Method of administering nitric oxide gas

Abstract

The present disclosure can be administered without special equipment and contains nitrogen dioxide (NO 2 The present invention relates to a method for producing nitric oxide (NO) gas without producing nitric oxide (NO) gas. The method includes combining nitrate and / or nitrite anions and an elemental metal in an acidic solution in a container capable of containing liquid and gaseous components, and NO gas is produced by reaction of the nitrate and / or nitrite anions and the elemental metal in the acidic solution. The method further includes administering the produced NO gas to a subject via inhalation. Compositions and kits for improved delivery of NO gas are also described.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 148,523, filed on 11 February 2021, and to U.S. Provisional Patent Application No. 63 / 180,039, filed on 26 April 2021, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background Inhaled nitric oxide (NO) is used to treat a wide range of cardiopulmonary conditions, including pulmonary hypertension, in children and adults. Inhaled NO gas has also been proposed as a hospital-based treatment for COVID-19 patients with hypoxic levels and dyspnea. Numerous mechanisms have been proposed for the therapeutic benefits of nitric oxide in COVID-19 patients (Figure 1): Inhaled NO gas is known to be a selective pulmonary vasodilator. NO can improve right ventricular function and reduce pulmonary vasoconstriction in subjects with acute and chronic pulmonary hypertension. Breathing NO gas has been shown to improve ventilation and result in bronchodilation in subjects with mild asthma. NO gas in the alveolar space improves oxygenation by increasing blood flow to the ventilating lung unit (i.e., improved ventilation-perfusion match). In vitro and in vivo data have shown that NO gas may act as an anti-inflammatory and antithrombotic agent. NO donors and NO gas have shown antibacterial and antiviral properties in in vitro and early clinical studies.

[0003] However, widespread use of inhaled NO is limited by logistical and economic barriers. Currently, inhaled NO therapy is expensive and impractical for home use because it requires the use of special ventilation equipment and NO canisters. Inhaled nitric oxide is an extremely expensive treatment. The direct cost of NO is at least $100 per hour of use, regardless of the dose. The average COVID-19 patient may require more than 80 hours of treatment, costing thousands of dollars. Therefore, despite studies showing the benefits of NO therapy in COVID-19 patients, practical considerations have so far prevented widespread use of the treatment, limiting it almost entirely to severely ill patients hospitalized. Thus, there is a need for a more economical and convenient method of generating and administering nitric oxide to patients, especially one that does not require the use of special equipment.

[0004] However, despite its therapeutic benefits, NO therapy unfortunately involves potentially serious exposure to toxic chemicals. Methemoglobinemia is also common with nitric oxide therapy (Raut and Maheshwari, "Inhaled nitric oxide, methemoglobinemia, and route of delivery," Saudi J Anaesth. 2017, 11(3):364). However, due to the challenges associated with NO gas inhalation, such as methemoglobinemia and nitric oxide formation, new evidence raises questions about whether NO inhalation can improve mortality in COVID-19 patients (Prakash et al., "Efficacy and safety of inhaled nitric oxide in the treatment of severe / critical COVID-19 patients: A systematic review." Indian Journal of Pharmacology, 2021, 53(3): 236-243). Methemoglobinemia is a high concern in these patients, as COVID-19 patients have been reported to develop it from the disease itself. (Naymagon et al., "The emergence of methemoglobinemia amidst the COVID-19 pandemic." Am J Hematol., 2020, 95(8):E196-E197).

[0005] Current methods of NO therapy also inevitably involve patient exposure to NO2 gas, which is considered a major toxic air pollutant and therefore has no therapeutic value. NO is rapidly oxidized to NO2 in the presence of oxygen (Glasson and Tuesday, "The Atmospheric Thermal Oxidation of Nitric Oxide," J. Am. Chem. Soc., 1963, 85(19): 2901-2904). The Occupational Safety and Health Administration (OSHA) sets the limit for NO at 25 ppm in workplace air during an 8-hour workday and 40-hour workweek, while the limit for NO2 exposure is only 5 ppm in workplace air for a mere 15 minutes. This is because most biochemical studies use 3160 μg / m³. 3 This is because the toxic effects are only evident after acute or subchronic exposure to nitrogen dioxide exceeding 2 ppm (Jarvis et al. "Nitrogen dioxide." In: WHO Guidelines for Indoor Air Quality: Selected Pollutants. Geneva: World Health Organization; 2010. 5). To minimize NO2 formation in NO therapy, NO stored in bottles must not contain oxygen, which increases the hurdles to making NO therapy available. Even with these precautions, NO2 exposure remains too high, posing a concern for patients requiring NO therapy. Van Meurs et al. described that in premature infants with severe respiratory failure, the use of inhaled NO at NO dose levels of 5–10 ppm exposed patients to NO2 concentrations of at least 3 ppm in four infants and 5 ppm in two infants, while NO2 concentrations did not increase in any infants in the placebo group (Van Murs et al., "Inhaled Nitric Oxide for Premature Infants with Severe Respiratory Failure," N Engl J Med, 2005; 353:13-22). Petit et al. found that when inhaled NO was administered using an existing compressed gas delivery system, NO2 was generated when NO was diluted with O2-enriched air before delivery to the patient (Petit et al., "The Pathophysiological of Nitrogen Dioxide During Inhaled Nitric Oxide Therapy," ASAIO Journal, 2017, 63(1): 7-13). Petit et al. also described how NO2 inhaled by patients oxidizes protective antioxidants in the epithelial lining fluid (ELF), causing extracellular damage in the airways, which may lead to edema, bronchoconstriction, and a decrease in forced expiratory volume per second. According to the Hazardous Substances Disease Registry, exposure to low concentrations of NO2 gas may initially cause mild shortness of breath, but after several hours to several days, exposed individuals may develop bronchospasm and pulmonary edema. Exposure to higher concentrations (>10 ppm) of NO2 gas may induce immediate responses in subjects, which may include cough, fatigue, nausea, choking, headache, abdominal pain, and dyspnea. This may be followed by the development of pulmonary edema with anxiety, confusion, lethargy, and loss of consciousness after a 3-30 hour asymptomatic period. Survival of higher concentrations of NO2 exposure may be followed by episodes of obstructive bronchiolitis several weeks later. Inhalation of very high concentrations (>50 ppm) can rapidly cause burns, convulsions, swelling of throat tissue, upper airway obstruction, and even death. Therefore, there is also a need for safer methods of administering nitric oxide to patients. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Van Murs et al. N Engl J Med (2005) 353:13~22 [Non-Patent Document 2] Petit et al., ASAIO Journal (2017) 63(1):7~13 [Overview of the Initiative] [Means for solving the problem]

[0007] overview This disclosure relates to compositions, kits, and methods for generating NO gas for NO inhalation therapy. In one embodiment, a method for generating NO gas for NO inhalation therapy includes combining a source of nitrate anions and an elemental metal in an acidic solution in a container capable of containing liquid and gaseous components, thereby generating NO gas. In another embodiment, a method for safely generating NO gas for NO inhalation therapy includes combining a source of nitrite anions and an elemental metal in an acidic solution in a container capable of containing liquid and gaseous components, thereby generating NO gas. In certain embodiments, the method further includes administering NO gas to a subject via a container capable of containing liquid and gaseous components, for example, the container capable of containing liquid and gaseous components is a water pipe. In some embodiments, administering NO gas to a subject via a container capable of containing liquid and gaseous components includes the subject inhaling from a water pipe. In certain embodiments, the water pipe is connected to a ventilator. Patients receiving NO gas are those who suffer from shortness of breath, migraines, have oxygen saturation levels below 95, are seeking improved exercise capacity, increased endurance, or improved mental performance.

[0008] The elemental metal is selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental potassium, elemental sodium, elemental beryllium, elemental barium, and elemental iron. In certain embodiments, the elemental metal is elemental magnesium and / or elemental zinc. The pH of the acidic solution is between 0.1 and 6.9, for example, between 2 and 4. In certain embodiments, the method further includes dissolving the acid powder in a solvent (e.g., water) to produce an acidic solution. In some embodiments, the acid powder is citric acid, malic acid, or fumaric acid. In certain embodiments, the acidic solution is produced by dissolving the acid powder in 1 ml to 10,000 ml of water.

[0009] In some embodiments of methods for producing NO gas for NO inhalation therapy, the source of nitrate anions is a plant-based source of nitrates or nitrates. In such embodiments, an effective amount of nitrate anion source and an effective amount of elemental metal are combined in an acidic solution to produce an effective amount of NO gas, where the effective amount of elemental metal is between 1 mg and 2000 mg, and the effective amount of nitrate anion source yields 30 mg to 4000 mg of nitrate anions. In certain embodiments, an effective amount of nitrate anion source and an effective amount of elemental metal are combined in an acidic solution in a ratio of 10:1 to 1:10 to produce an effective amount of NO gas. In some embodiments, an effective amount of nitrate anion source and an effective amount of elemental metal are combined in an acidic solution to produce at least 5 ppm of NO gas and 1000 ppm of H2 gas. In some embodiments, the gaseous components produced by combining the nitrate anion source and elemental metal in an acidic solution further include nitroxyl gas.

[0010] In some embodiments of methods for producing NO gas for NO inhalation therapy, the source of nitrite anions is a plant-derived source of nitrite or nitrite. In such embodiments, an effective amount of nitrite anion source and an effective amount of elemental metal are combined in an acidic solution to produce an effective amount of NO gas, where the effective amount of elemental metal is between 1 mg and 2000 mg, and the effective amount of nitrite anion source yields 1 mg to 1000 mg of nitrite anions. In certain embodiments, an effective amount of nitrite anion source and an effective amount of elemental metal are combined in an acidic solution in a ratio of 10:1 to 1:10 to produce an effective amount of NO gas. In some embodiments, an effective amount of nitrate anion source and an effective amount of elemental metal are combined in an acidic solution to produce at least 5 ppm of NO gas and 1000 ppm of H2 gas. In some embodiments, the gaseous components produced by combining the nitrate anion source and elemental metal in an acidic solution further include nitroxyl gas.

[0011] The above methods for generating NO gas for NO inhalation therapy do not produce unsafe levels of NO2 gas. For example, the level of NO2 gas produced by combining a source of nitrite anions and elemental metals in an acidic solution does not exceed 10 ppm, 5 ppm, or 2 ppm. In some embodiments, the gaseous component produced by combining a source of nitrite anions and elemental metals in an acidic solution does not contain any NO2 gas at all.

