PPE administration significantly reduced the lung weight of the mice. *P ⁇ 0.05, **P ⁇ 0.01.
  • mice were sacrificed after anesthesia, the trachea was dissected in the neck, and the lungs were lavaged 3 times with 0.6 mL of 0.9% sodium chloride.
  • the lavage fluid was combined, the lavage fluid was centrifuged, 1200 rpm, 5 min, and the supernatant was collected, dispensed, and stored frozen at -80 ° C for subsequent analysis.
  • the lung lavage (BAL) pellet was resuspended in 1 mL of 0.9% sodium chloride and the total number of cells was determined by counting on a hemocytometer. The cells were washed once with 0.9% sodium chloride and the cells were used for protein extraction.
  • Single cell preparation of lung tissue The whole lung tissue of the mice was taken out, the blood was washed away in 0.9% sodium chloride, the excess tissue was removed, the lungs were cut, and 5 mL of 1 mg/mL type I collagenase was digested at 37 ° C for 1 hour. It was filtered through a 70 ⁇ m sieve, centrifuged at 1200 rpm for 5 min, and 3 mL of red cracking solution was added for 3 minutes, and washed twice with PBS. The cells were counted by a hemocytometer, and macrophages, monocytes, T cells, and neutrophil flow detection antibodies were added for staining at 4 ° C for 30 min. After washing twice with PBS, the machine was tested.
  • Lung tissue staining is shown in Figure 4.
  • HE staining showed that the bronchial and alveolar structures in the control group were clear, the mucosal epithelial cells were arranged neatly, and the alveolar size was uniform.
  • the bronchial epithelial cells in the chronic obstructive pulmonary disease model group showed shedding, the alveolar wall collapsed, and the alveolar cavity showed irregular expansion. Different degrees of inflammatory cell infiltration occur around the airway wall and in the interstitial lung.
  • the bronchial mucosa shrinks, protrudes into the lumen, the lumen narrows or occludes, and mucus is visible in the lumen.
  • Pathological changes in the lungs of mice were significantly alleviated after NMN.
  • the lung tissue of the mice was cut and stained with 1 mg/mL type I collagenase and stained for flow detection (Fig. 5 and Fig. 6).
  • PPE induced neutrality in lung tissue of mice with chronic obstructive pulmonary disease.
  • the proportion of granulocytes was 18.74%, which was significantly higher than that of the control group (5.04%).
  • the proportion of neutrophils decreased significantly. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • mice The lungs of the mice were removed and fixed with 4% PFA (tetrafluoroethylene-perfluoroalkoxy vinyl ether copolymer).
  • PFA tetrafluoroethylene-perfluoroalkoxy vinyl ether copolymer
  • the fixed lungs were dehydrated, embedded in paraffin, and cut into 3 ⁇ m paraffin sections using a rotary microtome. Lung sections were H&E stained and analyzed using Meta Morph software.
  • Preparation of lung tissue protein 0.1 g of mouse lung tissue was taken, and 0.5 ml of radioimmunoprecipitation assay (RIPA) buffer (50 mmol/l Tris-HCl, 150 mmol/l NaCl, 1 mmol/l EDTA, 0.25% deoxycholate) was added. , 1 mmol/l Na 3 VO 4 , 1 mmol/l NaF, 1 mg/l leupeptin, 1 mg/l aprotinin and 1 mmol/l PMSF), homogenized with tissue homogenizer, kept on ice for 45 min In order to completely lyse the cells.
  • RIPA radioimmunoprecipitation assay
  • the cells were centrifuged at 13,000 rpm for 15 minutes, and the supernatant was collected as a tissue protein extract for use.
  • the total protein content was determined by BCA (n-butyl polycyanoacrylate) method, and the protein concentration of all samples was adjusted with reference to the lowest concentration.
  • BAL cell protein preparation 50 ⁇ L of RIPA buffer was added to BAL cells, lysed on ice for 30 min, and then vortexed for 15 seconds. After centrifugation at 13,000 rpm for 5 min, the supernatant was collected as a whole cell lysate for use.
  • the sample was loaded equally by quantifying the protein and ⁇ -actin hybridization.
  • DAB staining solution develops color, and washes the slice with tap water to stop color development.
  • Immunohistochemical staining (shown in Figure 10) of frozen sections (4-6 ⁇ m, original magnification *100) revealed that p16 and p21 were expressed in lung tissue of mice with chronic obstructive pulmonary disease model, after oral administration of NMN, p16 Both the levels of p21 and protein were decreased.
  • qPCR was found (shown in Figure 11): p16 protein was expressed in the lung tissue of mice with chronic obstructive pulmonary disease model, and the expression level of p16 protein was significantly decreased after oral administration of NMN. *P ⁇ 0.05, **P ⁇ 0.01, versus PBS, #P ⁇ 0.05, vers PPE.