[0012] The compositions relating to generating NO gas for NO inhalation therapy described herein comprise nitrites and elemental metals. In some embodiments, the compositions comprise acids. The elemental metals in the compositions are selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental sodium, elemental potassium, elemental beryllium, elemental rubidium, elemental cesium, elemental aluminum, elemental gallium, elemental indium, elemental tin, elemental bismuth, elemental scandium, elemental titanium, elemental vanadium, elemental chromium, elemental manganese, elemental cobalt, elemental manganese, elemental scandium, elemental titanium, nickel, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technitium, elemental ruthenium, elemental rhodium, elemental palladium, elemental silver, elemental cadmium, elemental lanthanum, elemental hafnium, elemental tantalum, elemental tungsten, elemental rhenium, elemental osmium, elemental iridium, elemental platinum, elemental gold, elemental manganese, and elemental iron. In some embodiments, the nitrite in the composition is a nitrite, such as sodium nitrite or potassium nitrite. In other embodiments, the nitrite in the composition is a plant-based source of nitrite standardized for its nitrite content, such as beetroot powder.

[0013] In some embodiments, the composition may be in the form of capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, pastilles, liquids, elixirs, syrups, tinctures, suspensions, emulsions, mouthwashes, sprays, drops, ointments, creams, gels, pastes, transdermal patches, suppositories, pessaries, creams, gels, pastes, foams, or combinations thereof. The composition may further contain acceptable additives and / or acceptable carriers. Acceptable additives may be selected from at least one member of the group consisting of solubilizers, enzyme inhibitors, anticoagulants, antifoaming agents, antioxidants, colorants, coolants, cryoprotectants, hydrogen bonding agents, flavoring and odor-correcting agents, plasticizers, preservatives, sweeteners, and thickeners. Acceptable carriers may be selected from at least one member of the group consisting of excipients, lubricants, binders, disintegrants, diluents, expanders, solvents, suspending agents, solubilizers, isotonic agents, buffering agents, soothing agents, and amphiphilic lipid delivery systems. In some embodiments, the composition is in a form suitable for oral administration. In other embodiments, the composition is in a form suitable for inhalation of gases generated when in contact with an acidifying solvent.

[0014] In some embodiments, the composition contains an effective amount of nitrite to produce a therapeutic effect and an effective amount of elemental metal to prevent or reduce the toxicity of the nitrite. The therapeutic effect of the nitrite may be to lower blood pressure or to treat and / or alleviate the symptoms of respiratory disease. Respiratory disease may be an infection caused by coronavirus, influenza virus, respiratory polynuclear virus, Streptococcus pneumoniae, Haemophilus influenzae type b, Pneumocystis jiroveci, fungi, or protozoa. In certain embodiments of the therapeutic composition, the effective amount of nitrite is 1 to 1000 mg and the effective amount of elemental metal is 1 to 10000 mg. In other embodiments, the effective amount of nitrite is 5 to 200 mg and the effective amount of elemental metal is 5 to 1000 mg. In certain embodiments of the therapeutic composition, the effective amount of nitrite is 30 to 100 mg and the effective amount of elemental metal is 10 to 400 mg.

[0015] In certain embodiments of the therapeutic composition, the nitrite is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets; the elemental metal is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets. In other embodiments, the nitrite is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets; the elemental metal is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets; and the acid is packaged separately from the nitrite and elemental metal. In some embodiments, the nitrite, elemental metal, and acid are in solid form. In certain embodiments, the nitrite and the elemental metal are packaged together, for example, in a capsule, a cachet, a pill, or a tablet.

[0016] The kit for safely administering NO gas to a patient as described herein includes a nitrite or nitrate; an elemental metal, where the nitrite and / or nitrate and the elemental metal are packaged together; an acid; and instructions for combining the nitrite, elemental metal and acid to produce NO gas without producing NO2 gas, and for administering the produced NO gas to a patient. In some embodiments, the kit further includes a container capable of containing liquid and gaseous components, such as a water pipe. In some embodiments, the nitrite or nitrate in the kit is a salt, such as a nitrite or nitrate. Exemplary salts include sodium nitrite, potassium nitrite, sodium nitrate, and potassium nitrate. The elemental metals in the kit are selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental sodium, elemental potassium, elemental beryllium, elemental rubidium, elemental cesium, elemental aluminum, elemental gallium, elemental indium, elemental tin, elemental bismuth, elemental scandium, elemental titanium, elemental vanadium, elemental chromium, elemental manganese, elemental cobalt, elemental manganese, elemental scandium, elemental titanium, elemental nickel, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technitium, elemental ruthenium, elemental rhodium, elemental palladium, elemental silver, elemental cadmium, elemental lanthanum, elemental hafnium, elemental tantalum, elemental tungsten, elemental rhenium, elemental osmium, elemental iridium, elemental platinum, elemental gold, elemental manganese, and elemental iron.

[0017] Furthermore, a method for administering inhaled nitric oxide gas with reduced toxicity to a subject is disclosed. In some embodiments, the reduction in toxicity manifests as reduced lung injury compared to the amount of lung injury that would be expected to occur with administration of NO gas alone at the same concentration, or the subject's blood methemoglobin level does not exceed 2%. The method comprises administering nitric oxide gas to a subject and administering hydrogen gas to the subject. In certain embodiments, the method further comprises administering nitroxyl gas to the subject. In some embodiments, a method for therapeutically administering inhaled NO gas is described as comprising co-administering an effective amount of hydrogen gas to the subject together with NO gas. The effective amount of hydrogen is an amount sufficient to reduce or prevent the formation of NO2 during the administration of NO gas to the subject. In some embodiments, the effective amount of hydrogen gas is at least 1000 ppm. In certain embodiments, the method comprises mixing an elemental metal with a nitrate and / or nitrite in an acidifying solvent to thereby produce NO gas and an effective amount of hydrogen gas, which are administered to the subject via inhalation.

[0018] Accordingly, a method for reducing inhaled NO toxicity is described, comprising inhaling NO together with an effective amount of hydrogen to reduce NO toxicity (e.g., lung tissue damage or increased nitrotyrosine levels in tissues exposed to NO). Accordingly, a composition comprising nitric oxide gas and hydrogen gas is described. In some embodiments, nitrite toxicity manifests as the development of methemoglobinemia. A method for preventing and / or treating methemoglobinemia in a subject is also described. The method comprises administering an effective amount of hydrogen gas to a subject via inhalation.

[0019] For compositions containing nitric oxide and hydrogen gas, the gas concentrations are at least 1 ppm of nitric oxide and at least 5 ppm of hydrogen gas. In certain embodiments, the composition contains 1 to 10,000 ppm of hydrogen gas and 1 to 500 ppm of nitric oxide gas. In compositions containing nitric oxide and hydrogen gas, the concentration of hydrogen gas does not result in the formation of liquid water.

[0020] In another aspect, methods for preventing and / or treating methemoglobinemia in a subject (e.g., methemoglobinemia caused by inhaled NO therapy, nitrite administration, or nitrate administration) are disclosed. The methods include orally administering to the subject an effective amount of elemental metal. In certain embodiments, the methods further include orally administering an acid to the subject, and the elemental metal and the acid are taken together. In some aspects, the methods include orally administering an effective amount of elemental metal and an acid that is effective to produce hydrogen gas in the stomach. By practicing the methods of the present disclosure for preventing and / or treating methemoglobinemia, NO2-induced toxicities exhibited by the subject, such as lung and / or airway inflammation, decreased lung function, worsening cough, worsening wheezing, increased asthma attacks, or a higher likelihood of emergency department visits and hospitalizations, are reduced. In some aspects, the subject does not exhibit NO2-induced toxicity upon oral administration of the elemental metal and / or the acid.

Brief Description of the Drawings

[0021] [Figure 1] Figure 1 shows various pathways by which NO functions in the lung.

[0022] [Figure 2] Figure 2 shows a quantitative analysis of nitric oxide in the presence of ambient concentrations of nitrogen dioxide.

[0023] [Figure 3] Figure 3 shows the administration of NO and H2 gas to an ICU patient connected to a ventilator in an exemplary implementation, where NO and H2 are administered through an air valve inlet, which is typically used for inserting nebulized medications.

[0024] [Figure 4]Figure 4 shows an exemplary apparatus that can be used to cost-effectively produce a combination of NO, HNO, and hydrogen gas. The apparatus has three compartments: the upper compartment contains a solution of acidified water (preferably acidified with citric acid), the middle compartment contains the SpO2 composition, and the lower compartment is a mixing chamber, where the acidified water in the upper compartment drips into the mixing chamber, where it mixes with the SpO2 composition, which also drips into the mixing chamber from the middle compartment. [Modes for carrying out the invention]

[0025] Detailed explanation Detailed aspects and applications of this disclosure are described below in the following detailed technical description. Unless otherwise specifically stated, the words and phrases in this specification and the claims are intended to have their plain, ordinary, and customary meanings to those skilled in the applicable art.

[0026] In the following description, for illustrative purposes, numerous specific details are provided to provide a complete understanding of the various aspects of this disclosure. However, those skilled in the art will understand that the implementation of the technology disclosed herein may be practiced without these specific details. It should be noted that there are many different alternative configurations, devices, and techniques to which the technology disclosed herein may be applied. The full scope of the technology disclosed herein is not limited to the examples described below.

[0027] The singular forms "a," "an," and "the" include multiple references unless the context clearly indicates otherwise. Therefore, for example, a reference to "a step" includes a reference to one or more such steps.

[0028] As used herein, the term “about” means a deviation of 5% or less of a given value, for example, a deviation of 3%, 2%, 1%, 0.5%, or 0.1% of a given value.

[0029] As used herein, the term “acceptable” is used in its broadest sense and may describe components of a composition that meet Food and Drug Administration (FDA) standards, United States Pharmacopeia (USP) standards, U.S. Department of Agriculture (USDA) standards for food-grade materials, generally accepted standards in the dietary supplement industry, industry standards, botanical standards, or standards established by any individual. These standards may describe the acceptable range of aspects of the components of a composition, such as edibility, toxicity, pharmacological effects, or any other aspects of the chemicals, composition, or preparation used in the implementation of the composition.

[0030] As used herein, the term “composition” refers to both a component or mixture of components, and a combination of capsules containing different components or components. Thus, in certain embodiments, the composition encompasses separate capsules that are packaged together and intended to be taken together.

[0031] As used herein, the term “elemental metal” refers to a metallic element in a neutral charge state, in other words, a metal that exists in its elemental form and not in a salt or charged form (exemplary salt and charged forms include metal oxides, hydroxides, carbonates, chlorides, lactates, citrates, aspartates, glycines, and glucons). Therefore, as used herein, an elemental metal and a salt of the same metal are different components. A statement that a composition contains an elemental metal cannot be satisfied by the presence of a metal salt, and vice versa. For example, a composition consisting of magnesium citrate is not a composition containing elemental magnesium, regardless of whether it is stated that magnesium citrate yields some amount of elemental magnesium. The elemental metals described herein include elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental sodium, elemental potassium, elemental beryllium, elemental rubidium, elemental cesium, elemental aluminum, elemental gallium, elemental indium, elemental tin, elemental bismuth, elemental scandium, elemental titanium, elemental vanadium, elemental chromium, elemental manganese, elemental cobalt, elemental manganese, elemental scandium, elemental titanium, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technitium, elemental ruthenium, elemental rhodium, elemental palladium, elemental silver, elemental cadmium, elemental lanthanum, elemental hafnium, elemental tantalum, elemental tungsten, elemental rhenium, elemental osmium, elemental iridium, elemental platinum, elemental gold, elemental manganese, and elemental iron.

[0032] As used herein, the term “SpO2 composition” refers to a composition comprising nitrate anions and / or nitrite anions, as well as elemental metals. In some embodiments, the composition is in powder form; therefore, the composition may be referred to as “SpO2 powder.”

[0033] This disclosure relates to the discovery that by combining an acid, an elemental metal, and a nitrate anion in solution, an inhalable nitric oxide (NO) gas is produced, as can be confirmed by an NO sensor. Nitroxyl gas can also be formed, which may contribute to the remarkable therapeutic benefits of the formulation. Nitroxyl formation was confirmed by placing the gas mixture in an airtight chamber with a vial containing nitrosobenzene in an ammonia solution, resulting in the formation of a characteristic bright yellow cuperone. Surprisingly, the generated NO gas can be administered to a subject, for example, via a water pipe, and such administration of NO has been found to improve attention and vitality levels, cure headaches / migraines, and increase athletic performance, as indicated by increased strength and endurance. Accordingly, a method for administering NO gas to a subject in need is disclosed herein.

[0034] Surprisingly, the described method for producing NO gas does not produce NO2 gas at concentrations up to 40 ppm, while at higher NO concentrations, the amount of NO2 gas produced is far less than that described in various studies. Therefore, in some implementations, subjects requiring NO gas are those requiring treatment for respiratory illness. In certain embodiments, subjects exhibit at least one symptom selected from the group consisting of shortness of breath, respiratory problems, chest pain, pneumonia, and decreased oxygen saturation. In some embodiments, the respiratory illness is caused by infection, e.g., coronavirus, influenza virus, polynuclear respiratory virus, Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and / or Pneumocystis jiroveci. In certain implementations, subjects requiring treatment for respiratory illness are diagnosed with pneumonia or severe acute respiratory syndrome caused by coronavirus, e.g., alpha-coronavirus selected from 299E and NL63, or beta-coronavirus selected from OC43, HKU1, MERS-CoV, SARS-CoV, or SARS-CoV-2. In some other embodiments, subjects have a condition selected from the group consisting of post-COVID-19 hypoxia, acute respiratory distress syndrome (ARDS), post-ARDS hypoxia, pneumonia, chronic obstructive pulmonary disease (COPD), mesothelioma, anemia, asthma, interstitial lung disease, pulmonary embolism, collapsed lung, congenital heart defect or disease, pulmonary edema, high altitude sickness, hypopnea, pulmonary fibrosis, sleep apnea, gastrointestinal infection, Heliobacter pylori infection, and respiratory infection.

[0035] In other implementations, subjects requiring NO gas are those who are expected to benefit from increased NO levels, such as those seeking improved athletic performance, increased vitality or endurance, improved health, and treatment for migraines.

[0036] A method for administering NO gas to a subject in need includes the steps of combining a source of nitrate anions and / or a source of nitrite anions, as well as an elemental metal, in an acidic solution in a container (e.g., a water pipe) capable of containing liquid and gaseous components, thereby generating NO gas, and administering NO gas to the subject via the container capable of containing liquid and gaseous components. In some embodiments, nitroxyl and hydrogen gases are also produced by the reaction. In some embodiments, the pH of the acidic solution is between 0.1 and 6.9. In preferred embodiments, the pH of the acidic solution is between 2 and 4. The subject is administered NO gas by inhaling the gaseous contents in a water pipe or some other suitable container capable of containing liquid and gaseous components that allows for the inhalation of gaseous components. In certain embodiments, the method includes combining a therapeutically effective amount of nitrate anions and a therapeutically effective amount of elemental metal in an acidic solution in a water pipe, thereby generating a therapeutically effective amount of NO gas. In some embodiments, the therapeutically effective amounts of elemental metal and nitrate anion are between 1 mg and 2000 mg, and between 30 mg and 4000 mg, respectively. In certain embodiments, the therapeutically effective amounts of nitrate anion and elemental metal are in a 1:1 molar ratio.

[0037] Elemental metals are alkaline earth metals, alkali metals, or transition metals. Because elemental metals are reactive, they are not found in nature. Rather, they exist as ores containing mixtures of various metallic compounds, such as salts and oxides. Therefore, complex extraction and purification using physicochemical methods are necessary to produce elemental metals. In some embodiments, the elemental metal is elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental sodium, elemental potassium, elemental beryllium, elemental rubidium, elemental cesium, elemental aluminum, elemental gallium, elemental indium, elemental tin, elemental bismuth, elemental scandium, elemental titanium, elemental vanadium, elemental chromium, elemental manganese, elemental cobalt, elemental manganese, elemental scandium, elemental titanium, elemental nickel, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technitium, elemental ruthenium, elemental rhodium, elemental palladium, elemental silver, elemental cadmium, elemental lanthanum, elemental hafnium, elemental tantalum, elemental tungsten, elemental rhenium, elemental osmium, elemental iridium, elemental platinum, elemental gold, elemental manganese, or elemental iron. In some embodiments, the elemental metal is selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, and elemental iron. In some embodiments, the subject is administered a combination of elemental metals. Therefore, in some embodiments, the composition administered to the subject contains two or more elemental metals. The elemental metals may be in any form, for example, powder or granules. The reaction rate between the metal and the nitrate and the acid may be influenced by changing the size and surface area of ​​the elemental metals. Thus, it has been found that the smaller the particle size of the metal, the faster the reaction, and the larger the amount of NO produced in a shorter time.

[0038] In some embodiments, the nitrate anion (NO3 -The sources of nitrates are amino acid or amino acid derivative nitrates (e.g., creatine nitrate, arginine nitrate, carnitine nitrate, n-acetylcarnitine nitrate, citrulline nitrate, betaine nitrate, and proline nitrate), inorganic nitrates (e.g., magnesium nitrate, sodium nitrate, potassium nitrate, calcium nitrate, and lithium nitrate, or mixed salts, co-crystal formulations, and hydrates thereof), or natural nitrate sources. For natural nitrate sources, the nitrates are concentrated and / or isolated from natural sources, e.g., plant-based nitrate sources. Examples of natural nitrate sources, but not limited to these, include beet juice, beet juice powder, concentrated beet juice powder, celery powder, spinach and red spinach extracts, and amaranth extract. In a preferred embodiment, the nitrate content in the natural nitrate source is standardized to provide a sufficient amount of nitrate. In some embodiments, the composition includes two or more sources of nitrate anions.

[0039] In some embodiments, the nitrite anion (NO2 - The sources of nitrites are amino acid or amino acid derivative nitrites (e.g., creatine nitrite, arginine nitrite, carnitine nitrite, n-acetylcarnitine nitrite, citrulline nitrite, betaine nitrite, and proline nitrite), inorganic nitrites (e.g., magnesium nitrite, sodium nitrite, potassium nitrite, calcium nitrite, and lithium nitrite, or their mixed salts, co-crystal formulations, and hydrates), or natural nitrite sources. With regard to natural nitrite sources, nitrites can be concentrated and / or isolated from natural sources, such as plant-derived nitrite sources.

[0040] In some embodiments, elemental metals, as well as nitrate anions and / or nitrite anions, are included in the system for sustained NO release. For example, the system may be a time-release system (e.g., a diffusion system, a dissolution system, a permeation system, and an ion exchange resin), a floating system, a bio-attachment system, or a matrix system in which exposure to acid or an acidic solution is controlled. In other embodiments, metals and nitrates may be released into an acidic solution in a continuous manner by either mechanical or electrical means to enable sustained NO gas release. In a particular embodiment, the system for sustained NO release described herein includes three fluid-connected compartments (see, for example, Figure 4). The upper compartment contains a solution of acidified water (preferably containing citric acid), the middle compartment contains an SpO2 composition, and the lower compartment is a mixing chamber, where the acidified water in the upper compartment drips into the mixing chamber to mix with the SpO2 composition, which also drips into the mixing chamber from the middle compartment. The device allows for easy adjustment of the amount of NO, HNO, and H2 administered to the patient by controlling the reaction rate of the acidified water and SpO2 composition. The reaction rate may be controlled by adjusting the acidity of the solution, adjusting the dropping rate of the acidified water, adjusting the particle size of the SpO2 composition, or by adjusting the heating in the mixing chamber with a heating element having a built-in thermostat, for example (increasing the heating increases the reaction rate). A similar scheme can be used to administer NO / H2 / HNO gas to non-ICU patients using a respiratory system, either at home or in a hospital setting, the only difference being that the patient must wear a mask or equivalent gas delivery device instead of an endotracheal tube.

[0041] In an exemplary implementation, a patient connected to a ventilator may be administered NO / H2 gas through an air valve inlet typically used to deliver a nebulizer. The NO / H2 gas can be generated by the device shown in Figure 4. Similar schemes can be used to administer NO / H2 gas to non-ICU patients using the respiratory system, either at home or in a hospital setting, the only difference being that the patient must wear a mask, cannula, or similar device for gas delivery instead of an endotracheal tube (see Figure 3).

[0042] Accordingly, a kit for safely administering NO gas to a patient is disclosed herein. The kit includes a nitrite or nitrate; an elemental metal, where the nitrite and / or nitrate and the elemental metal are packaged together; an acid; and instructions for combining the nitrite, elemental metal and acid to produce NO gas without producing NO2 gas, and for administering the produced NO gas to a patient. In some embodiments, the kit further includes a container capable of containing liquid and gaseous components, such as a water pipe. In some embodiments, the nitrite or nitrate in the kit is a salt, such as a nitrite or nitrate. Exemplary salts include sodium nitrite, potassium nitrite, sodium nitrate, and potassium nitrate. The elemental metals in the kit are selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental sodium, elemental potassium, elemental beryllium, elemental rubidium, elemental cesium, elemental aluminum, elemental gallium, elemental indium, elemental tin, elemental bismuth, elemental scandium, elemental titanium, elemental vanadium, elemental chromium, elemental manganese, elemental cobalt, elemental manganese, elemental scandium, elemental titanium, elemental nickel, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technitium, elemental ruthenium, elemental rhodium, elemental palladium, elemental silver, elemental cadmium, elemental lanthanum, elemental hafnium, elemental tantalum, elemental tungsten, elemental rhenium, elemental osmium, elemental iridium, elemental platinum, elemental gold, elemental manganese, and elemental iron.