  • the lung FEV100 value of the chronic obstructive pulmonary disease model group was significantly lower than that of the PBS group, and the treatment group was significantly increased after NMN administration. *P ⁇ 0.05, **P ⁇ 0.01 (Fig. 13).
  • Example 1 demonstrate in many ways that NMN is effective in the treatment of chronic obstructive pulmonary disease. It has also been found that nicotinamide riboside (NR) also significantly reduces the pathological changes of chronic obstructive pulmonary disease in mice, and thus treats chronic obstructive pulmonary disease.
  • NR nicotinamide riboside
  • Example 2 ⁇ -nicotinamide mononucleotide NMN and ⁇ -nicotinamide ribose NR reduce the aging of pulmonary macrophages caused by carbon particles and the like
  • C57BL/6 peritoneal macrophages were extracted, and 10 ml of normal saline was injected into the peritoneal cavity of the mice.
  • the saline and the abdominal cavity were fully contacted on both sides of the abdominal cavity of the mice, and physiological saline was drawn into the BD tube.
  • the liquid was centrifuged, 1,000 rpm, 5 min, resuspended in DMEM medium and washed once, then resuspended in DMEM medium containing 10% calf serum, and incubated for 2 h to remove the culture medium containing the suspended cells. After washing once with DMEM medium, adherent macrophages were obtained.
  • CBNPs induce aging of lung macrophages and verify whether NR inhibits the aging of CBNPs on macrophages, using ⁇ h2ax antibody (1:5000 dilution) and Sa-beta-gal antibody (1:50 dilution) for three groups.
  • Immunofluorescence staining macrophages were treated differently for one week, the original medium was removed, the slides were taken out, washed once with PBS, and pre-cooled with -20 ° C for 15 min. After fixation, wash 3 times with PBS for 5 min each time. Subsequently, PBS diluted ⁇ h2ax antibody was added and incubated overnight at 4 ° C in a wet box.
  • the concentration was 0.05 mg/ml in DMEM medium and diluted in a Petri dish. Cbnps suspension, will The solution was added to peritoneal macrophages of freshly extracted C57 mice and observed for cell morphology in a 24-well plate (growth area 2 cm 2 ) for 1 week. It was further found (as shown in Figs. 17A and 17B) that the morphology of macrophages changed, the diameter of macrophages increased, cell synapses increased, and cells were activated, but the cells of the NR-treated group were reduced in size.
  • CBNPs can induce aging of alveolar macrophages by immunofluorescence, Western and sa-beta-gal staining. Moreover, NR has an aging effect of inhibiting CBNPs.
  • the intracellular reactive oxygen species concentration is determined by H2DCF-DA. Different concentrations of CBNPs (concentrations are ) The cells were treated with ⁇ NR (concentration 0.5 mM) for 20 min.
  • CBNPs Concentration is The cells were treated with ⁇ NR (concentration: 0.5 mM) for 1 week, the original medium was removed, and the serum-free DMEM was washed 3 times, and the H2DCF-DA probe (final concentration: 0.1 ⁇ M) was added, and the mixture was incubated at 37 ° C for 30 min in the dark. After collecting and collecting the adherent cells, they were tested on the machine.
  • Fig. 19 The experimental results are shown in Fig. 19: the concentration of active oxygen in the cells increased after one week of treatment with CBNPs, and NR inhibited the concentration of active oxygen in the cells. It is shown that CBNPs can stimulate the increase of ROS, and NR can inhibit this effect.
  • the results of Example 2 demonstrate in many ways that nicotinamide riboside (NR) NR can effectively alleviate the aging of lung macrophages caused by nano carbon particles. It has also been found that ⁇ -Nicotinamide Mononucleotide (NMN) also significantly reduces the aging of lung macrophages caused by nano carbon particles.
  • NR nicotinamide riboside
  • NNN ⁇ -Nicotinamide Mononucleotide
  • inhalable particles in the air such as PM10 particles, PM2.5 particles or carbon black particles
  • inhalable particles in the air cause aging of pulmonary macrophages, which in turn causes lung damage, leading to chronic obstructive pulmonary disease or respiratory disorders.
  • ⁇ -nicotinamide mononucleotide or its precursor has the effect of alleviating the above lung damage, and therefore the present invention provides a ⁇ -nicotinamide mononucleotide or a precursor thereof in the preparation of a treatment or
  • the use of drugs or health supplements for relieving respiratory disorders or diseases provides a new therapeutic option for the treatment of lung disease-like lung diseases caused by inhalable particles, which is of great significance.