[0043] In some embodiments, the method involves providing an acid in powder form and mixing it with a nitrate anion or nitrite anion and / or an elemental metal, then dissolving it in a solvent to produce NO gas. The acid in powder form may be, for example, citric acid, malic acid, or fumaric acid. In preferred embodiments, the solvent used is water, because it is safe, non-toxic, and readily available. However, other protic and / or polar solvents, such as ammonia, ethanol, acetic acid, etc., can be used. The water or solvent does not need to be pure and may contain dissolved other compounds, such as aromas, perfumes (scents), other pharmaceuticals, etc. In some embodiments, the acid is a salt of a strong acid and a weak base, which, when dissolved in water or some other polar protic solvent, forms an acidic solution. Thus, the acid may be ammonium chloride, ammonium nitrate, or creatine nitrate. In certain embodiments, when the nitrate anion is provided as a nitrate formed by a weak base (e.g., creatine nitrate or proline nitrate), the nitrate can serve as a source for both the acid and the nitrate anion.

[0044] In the usual order of adding the components of a formulation, an acid solution is prepared first, followed by the simultaneous addition of the elemental metal and the nitrate; however, it is understood that such an order is not mandatory and can vary. For example, the step of combining the nitrate anion and the elemental metal in an acidic solution may include simultaneously adding the nitrate, powdered acid, and elemental metal to water, or preparing a solution of the nitrate in water, followed by the addition of the acid and the elemental metal. An essential feature of the method of this disclosure is to prevent the elemental metal from reacting completely with the acid, thereby forming a salt of the elemental metal and not NO gas. Thus, by adding elemental magnesium metal to an acidic solution, and then, after the completion of the reaction (indicated by the dissolution of magnesium in liquid in its salt form), adding the nitrate, no nitric oxide gas is formed.

[0045] Methods for generating NO gas for NO inhalation therapy do not produce unsafe levels of NO2 gas, and therefore the generated gaseous components do not contain NO2 gas. For example, the level of NO2 gas produced by combining a source of nitrite anions and an elemental metal in an acidic solution does not exceed 10 ppm, 5 ppm, or 2 ppm. In some embodiments, the gaseous components produced by combining a source of nitrite anions and an elemental metal in an acidic solution do not contain any NO2 gas at all.

[0046] The compositions relating to generating NO gas for NO inhalation therapy described herein comprise nitrites and elemental metals. In some embodiments, the compositions comprise acids. The elemental metals in the compositions are selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental sodium, elemental potassium, elemental beryllium, elemental rubidium, elemental cesium, elemental aluminum, elemental gallium, elemental indium, elemental tin, elemental bismuth, elemental scandium, elemental titanium, elemental vanadium, elemental chromium, elemental manganese, elemental cobalt, elemental manganese, elemental scandium, elemental titanium, nickel, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technitium, elemental ruthenium, elemental rhodium, elemental palladium, elemental silver, elemental cadmium, elemental lanthanum, elemental hafnium, elemental tantalum, elemental tungsten, elemental rhenium, elemental osmium, elemental iridium, elemental platinum, elemental gold, elemental manganese, and elemental iron. In some embodiments, the nitrite in the composition is a nitrite, such as sodium nitrite or potassium nitrite. In other embodiments, the nitrite in the composition is a plant-based source of nitrite standardized for its nitrite content, such as beetroot powder.

[0047] In some embodiments, the composition may be in the form of capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, oral tablets, liquids, elixirs, syrups, tinctures, suspensions, emulsions, mouthwashes, sprays, drops, ointments, creams, gels, pastes, transdermal patches, suppositories, pessaries, creams, gels, pastes, foams, or combinations thereof. The composition may further contain acceptable additives and / or acceptable carriers. Acceptable additives may be selected from at least one member of the group consisting of solubilizers, enzyme inhibitors, anticoagulants, antifoaming agents, antioxidants, colorants, coolants, cryoprotectants, hydrogen bonding agents, flavoring and odor-correcting agents, plasticizers, preservatives, sweeteners, and thickeners. Acceptable carriers may be selected from at least one member of the group consisting of excipients, lubricants, binders, disintegrants, diluents, expanders, solvents, suspending agents, solubilizers, isotonic agents, buffers, sedatives, and amphiphilic lipid delivery systems. In some embodiments, the composition is in a form suitable for oral administration. In other embodiments, the composition is in a form suitable for inhalation of gases generated when in contact with an acidifying solvent.

[0048] In some embodiments, the composition contains an effective amount of nitrite to produce a therapeutic effect and an effective amount of elemental metal to prevent or reduce the toxicity of the nitrite. The therapeutic effect of the nitrite may be to lower blood pressure or to treat and / or alleviate the symptoms of respiratory disease. Respiratory disease may be an infection caused by coronavirus, influenza virus, respiratory polynuclear virus, Streptococcus pneumoniae, Haemophilus influenzae type b, Pneumocystis jiroveci, fungi, or protozoa. In certain embodiments of the therapeutic composition, the effective amount of nitrite is 1 to 1000 mg and the effective amount of elemental metal is 1 to 10000 mg. In other embodiments, the effective amount of nitrite is 5 to 200 mg and the effective amount of elemental metal is 5 to 1000 mg. In certain embodiments of the therapeutic composition, the effective amount of nitrite is 30 to 100 mg and the effective amount of elemental metal is 10 to 400 mg.

[0049] In certain embodiments of the therapeutic composition, the nitrite is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets; the elemental metal is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets. In other embodiments, the nitrite is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets; the elemental metal is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets; and the acid is packaged separately from the nitrite and elemental metal. In some embodiments, the nitrite, elemental metal, and acid are in solid form. In certain embodiments, the nitrite and the elemental metal are packaged together, for example, in a capsule, a cachet, a pill, or a tablet.

[0050] Methemoglobinemia, a condition that can be monitored by a decrease in SpO2 levels, is a side effect associated with inhaled NO therapy (Raut and Maheshwari, "Inhaled nitric oxide, methemoglobinemia, and route of delivery." Saudi J Anaesth. 2017, 11(3):364). Surprisingly, it has been found that methemoglobinemia did not develop as a result of NO gas administration by the method described herein. The mechanism by which methemoglobinemia was not induced by the method disclosed herein is under investigation, but the hydrogen gas products of the reaction between nitrate anions and elemental metals in acidic solutions may have a protective effect. If the prevention and treatment of methemoglobinemia is a result of using this method, it should be noted that some elemental metals, such as aluminum, can produce hydrogen by reacting with a base: 2Al + 2NaOH + 2H2O → 2NaAlO2 + 3H. The objective of this invention is to produce NO gas by the reaction of nitrite with an acid in a single beaker, and to produce H2 gas by the reaction of a metal that generates hydrogen when in contact with a base such as aluminum.

[0051] During the development of the present invention, the principal inventor found that he himself was repeatedly exposed to NO levels exceeding 25 ppm (measured with a BW BWS-NY yellow housing, single nitric oxide (NO) gas detector) over extended periods, and no disease effects were observed. In fact, his oxygenation levels, measured by an SpO2 oximeter, were consistently in the range of 97–100. Accordingly, a method for preventing the development of methemoglobinemia from nitrate, nitrite, or NO exposure is also disclosed herein, comprising administering hydrogen to a source of nitrate, a source of nitrite, or a subject exposed to NO.

[0052] In some embodiments, a method is described for administering inhaled nitric oxide gas having reduced toxicity to a subject. In some embodiments, the reduction in toxicity manifests as reduced lung injury compared to the amount of lung injury that would be expected to occur with administration of NO gas alone at the same concentration. In other embodiments, the reduction in toxicity manifests as a subject's blood methemoglobin level not exceeding 2%. In other embodiments, a method for reducing inhaled NO toxicity is described, comprising inhaling NO with an effective amount of hydrogen to reduce NO toxicity (e.g., lung tissue damage, increased nitrotyrosine levels in NO-exposed tissues, and development of methemoglobinemia). The method comprises administering nitric oxide gas to a subject and administering hydrogen gas to a subject. In certain particular implementations, the method further comprises administering nitroxyl gas to a subject. In some embodiments, a method for therapeutically administering inhaled NO gas is described as comprising co-administering an effective amount of hydrogen gas with NO gas to a subject. The effective amount of hydrogen is sufficient to reduce or prevent NO2 formation during the administration of NO gas to the subject. In some embodiments, the effective amount of hydrogen gas is at least 1000 ppm. In a particular embodiment, the method involves mixing an elemental metal with a nitrate and / or nitrite in an acidifying solvent to thereby produce NO gas and an effective amount of hydrogen gas, which is then administered to a subject by inhalation.

[0053] Compositions containing nitric oxide gas and hydrogen gas are also described. The concentrations of the gases in the composition are at least 1 ppm of nitric oxide gas and at least 5 ppm of hydrogen gas. In certain embodiments, the composition contains 1 to 10,000 ppm of hydrogen gas and 1 to 500 ppm of nitric oxide gas. In compositions containing nitric oxide gas and hydrogen gas, the concentration of hydrogen gas does not result in the formation of liquid water. [Examples]

[0054] (Example 1) An acid solution was prepared by dissolving 5 grams of citric acid in 100 ml of warm water in a 1000 ml beaker. Elemental magnesium (200 mg) and potassium nitrate (1000 mg) were simultaneously added to the acid solution. Using FeNO with a Niox instrument capable of measuring ambient NO levels, the formation of NO gas from the addition of elemental magnesium and potassium nitrate to the acid solution was tested. The room NO level before the experiment was 0. Immediately after the addition of elemental magnesium and potassium nitrate to the acid solution, the instrument recorded 200 ppb of NO. Since 200 ppb is the detection limit of the instrument, more NO may have been generated.

[0055] (Example 2) An acid solution was prepared by mixing 1000 mg of citric acid in a beaker bong containing warm water. 200 mg of elemental magnesium and 1000 mg of potassium nitrate were emptied from pre-filled capsules into the bong containing the acid solution. A 58-year-old male subject suffering from migraines inhaled the gas produced through the beaker bong. The subject reported that his headache had stopped and his breathing had become easier. The subject also reported an increase in his energy and concentration levels.

[0056] (Example 3) In a comparison of the time to fatigue on an exercise bike, a 39-year-old subject reported that after inhaling the gas produced in a bicarbonate according to the same method described in Example 2, his time to fatigue on the exercise bike at its highest intensity setting increased by 5 minutes. In another case, a subject reported that after inhaling NO gas produced by mixing elemental magnesium and potassium nitrate, the maximum number of push-ups he could perform increased by 10 (the maximum number of push-ups increased from 50 to 60).

[0057] (Example 4) To confirm that hydrogen gas is a byproduct of combining elemental metals with acids, one teaspoon of elemental magnesium powder was added to a vial containing 100 ml of saturated citric acid water. The air at the top of the vial was flammable.

[0058] (Example 5) Sodium nitrite is known to be toxic in high doses. Due to its toxicity, its use as an NO source in therapeutics is limited to antidotes used for cyanide poisoning. The lowest calculated lethal dose is 2.6 grams (Katabami et al., "Severe Methemoglobinemia due to Sodium Nitrite Poisoning", Case Reports in Emergency Medicine, 2016, Article ID 9013816), but cases of severe methemoglobinemia have been reported at much lower doses. A 600 mg dose to adults for the treatment of cyanide toxicity resulted in a 58% methemoglobin level (van Heijst et al., "Therapeutic Problems in Cyanide Poisoning", Journal of Toxicology: Clinical Toxicology, 1987, 25(5): 383-398). Moderate to severe poisoning is associated with cyanosis (bluish skin), confusion, loss of consciousness, seizures, abnormal cardiac rhythms, and death. Since there are no observed cases of methemoglobinemia in subjects ingesting combinations of single metal and nitrate sources, or inhaling gases produced by this combination in acidic solutions, it has been hypothesized that exposure to hydrogen gas and / or zinc / magnesium ions may prevent the development of methemoglobinemia. Methemoglobinemia can be monitored both directly by time-consuming blood tests and indirectly by SpO2 measurement. Because methemoglobin cannot carry oxygen, higher methemoglobin levels result in lower oxygen saturation levels.

[0059] One of the inventors, who had fasted overnight, ingested a capsule containing 310 mg of NaNO2 and another capsule containing 1000 mg of citrate for the purpose of inducing methemoglobinemia, while the other inventor monitored the condition of the test inventor. After the first 15 minutes, the test inventor began to experience undesirable side effects, including gastrointestinal distress, dizziness, brain fog, confusion, shortness of breath, migraine, abnormal cardiac palpitations, tachycardia with a peak of 240 beats / min, and, approximately 25 minutes after the start of the experiment, a low SpO2 level with a lowest reading of 91. The test inventor's SpO2 levels and heart rate throughout the experiment are summarized in Table 1. SpO2 levels and heart rate readings were recorded and can be found in the chart below. [Table 1]

[0060] After a 48-hour washout period, the inventors under test prepared three capsules, each containing 1000 mg of elemental magnesium powder, and three other capsules, each containing 1000 mg of citric acid. Elemental magnesium powder reacts violently with acid in a highly exothermic reaction. Therefore, it was unclear whether the ingestion of such large amounts of elemental magnesium was safe, or even tolerable, and whether their reaction with toxic doses of nitrite was tolerable. Nevertheless, the inventors under test ingested capsules containing 310 mg of sodium nitrite and 1000 mg of elemental magnesium, along with two capsules containing 1000 mg of citric acid in each capsule (the amount of citric acid was doubled compared to the initial dose in the first experiment, as it was assumed that some of the acid would be consumed by the elemental magnesium). After 30 and 60 minutes, the inventors under test ingested another 1000 mg of elemental magnesium and 1000 mg of citric acid in capsule form. The inventor did not experience any of the undesirable side effects of the first experiment. The only side effect observed was drowsiness, which he had experienced many times in the past and was associated with low blood pressure. His SpO2 level remained elevated compared to the first experiment and never dropped below the 95% threshold level. Table 2 summarizes the inventor's SpO2 level and heart rate throughout the course of the second experiment. [Table 2-1] [Table 2-2]

[0061] The inventor being tested was in perfect health 90 minutes after the experiment. His SpO2 level was in the range of 95% to 97%.

[0062] (Example 6) Nitrogen dioxide is an orange, odorous gas that can be formed from the reaction of high concentrations of nitric acid with air (concentrated HNO3 is called "red fuming nitric acid" because it constantly produces orange NO2 in open air) and from the oxidation of nitric oxide (NO) by atmospheric oxygen (Holleman and Wiberg, Inorganic Chemistry. Academic Press: San Diego, 2001). When nitrogen is released during the combustion of fuel, it combines with oxygen atoms to produce NO. NO further combines with oxygen to produce nitrogen dioxide (NO2). NO is not considered harmful to health at typical ambient concentrations, but nitrogen dioxide can be harmful. NO2 is also formed by the decomposition of nitrites in acidic solutions. If strongly acidified sodium nitrite is used, this can be converted to nitrite. Nitrite is very unstable and readily decomposes into NO2, NO (which can further react with oxygen in air to become NO2), and water. Therefore, inhalation of gas products from the reaction of nitrites with acids in solution is generally considered unsafe due to the resulting NO2 levels. NO2 is a major issue in the therapeutic use of NO gas. Current NO tanks typically contain 0.1% NO gas in inert nitrogen gas, but NO2 remains a major challenge in the therapeutic use of NO gas.

[0063] Administration of inhaled nitric oxide (NO) using existing compressed gas delivery systems inevitably results in the simultaneous delivery of nitrogen dioxide (NO2). Under average atmospheric conditions, NO2 concentration is higher than NO concentration (Levaggi, et al., "Quantitative analysis of nitric oxide in presence of nitrogen dioxide at atmospheric concentrations," Environ. Sci. Technol., 1974, 8(4): 348-350) (see Figure 2).

[0064] Equilibrium is expected to be much higher in atmospheres with higher oxygen saturation, such as those experienced by individuals treated with 100% oxygen.

[0065] Totapally et al. showed that in a mechanical ventilation model designed to mimic NO delivery in humans, NO2 increased to a high toxic concentration of 19.4 ppm by the time NO reached the lungs. Meanwhile, NO2 levels continued to rise, while NO concentration decreased, so the total NO+NO2 concentration remained the same. NO concentrations decreased significantly from the proximal port (site 11 in the inspiratory circuit) (86.16 ± 0.38 ppm) to the lung bellows (site 4) (70.08 ± 0.23 ppm) (P<.001). NO2 concentrations increased significantly from site 1 (3.25 ± 0.04 ppm) to site 4 (19.4 ± 0.19 ppm) (P<.001). NO2 concentrations in the lungs increased significantly above normally acceptable toxic concentrations during ventilation with high concentrations of NO (80 ppm) and high fractional concentrations of oxygen (emphasis added). (Totapally et al., "Nitric oxide and nitrogen dioxide concentrations during in vitro high-frequency oscillatory ventilation," J Crit Care. 1999, 14(3):141-149).

[0066] Even in the proximal port (considered to be the nose or throat), NO2 levels were already well above what is considered safe / acceptable (less than 2 ppm, the U.S. Environmental Protection Agency's standard for air quality regarding nitrogen oxides, EPA reference number EPA / 600 / 8-91 / 049aF-cF). Numerous biochemical studies have found levels as high as 3160 μg / m³. 3 Studies have shown that acute or subchronic exposure to high levels of nitrogen dioxide (NO2) above 2 ppm can cause adverse effects, and this is currently the maximum WHO recommended level. For individuals with respiratory tract conditions such as asthma, COVID-19, pneumonia, and COPD, NO2 levels must be kept as low as possible during NO therapy.

[0067] experiment: 500 ml of room temperature (approximately 20°C) water was added to a 700 ml glass. A BW BWS-DY yellow housing, single nitrogen dioxide (NO2) gas detector (wired) was clipped to the rim of the glass so that the sensor was as close to the water surface as possible without touching the water. 3000 mg of citric acid was dissolved in the water to simulate stomach acidic conditions, but for the purpose of producing "clean" NO gas, citric acid can be replaced with any other suitable acidifying agent. SpO2max capsules (1200 mg KNO3, 200 mg elemental magnesium, 50 mg elemental zinc) were dissolved in the solution, and the entire process was recorded. The reaction immediately produced therapeutic concentrations of NO (>20 ppm), providing similarly beneficial effects to patients and healthy individuals. For the first approximately 10 minutes of the reaction, no NO2 was released. For the next 20 minutes, a small release of NO2 occurred (less than 2 ppm, especially less than 1.7 ppm). Therefore, if it is necessary to administer the reaction product during the first 10 minutes of the reaction and then administer more NO, it is possible to administer NO without the presence of NO2 by re-preparing the reaction mixture. Naturally, it is possible to produce "clean" NO gas with different reaction rates and / or reactants, over longer periods, and without any NO2 gas at all, a possibility that the applicant intends to fully explore. Thus, the described method of administering NO is easier, healthier, cheaper, and safer than current NO gas delivery methods.

[0068] (Example 7) In the process of developing the described method for generating NO for a more readily available, effective, and safe source of NO therapy, one of the inventors was accidentally exposed to NO gas chronically and acutely. The day after exposure to high levels of ambient NO (ambient NO > 80 ppm), he began to experience symptoms of methemoglobinemia and had pneumonia, as indicated by an 85% SpO2, dizziness, lung pain, and weakness. From the onset of symptoms, the inventor inhaled H2 gas produced by reacting elemental magnesium and citrate in a glass of water. He also ingested 2000 mg of elemental magnesium powder with water, which was thought to react with HCl in his stomach to produce H2 gas.

[0069] His condition and SpO2 worsened throughout the day, and later that night he was admitted to the ER, where his SpO2 recorded 45%. The hospital confirmed by X-ray and CAT scans that the inventor had developed NO-induced pneumonia. At the time of diagnosis, a blood sample was taken from the inventor to measure his methemoglobin levels. To the medical staff's surprise, no methemoglobin was detected, even while the inventor had an SpO2 of 45%. The normal methemoglobin fraction is approximately 1%. During his transfer, he also showed no cyanosis (blue skin), which is associated with people with 3-15% methemoglobin. For this reason, methemoglobin treatment (iv methylene blue) was not administered to the inventor.

[0070] Therefore, NO-induced methemoglobinemia was treated and / or alleviated by hydrogen inhalation and ingestion (in the form of an elemental metal, in this case magnesium). However, the inventors caution that the presence of fluid in the lungs must be in a concentrated state that does not form liquid water in the lungs.