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Abstract

La présente invention concerne le domaine de la technologie médicale, et concerne en particulier l'utilisation de β-nicotinamide mononucléotide ou d'un précurseur de ce dernier dans la préparation d'un médicament ou d'un produit de soins de santé pour traiter ou soulager un trouble respiratoire ou une maladie respiratoire. Le problème technique que cherche à résoudre la présente invention est de fournir une nouvelle solution alternative permettant de préparer un médicament ou un produit de soins de santé pour traiter ou soulager un trouble respiratoire ou une maladie respiratoire, et la solution technique pour résoudre le problème technique ci-dessus est d'utiliser le β-nicotinamide mononucléotide ou un précurseur de ce dernier dans la préparation d'un médicament ou d'un produit de soins de santé pour traiter ou soulager un trouble respiratoire ou une maladie respiratoire. Le β-nicotinamide mononucléotide ou le β-nicotinamide ribose peuvent traiter efficacement des maladies pulmonaires telles que la bronchopneumopathie chronique obstructive, et peuvent évidemment atténuer le vieillissement des macrophages pulmonaires provoqué par des particules inhalables, ayant une bonne perspective d'application.
PCT/CN2019/073917 2018-02-12 2019-01-30 Utilisation de bêta-nicotinamide mononucléotide ou d'un précurseur de ce dernier dans la préparation d'un médicament ou d'un produit de soins de santé destiné au traitement ou au soulagement d'un trouble respiratoire ou d'une maladie respiratoire Ceased WO2019154220A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3949964A1 (fr) * 2020-08-06 2022-02-09 Nuvamid SA Combinaison de dérivés de nicotinamide mononucléotidique et d'autres agents thérapeutiques pour leur utilisation dans le traitement des infections virales
WO2022029275A1 (fr) * 2020-08-06 2022-02-10 Nuvamid Sa Combinaison de dérivés de nicotinamide mononucléotide et d'autres agents thérapeutiques destinée à être utilisée dans le traitement d'infections à coronavirus et de la covid-19

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110483601A (zh) * 2019-08-12 2019-11-22 上海龙翔生物医药开发有限公司 制备β-烟酸胺单核苷酸的方法及其应用
CN110548040A (zh) * 2019-10-17 2019-12-10 苏州大学 β-NMN在制备脓毒症器官损伤的治疗、预防药物中的应用

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2014059031A2 (fr) * 2012-10-09 2014-04-17 President And Fellows Of Harvard College Biosynthèse et précurseurs de nad pour la prévention et le traitement de l'inflammation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014059031A2 (fr) * 2012-10-09 2014-04-17 President And Fellows Of Harvard College Biosynthèse et précurseurs de nad pour la prévention et le traitement de l'inflammation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3949964A1 (fr) * 2020-08-06 2022-02-09 Nuvamid SA Combinaison de dérivés de nicotinamide mononucléotidique et d'autres agents thérapeutiques pour leur utilisation dans le traitement des infections virales
WO2022029275A1 (fr) * 2020-08-06 2022-02-10 Nuvamid Sa Combinaison de dérivés de nicotinamide mononucléotide et d'autres agents thérapeutiques destinée à être utilisée dans le traitement d'infections à coronavirus et de la covid-19

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