[0071] (Example 8) Place a flask containing 100 ml of 0.1 M HCl into a Bel-Art Secador polystyrene mini dryer cabinet (0.31 ft 3The contents of one capsule containing 1200 mg of KNO3, 200 mg of elemental magnesium, and 50 mg of elemental zinc, and the contents of a second capsule containing 1000 mg of citrate were added to the flask. The NO sensor was placed in a drying cabinet. After 10 minutes, the NO level rose from 0 ppm to 6.4 ppm. Therefore, theoretically, in an average stomach with a size of 1 liter, the amount of NO in the stomach resulting from the ingestion of two capsules should be 56 ppm.

[0072] In particular, adding one teaspoon of KNO3 to 50 ml of 25% HCl did not produce any measurable amount of NO gas.

[0073] (Example 9) A 100ml vial containing 100mg of NaNO3 and 50mg of elemental magnesium is placed in a Bel-Art Secador polystyrene mini dryer cabinet (0.31ft 3 The samples were placed in a dryer cabinet. The Honeywell NO and Honeywell NO2 detectors were activated and also placed in the dryer cabinet. The vials were filled with 0.1N HCl and the containers were quickly sealed. Within 3 minutes, the NO gas concentration exceeded the therapeutic level of 20 ppm. NO2 was not detected.

[0074] Five minutes after adding hydrochloric acid, NO levels reached 31.4 ppm, while NO2 levels remained below 2 ppm, a level recognized as causing harmful biological effects.

[0075] (Example 10) Honeywell NO and Honeywell NO2 detectors, along with vials, in a Bel-Art Secador polystyrene mini dryer cabinet (0.31 ft 3A gelatin capsule containing 1000 mg of citric acid, as well as gelatin capsules containing 1200 mg of KNO3, 200 mg of elemental (metallic) magnesium, and 50 mg of elemental (metallic) zinc, were added to the vial. After adding 100 ml of 0.1 N HCl (to simulate stomach acid conditions) to the vial, the door of the drying cabinet was quickly closed. The NO level rose to a concentration of 10.6 ppm at 40-minute intervals, at which point 1 ppm of NO2 was formed. Therefore, the remarkable effect of this oral formulation in the treatment of respiratory diseases is due not only to the formation of NO, but also to the fact that NO is not converted to NO2.

[0076] (Example 11) To further investigate the mechanism behind the unexpected results in Examples 9 and 10, hydrogen and oxygen sensors were placed in the drying cabinet along with NO and NO2 sensors under the same conditions (same reactants) as in Example 10.

[0077] During the reaction, the H2 level rose rapidly. The rise in H2 levels was detected 3 minutes after HCl was added to the flask, which preceded the rise in NO levels. Approximately 20 minutes after the start of the reaction, the H2 concentration reached 1000 ppm, the maximum capacity of the sensor. Approximately 50 minutes after the start of the reaction, the NO concentration reached 15 ppm and the NO2 concentration reached 2 ppm.

[0078] Surprisingly, oxygen loss was not monitored by the oxygen sensor. In previous experiments, the inventors found that excessive inhalation of H2 gas could lead to a decrease in SpO2, which may be due to the formation of water in the lungs through the reaction of atmospheric oxygen and hydrogen. The hypothesis that high concentrations of hydrogen can react with atmospheric oxygen to form water in the lungs was confirmed in a later experiment in which 10 grams of elemental magnesium were added to 500 ml of water in a vial placed in a dehydrator cabinet. As a result, the O2 level decreased simultaneously with an increase in the humidity level, which was measured by an increase in the specific gravity of the liquid. In fact, obvious water droplets were observed on the walls of the dehydrator cabinet.

[0079] In light of the results of this application, exposure to 1000 ppm of H2 is presumed to be safe, but further experiments are needed to find the safest and most effective ratio of NO, nitrogen gas, and hydrogen gas.

[0080] (Example 12) Three experiments were conducted to further clarify the relationship between NO, NO2, and H2, and their use for treating patients through the inhalation or ingestion of NO-producing preparations.

[0081] In the first experiment, a 100 ml vial containing 200 mg of elemental (metallic) magnesium in 100 ml of 0.1 N HCl was placed in the same cabinet used in Examples 9-11, along with the NO, NO2, and H2 sensors used in those examples, and the cabinet door was quickly closed. The H2 level rose rapidly to over 1000 ppm. The NO and NO2 levels remained at zero for one hour, as recorded after the vial was placed in the drying cabinet.

[0082] In the second experiment, a 100 ml vial containing 100 mg of NaNO2 and 100 ml of 0.1 N HCl was placed in the same cabinet used in Examples 9-11, along with NO, NO2, and H2 sensors. After 2 minutes, the levels of NO and NO2 began to rise rapidly, with the NO2 level exceeding 2 ppm and the NO level exceeding 4.2 ppm. The H2 level remained at 0 ppm.

[0083] Three minutes after the start of the reaction, the NO2 level exceeded the safety limit of 5 ppm, while the NO level rose to 13 ppm. The H2 level remained at 0 ppm. Thirty minutes after the reaction, the NO2 level reached 58 ppm, which is theoretically high enough to kill a person with just a few minutes of inhalation exposure. The NO level was approximately 58 ppm, almost equal to the NO2 level. Interestingly, the H2 level rose to 112 ppm. The reaction mechanism for hydrogen production is unknown (possibly due to partial evaporation of HCl gas), but this concentration of H2 was not high enough to affect a person, and its presence did not have a positive effect on the decrease in the NO / NO2 ratio.

[0084] In the third experiment, two 100 ml vials were placed in the same cabinet used in Examples 9-11, along with the NO, NO2, and H2 sensors used in those examples. One vial contained 200 mg of elemental (metallic) magnesium in 100 ml of 0.1 N HCl, which has been shown to rapidly generate H2 at levels exceeding 1000 ppm. The other vial contained 100 mg of NaNO2 in 100 ml of 0.1 N HCl. Throughout the 30-minute recording, the NO / NO2 ratio remained at approximately 2:1. At 30 minutes after the start of the reaction, the NO level was 44 ppm NO and the NO2 level was 22 ppm NO2. The H2 level rapidly rose to 1000 ppm, the detection limit of the sensor, as in the previous experiment, and remained at this level throughout the 30-minute recording period. Therefore, the simultaneous presence of hydrogen gas and NO may reduce NO2 formation and improve the safety and effectiveness of NO inhalation.

[0085] (Example 13) A pair of sheep lungs were obtained from Carolina Chemicals. Each lung was placed in a Bel-Art Secador polystyrene mini dryer cabinet (0.31 ft) for a study on the effects of exposure to NO based on how the gas is produced. 3The lung was inserted into a chamber. In one lung, NO and its byproduct, nitrogen dioxide, were generated in the chamber by mixing 200 mg of sodium nitrite with 1 gram of citrate in 100 ml of water. The lung was exposed to the gas for 4 hours. The lung was sectioned and examined under a microscope, revealing significant histopathological damage (alveolar wall lysis) and tissue discoloration. The experiment was repeated with a second lung, this time exposed to NO generated via a mixture of 200 mg of elemental magnesium, 50 mg of elemental zinc, 1200 mg of KNO3, and 1000 mg of citrate in 100 ml of water. After 2 hours, the lung was removed, sectioned, and examined under a microscope for histopathological damage or tissue discoloration. No histopathological damage or tissue discoloration was observed in the lung.

[0086] (Example 14) The size of elemental magnesium affects the efficacy, safety, and side effect profile of the administered composition.

[0087] Multiple iterations of compositions containing elemental metals with varying mesh sizes were prepared and tested in subjects to determine whether the mesh size of the elemental metals affects the benefits and / or side effects that subjects may experience upon ingestion. Table 3 lists the formulations tested. [Table 3]

[0088] Different formulations demonstrated varying efficacy in alleviating respiratory illnesses. In some cases, subjects experienced side effects, including gastrointestinal disturbances, diarrhea, nausea, and vomiting. Adverse effects were far more common with magnesium dust formulations than with other formulations.

[0089] (Example 15) Various forms of elemental magnesium can produce potassium nitrate and H2, NO, and NO2 gases.

[0090] Using single magnesium in three forms (and sizes) of 200 mg amounts, after mixing with 1200 mg of KNO3 and 1000 mg of citric acid powder, the generation of H2, NO, and NO2 gases upon addition of 100 ml of water was compared. Immediately after adding 100 ml of distilled water at room temperature, the beaker containing magnesium was placed in a Bel-Art Secador polystyrene mini drying machine cabinet (0.31 ft 3 ). At the start of the experiment with magnesium powder, granular magnesium, and magnesium beads, all sensors for H2, NO, and NO2 were zero.

[0091] Approximately 90 seconds after adding water to the beaker containing magnesium powder (60 - 200 mesh size) and 1200 mg of KNO3 and 1000 mg of citric acid powder, the concentration of NO gas was 12.8 ppm, the concentration of NO2 gas was 0 ppm, and the concentration of H2 gas was 142 ppm. As the experiment continued, the concentrations of NO and H2 gases continued to increase. Two minutes after adding water to the powder, the concentration of NO gas was 39.2 ppm, the concentration of H2 gas was 435 ppm, and the concentration of NO2 gas was 0 ppm. This ratio of NO to NO2 is remarkable. Reaching nearly 40 ppm of NO gas with zero NO2 has never been heard of before. Five minutes after adding water to the powder, the NO gas reached 49 ppm while the NO2 gas increased to 3.0 ppm. The hydrogen gas increased to over 1000 ppm (the maximum detection range of the sensor).

[0092] In the experiment with granular magnesium (approx. 35 mesh size) and 1200 mg of KNO3 and 1000 mg of citric acid powder, the concentrations of NO gas, H2 gas, and NO2 gas were 3.8 ppm, 66 ppm, and 0 ppm respectively at 1 minute after adding water. At 5 minutes after adding water, the sensor readings were 11.4 ppm for NO gas, 186 ppm for H2 gas, and 0 ppm for NO2 gas. Thus, using granular magnesium produced much less NO and H2 gases, approximately one-fourth of NO in the same time frame compared to magnesium powder.

[0093] In experiments using magnesium beads (approximately 5 mm in diameter) and 1200 mg of KNO3 and 1000 mg of citric acid powder, neither NO gas nor NO2 gas was produced at 1 minute and 20 seconds into the experiment. Five minutes after the addition of water, the sensor reading for NO gas was 16.2 ppm, for NO2 gas it was 0 ppm, and for hydrogen it was 337 ppm.

[0094] Our experiments demonstrate that the simultaneous generation of H2 gas and NO gas by the methods and compositions of this disclosure reduces or even eliminates the generation of NO2 gas.

[0095] (Example 16) It should also be noted that the inventors noticed that high concentrations of hydrogen, when inhaled for extended periods, can lead to water formation, which in turn can result in water accumulation in the lungs, potentially hindering oxygen absorption from the lungs. This is thought to explain the low SpO2 experienced by the inventors when they inhaled H2 gas for extended periods to combat methemoglobinemia caused by NO. In a series of experiments comparing atmospheric humidity with the H2 concentration obtained from the formulation at an ambient temperature of 30°C, the inventors noticed that relative humidity increased by 1% for every approximately 40 ppm increase in H2 concentration (the amount of water vapor present in the air is expressed as a percentage of the amount required for saturation at the same temperature). The results of the increase in relative humidity with increasing H2 concentration are shown in Table 4 below. [Table 4] Although the sensor reached its limit at 1000 ppm, these experiments, and the absence of any symptoms such as the presence of fluid in the lungs (edema) in any of the subjects, indicate that an H2 concentration of 1000 ppm is safe. H2 concentrations up to 1500 ppm are also assumed to be safe, as there is no recognizable H2O formation in the lungs of subjects inhaling the gas produced from the composition. The present invention provides, for example, the following items: (Item 1) A method for generating NO gas for NO inhalation therapy, comprising combining a source of nitrate anions and an elemental metal in an acidic solution in a container capable of containing liquid and gaseous components, thereby generating NO gas. (Item 2) The method according to item 1, wherein the elemental metal is selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental potassium, elemental sodium, elemental beryllium, elemental barium, and elemental iron. (Item 3) The method according to item 2, wherein the elemental metal is elemental magnesium. (Item 4) The method according to item 3, wherein the elemental metal is elemental zinc. (Item 5) The method according to item 1, wherein the source of the nitrate anion is a nitrate. (Item 6) The method according to item 1, wherein the source of the nitrate anion is a plant-based source of nitrate. (Item 7) A supply of an effective amount of nitrate anion and an effective amount of the elemental metal are combined in the acidic solution to produce an effective amount of NO gas. The effective amount of the aforementioned elemental metal is between 1 mg and 2000 mg. The source of the effective amount of nitrate anion yields between 30 mg and 4000 mg of nitrate anion. The method described in item 1. (Item 8) The method according to item 1, wherein an effective amount of the nitrate anion source and an effective amount of the elemental metal are combined in the acid solution in a ratio of 10:1 to 1:10 to produce an effective amount of NO gas. (Item 9) An effective amount of the nitrate anion source and an effective amount of the elemental metal are combined in the acid solution to form at least 5 ppm of NO gas and 1000 ppm of H 2 The method described in item 1 for generating gas. (Item 10) The method according to any one of items 1 to 9, wherein the pH of the acidic solution is between 0.1 and 6.9. (Item 11) The method according to any one of items 1 to 9, wherein the pH of the acidic solution is between 2 and 4. (Item 12) The method according to any one of items 1 to 9, further comprising dissolving an acid powder in a solvent to produce the acidic solution. (Item 13) The method according to item 12, wherein the acid powder is citric acid, malic acid, or fumaric acid. (Item 14) The method according to item 12, wherein the solvent is water. (Item 15) The method according to item 15, wherein the acid powder is dissolved in water between 1 ml and 10,000 ml. (Item 16) The gaseous component produced by combining the source of nitrate anions and the elemental metal in the acidic solution is at an unsafe level of NO 2 A method according to any one of items 1 to 9, which does not involve gas. (Item 17) NO produced by combining the nitrate anion source and the elemental metal in the acidic solution. 2 The method described in item 16, wherein the gas level does not exceed 2 ppm. (Item 18) NO produced by combining the nitrate anion source and the elemental metal in the acidic solution.2 The method described in item 16, wherein the gas level does not exceed 5 ppm. (Item 19) NO produced by combining the nitrate anion source and the elemental metal in the acidic solution. 2 The method described in item 16, wherein the gas level does not exceed 10 ppm. (Item 20) The gaseous component produced by combining the nitrate anion source and the elemental metal in the acidic solution is NO 2 The method described in item 16, which contains no gas at all. (Item 21) The method according to any one of items 1 to 9, wherein the gaseous component produced by combining the source of the nitrate anion and the elemental metal in the acidic solution further comprises nitroxyl gas. (Item 22) A method for safely producing NO gas for NO inhalation therapy, comprising combining a source of nitrite anions and an elemental metal in an acidic solution in a container capable of containing liquid and gaseous components, thereby producing NO gas. (Item 23) The method according to item 22, wherein the elemental metal is selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental potassium, elemental sodium, elemental beryllium, elemental barium, and elemental iron. (Item 24) The method according to item 22, wherein the elemental metal is elemental magnesium. (Item 25) The method according to item 22, wherein the elemental metal is elemental zinc. (Item 26) The method according to item 22, wherein the source of the nitrite anion is a nitrite. (Item 27) The method according to item 22, wherein the source of the nitrite anion is a plant-based source of nitrite. (Item 28) The method according to item 22, wherein an effective amount of the nitrite anion source and an effective amount of the elemental metal are combined in the acidic solution to produce an effective amount of NO gas, the effective amount of the elemental metal being between 1 mg and 2000 mg, and the effective amount of the nitrite anion source yielding 1 mg to 1000 mg of nitrite anion. (Item 29) The method according to item 22, wherein an effective amount of the nitrite anion source and an effective amount of the elemental metal are combined in the acid solution in a ratio of 10:1 to 1:10 to produce an effective amount of NO gas. (Item 30) An effective amount of the nitrite anion source and an effective amount of the elemental metal are combined in the acid solution to form at least 5 ppm of NO gas and 1000 ppm of H 2 The method described in item 22 for generating gas. (Item 31) The method according to any one of items 22 to 30, wherein the pH of the acidic solution is between 0.1 and 6.9. (Item 32) The method according to any one of items 22 to 30, wherein the pH of the acidic solution is between 2 and 4. (Item 33) The method according to any one of items 22 to 30, further comprising dissolving an acid powder in a solvent to produce the acidic solution. (Item 34) The method according to item 33, wherein the acid powder is citric acid, malic acid, or fumaric acid. (Item 35) The method according to item 33, wherein the solvent is water. (Item 36) The method according to item 35, wherein the volume of water is between 1 ml and 10,000 ml. (Item 37) The gaseous component produced by combining the source of nitrate anions and the elemental metal in the acidic solution is at an unsafe level of NO 2 The method described in any one of items 22 to 30, excluding gases. (Item 38) NO produced by combining the nitrite anion source and the elemental metal in the acidic solution. 2 The method described in item 37, wherein the gas level does not exceed 2 ppm. (Item 39) NO produced by combining the nitrite anion source and the elemental metal in the acidic solution. 2 The method described in item 37, wherein the gas level does not exceed 5 ppm. (Item 40) NO produced by combining the nitrite anion source and the elemental metal in the acidic solution. 2 The method described in item 37, wherein the gas level does not exceed 10 ppm. (Item 41) The gaseous component produced by combining the nitrite anion source and the elemental metal in the acidic solution is NO 2 The method described in item 37, which contains no gas at all. (Item 42) The method according to items 22-30, wherein the gaseous component produced by combining the nitrite anion source and the elemental metal comprises nitroxyl gas. (Item 43) The method according to any one of items 1 to 42, further comprising administering the NO gas to a subject through a container capable of containing liquid and gaseous components. (Item 44) The method according to item 43, wherein the container capable of containing liquid and gaseous components is a water pipe. (Item 45) The method according to item 44, wherein administering the NO gas to the subject through a container capable of containing liquid and gaseous components is performed by the subject inhaling it through a water pipe. (Item 46) The method according to item 45, wherein the container is connected to a ventilator via a pipe. (Item 47) The methods described in items 44-46, relating to the subject who suffers from shortness of breath, suffers from migraines, has an oxygen saturation level below 95, seeks to improve exercise capacity, seeks to increase endurance, or seeks to improve mental performance. (Item 48) A method for therapeutically administering inhaled NO gas, comprising simultaneously administering an effective amount of hydrogen gas to a subject together with NO gas, wherein the effective amount of hydrogen is equivalent to the amount of NO gas administered to the subject during the NO gas administration. 2 A method that is sufficient in quantity to reduce or prevent the formation of [unclear]. (Item 49) The method according to item 48, wherein the effective amount of hydrogen gas is at least 1000 ppm. (Item 50) The method according to item 48 or 49, comprising mixing an elemental metal with a nitrate and / or nitrite in an acidifying solvent to generate NO gas and the effective amount of hydrogen gas, and administering it to the subject by inhalation. (Item 51) A method of administering inhaled nitric oxide gas with reduced toxicity to a subject, Administering nitric oxide gas to the subject, and Administering hydrogen gas to the aforementioned subject Methods that include... (Item 52) The method according to item 51, wherein the subject is also administered nitroxyl gas. (Item 53) The method according to item 51 or 52, wherein the reduced toxicity manifests as reduced lung injury compared to the amount of lung injury that would be expected to occur with administration of NO gas alone at the same concentration. (Item 54) The method according to item 51 or 52, wherein the reduced toxicity manifests as the absence of methemoglobinemia. (Item 55) The method according to item 54, wherein the blood methemoglobin level of the subject does not exceed 2%. (Item 56) Nitrite; and Elemental metal A composition containing the following: (Item 57) The composition according to item 56, wherein the nitrite is a nitrite. (Item 58) The composition according to item 57, wherein the nitrite is sodium nitrite or potassium nitrite. (Item 59) The composition according to item 56, wherein the nitrite is a plant-based source of nitrite standardized for its nitrite content. (Item 60) The composition according to item 59, wherein the plant source of nitrite, standardized with respect to nitrite content, is fermented beetroot powder. (Item 61) The composition according to item 56, wherein the elemental metal is selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental sodium, elemental potassium, elemental beryllium, elemental rubidium, elemental cesium, elemental aluminum, elemental gallium, elemental indium, elemental tin, elemental bismuth, elemental scandium, elemental titanium, elemental vanadium, elemental chromium, elemental manganese, elemental cobalt, elemental manganese, elemental scandium, elemental titanium, nickel, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technitium, elemental ruthenium, elemental rhodium, elemental palladium, elemental silver, elemental cadmium, elemental lanthanum, elemental hafnium, elemental tantalum, elemental tungsten, elemental rhenium, elemental osmium, elemental iridium, elemental platinum, elemental gold, elemental manganese, and elemental iron. (Item 62) The compositions described in any one of items 56 to 61, which are in the form of capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, oral tablets, liquids, elixirs, syrups, tinctures, suspensions, emulsions, mouthwashes, sprays, drops, ointments, creams, gels, pastes, transdermal patches, suppositories, pessaries, creams, gels, pastes, foams, and combinations thereof. (Item 63) A composition according to any one of items 56 to 61, further comprising an acceptable additive and / or an acceptable carrier. (Item 64) The permitted additive is selected from at least one member of the group consisting of solubilizers, enzyme inhibitors, anticoagulants, antifoaming agents, antioxidants, colorants, coolants, cryoprotectants, hydrogen bonding agents, flavoring and odor-correcting agents, plasticizers, preservatives, sweeteners, and thickeners; The acceptable carrier is selected from at least one member of the group consisting of excipients, lubricants, binders, disintegrants, diluents, bulking agents, solvents, suspending agents, solubilizers, isotonic agents, buffering agents, sedatives, and amphiphilic lipid delivery systems. The composition described in item 63. (Item 65) A composition according to any one of items 56 to 61, comprising an effective amount of nitrite to produce a therapeutic effect, and an effective amount of elemental metal to prevent or reduce the toxicity of nitrite. (Item 66) The composition described in item 65, in which the toxicity of nitrite manifests as the development of methemoglobinemia. (Item 67) The composition according to item 65, wherein the therapeutic effect of the nitrite is to lower blood pressure or to treat and / or alleviate symptoms of respiratory disease. (Item 68) The composition according to item 67, wherein the respiratory disease is an infection caused by coronavirus, influenza virus, polynuclear respiratory virus, Streptococcus pneumoniae, Haemophilus influenzae type b, Pneumocystis jiroveci, fungi, or protozoa. (Item 69) The effective amount of the nitrite is 1 to 1000 mg, and the effective amount of the elemental metal is 1 to 10000 mg; or The effective amount of the nitrite is 5 to 200 mg, and the effective amount of the elemental metal is 5 to 1000 mg; or The effective amount of the nitrite is 30 to 100 mg, and the effective amount of the elemental metal is 10 to 400 mg. The composition described in item 65. (Item 70) A composition described in item 63, which is in a form suitable for oral administration. (Item 71) The composition described in item 63, which is suitable for inhalation of gases generated when in contact with an acidifying solvent. (Item 72) The nitrite is packaged in the form of capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets; The aforementioned individual metals are packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets. The composition described in item 63. (Item 73) A composition according to any one of items 56 to 61, further comprising an acid. (Item 74) The nitrite is packaged in the form of capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets; The aforementioned individual metals are packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, particles, lozenges, or oral tablets. The acid is packaged separately from the nitrite and the elemental metal. The composition described in item 73. (Item 75) The composition according to item 73, wherein the nitrite, the elemental metal, and the acid are in solid form. (Item 76) The composition according to item 73, wherein the nitrite and the elemental metal are packaged together. (Item 77) The composition according to item 76, wherein the nitrite and the elemental metal are packaged in capsules, cachets, pills, or tablets. (Item 78) A kit for safely administering NO gas to patients, Nitrite or nitrate; A single metal, where the nitrite or nitrate and the single metal are packaged together; Acid; and The nitrite or nitrate, the elemental metal, and the acid are combined to form NO 2 Instructions for generating NO gas without generating gas itself, and for administering the generated NO gas to a patient. A kit that includes this. (Item 79) The kit described in item 78 further includes containers capable of holding liquid and gaseous components. (Item 80) The kit according to item 79, wherein the container capable of containing liquid and gaseous components is a water pipe. (Item 81) The kit according to any one of items 78 to 80, wherein the nitrite or nitrate is a nitrite or nitrate. (Item 82) The kit according to item 81, wherein the nitrite is sodium nitrite or potassium nitrite. (Item 83) The kit according to item 81, wherein the nitrate is sodium nitrate or potassium nitrate. (Item 84) The kit described in any one of items 78 to 80, wherein the elemental metal is selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental sodium, elemental potassium, elemental beryllium, elemental rubidium, elemental cesium, elemental aluminum, elemental gallium, elemental indium, elemental tin, elemental bismuth, elemental scandium, elemental titanium, elemental vanadium, elemental chromium, elemental manganese, elemental cobalt, elemental manganese, elemental scandium, elemental titanium, nickel, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technitium, elemental ruthenium, elemental rhodium, elemental palladium, elemental silver, elemental cadmium, elemental lanthanum, elemental hafnium, elemental tantalum, elemental tungsten, elemental rhenium, elemental osmium, elemental iridium, elemental platinum, elemental gold, elemental manganese, and elemental iron. (Item 85) Nitric oxide gas; and hydrogen gas A composition containing the following: (Item 86) The composition according to item 85, further comprising nitroxyl gas. (Item 87) The composition according to item 85 or 86, wherein the nitric oxide gas is at least 1 ppm in concentration and the hydrogen gas is at a concentration higher than 0.55 ppm. (Item 88) The composition according to item 85 or 86, wherein the concentration of the hydrogen gas is between 1 and 10,000 ppm, and the concentration of the nitric oxide gas is between 1 and 500 ppm. (Item 89) The composition according to item 85 or 86, wherein the concentration of the hydrogen gas does not result in the formation of liquid water. (Item 90) A method for reducing inhaled NO toxicity, comprising inhaling NO together with an effective amount of hydrogen to reduce NO toxicity. (Item 91) The method according to item 90, wherein the reduced NO toxicity is lung tissue damage. (Item 92) The method according to item 90, wherein the NO toxicity to be prevented is an increase in nitrotyrosine levels in tissue exposed to NO. (Item 93) A method for preventing and / or treating methemoglobinemia in a subject, comprising administering an effective amount of hydrogen gas to the subject via inhalation. (Item 94) A method for preventing and / or treating methemoglobinemia in a subject, comprising orally administering an effective amount of a single metal to the subject. (Item 95) The method according to item 94, further comprising orally administering an acid to the subject, wherein the elemental metal is ingested together with the acid. (Item 96) The method according to item 95, wherein the elemental metal and the acid are in amounts effective for generating hydrogen gas in the stomach. (Item 97) The method according to any one of items 93 to 96, wherein the methemoglobinemia is caused by inhaled NO therapy, administration of nitrite, or administration of nitrate. (Item 98) The aforementioned subject is NO 2 A method described in any one of items 93 to 96, which does not exhibit induced toxicity. (Item 99) The aforementioned target is reduced NO 2 A method described in any one of items 93 to 96 that exhibits induced toxicity. (Item 100) The aforementioned NO 2 The method described in item 98 or 99, wherein the induced toxicity is a higher likelihood of lung and / or airway inflammation, decreased lung function, worsening cough, worsening wheezing, increased asthma attacks, or emergency department visit and hospitalization.

Claims

1. A method for producing nitric oxide (NO) gas for NO inhalation therapy, comprising combining a source of nitrate anions or nitrite anions and an elemental metal in an acidic solution in a container capable of holding liquid and gaseous components, wherein the elemental metal is selected from the group consisting of elemental magnesium, elemental calcium, elemental lithium, elemental zinc, elemental potassium, elemental sodium, elemental beryllium, elemental barium, and elemental iron.

2. The method according to claim 1, wherein the elemental metal is selected from the group consisting of elemental magnesium and elemental zinc.

3. The method according to claim 2, wherein the elemental metal is elemental magnesium.

4. The method according to claim 2, wherein the elemental metal is elemental zinc.

5. The method according to claim 1, wherein the source of the nitrate anion or nitrite anion is a nitrate or a nitrite, respectively.

6. The method according to claim 1, wherein the source of the nitrate anion or nitrite anion is a plant-based source of nitrate or nitrite, respectively.

7. A source of an effective amount of nitrate anion or nitrite anion and an effective amount of the elemental metal are combined in the acidic solution to produce an effective amount of NO gas. The effective amount of the aforementioned elemental metal is between 1 mg and 2000 mg. The method according to claim 1, wherein the source of the effective amount of nitrate anions or nitrite anions provides nitrate anions in the range of 30 mg to 4000 mg or nitrite anions in the range of 1 mg to 1000 mg, respectively.

8. The method according to claim 1, wherein an effective amount of a source of nitrate anions or nitrite anions and an effective amount of the elemental metal are combined in the acidic solution in a ratio of 10:1 to 1:10 to produce an effective amount of NO gas.

9. A source of an effective amount of nitrate anion or nitrite anion and an effective amount of the elemental metal are combined in the acidic solution to provide at least 5 ppm of NO gas and at least 1000 ppm of H ２ The method according to claim 1, comprising generating a gas.

10. The method according to any one of claims 1 to 9, wherein the pH of the acidic solution is one of the ranges between 0.1 and 6.9 and between 2 and 4.

11. The method according to any one of claims 1 to 9, further comprising dissolving an acid powder in a solvent to produce the acidic solution.

12. The method according to claim 11, wherein the acid powder is citric acid, malic acid, or fumaric acid.

13. The method according to claim 12, wherein the solvent is water.

14. The method according to claim 13, wherein the water has a volume between 1 ml and 10,000 ml.

15. The gaseous component produced by combining the source of nitrate anions or nitrite anions and the elemental metal in the acidic solution is nitrogen dioxide (NOx) at a level exceeding one of 1 ppm, 2 ppm, 5 ppm, and 10 ppm. ２ The method according to any one of claims 1 to 9, which does not contain gas.

16. The method according to any one of claims 1 to 9, wherein the gaseous component produced by combining the source of the nitrate anion or nitrite anion and the elemental metal in the acidic solution further comprises nitroxyl gas.

17. A kit for safely administering nitric oxide (NO) gas to patients, Nitrite or nitrate; A single metal, wherein the single metal is selected from the group consisting of single magnesium, single calcium, single lithium, single zinc, single potassium, single sodium, single beryllium, single barium, and single iron, and the nitrite or nitrate and the single metal are packaged together; Acid; and The nitrite or nitrate, the elemental metal, and the acid are combined to form nitrogen dioxide (NO ２ Instructions for generating NO gas without generating gas, and for administering the generated NO gas to a patient. A kit that includes this.

18. The kit according to claim 17, further comprising a container capable of containing liquid and gaseous components.

19. The kit according to claim 18, wherein the container capable of containing liquid and gaseous components is a water pipe.

20. The kit according to any one of claims 17 to 19, wherein the nitrite or nitrate is a nitrite or a nitrate.

21. The kit according to claim 20, wherein the nitrite is sodium nitrite or potassium nitrite, and the nitrate is sodium nitrate or potassium nitrate.

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