CN117177758A

CN117177758A - Method for applying nitric oxide gas

Info

Publication number: CN117177758A
Application number: CN202280027669.2A
Authority: CN
Inventors: R·克雷默; A·尼古拉迪斯
Original assignee: Semer Life International
Current assignee: Semer Life International
Priority date: 2021-02-11
Filing date: 2022-02-11
Publication date: 2023-12-05

Abstract

The present disclosure relates to methods of generating Nitric Oxide (NO) gas, which methods are applicable without special equipment and do not provide nitrogen dioxide (NO) ₂ ) And (3) gas. The method comprises combining nitrate and/or nitrite anions with an elemental metal in an acidic solution in a vessel capable of containing a liquid and a gaseous component, wherein NO gas is generated by the reaction of nitrate and/or nitrite anions with the elemental metal in the acidic solution. The method further comprises administering the generated NO gas to the subject via inhalation. Compositions and kits for improving NO gas delivery are also described.

Description

Method for applying nitric oxide gas

Technical Field

Cross Reference to Related Applications

The present application claims priority from U.S. provisional patent application Ser. No.63/148,523, filed on 11/2/2021, and U.S. provisional patent application Ser. No.63/180,039, filed on 26/4/2021, each of which is incorporated herein by reference in its entirety.

Background

Nitric Oxide (NO) inhalation is used to treat a range of cardiopulmonary disorders including pulmonary hypertension in children and adults. Inhalation of NO gas has also been proposed as a method for hospital treatment of patients with low oxygen levels and dyspnea in COVID-19. There are several mechanisms of nitric oxide therapeutic benefit to covd-19 patients (fig. 1): inhaled NO gas is known to be a selective pulmonary vasodilator. NO can improve right heart function and reduce pulmonary vasoconstriction in subjects with acute and chronic pulmonary hypertension. Inhalation of NO gas has been shown to improve ventilation and provide bronchodilation in subjects with mild asthma. NO gas in the alveolar space improves oxygenation (i.e., improves ventilation perfusion matching) by increasing the blood flow of the ventilated lung unit. In vitro and in vivo data indicate that NO gas can act as an anti-inflammatory and anti-thrombotic agent. NO donors and NO gases show antibacterial and antiviral properties in vitro studies and early clinical studies.

However, widespread use of inhaled NO is limited by logistical and financial barriers. Currently, inhaled NO therapy requires the use of specialized ventilators and NO canisters, which makes it expensive and impractical for home use. Inhaled nitric oxide is a very expensive treatment. Regardless of dose, the direct cost of using NO is at least $ 100 per hour. An average patient with covd-19 may require more than 80 hours of treatment, thereby increasing costs to thousands of dollars. Thus, although studies have shown that NO therapy is beneficial to covd-19 patients, practical considerations have so far prevented widespread use of this therapy and have been used primarily in hospitalized critically ill patients. Thus, there is a need for more economical and convenient methods of generating and administering nitric oxide to patients, particularly methods that do not require the use of specialized equipment.

However, despite the therapeutic benefit of NO therapy, it is unfortunately accompanied by potentially serious exposure to toxic chemicals. Methemoglobinemia is also a common phenomenon of nitric oxide therapy (Raut and Maheshwari, "Inhaled nitric oxide, metaglobinemia, and route of delivery," Saudi Canaesth.2017, 11 (3): 364). However, due to problems associated with NO gas inhalation, such as methemoglobinemia and the formation of nitrogen dioxide, emerging evidence has made it a question of whether NO inhalation will increase mortality in COVID-19patients (Prakash et al, "Efficacy and safety of inhaled nitric oxide in the treatment of severe/critical COVID-19patients:A systematic review." Indian Journal of Pharmacology,2021,53 (3): 236-243). Methemoglobinemia is an increasing concern for patients with covd-19, as these patients have been documented for the occurrence of methemoglobinemia due to the disease itself (Naymagon et al, "The emergence of methemoglobinemia amidst the COVID-19 handmic." Am J Hematol.,2020,95 (8): E196-E197).

Current NO treatment methods have inevitably exposed patients to NO ₂ Gas, NO ₂ Gases are considered to be the main toxic air pollutant and have no therapeutic value. Rapid oxidation of NO to NO in the presence of oxygen ₂ (Glasson and Tuesday, "The Atmospheric Thermal Oxidation of Nitric Oxide, J.am. Chem. Soc.,1963,85 (19): 2901-2904). Although the occupational safety and health administration (Occupational Safety and Health Administration, OSHA) prescribes that during each workday of 8 hours, the limit of NO in workplace air is 25ppm during each week of 40 hours of operation, NO in workplace air ₂ The limit of 15 minutes of exposure was 5ppm. This is because most biochemical studies have shown that exposure to more than 3160. Mu.g/m is only acute or sub-chronic ³ (2 ppm) of Nitrogen dioxide before a significant toxic effect is produced (Jarvis et al, "Nitrogen dioxide" In WHO Guidelines for Indoor Air Quality: selected pollutes. Geneva: world Health)Organization; 2010.5). In order to treat NO ₂ The formation of NO in the bottle must be oxygen-free, which increases the barrier to the acquisition of NO therapy. Even if these precautions are taken, NO ₂ Exposure remains too high and patients requiring NO therapy are still concerned.

Van Meurs et al noted that inhaled NO was used at a NO dosage level of 5 to 10ppm in premature infants with severe respiratory failure, four infants were exposed to at least 3ppm NO ₂ Concentration, exposure of two infants to at least 5ppm NO ₂ Concentration, NO infant in placebo group ₂ Concentration elevation (Van Murs et al, "Inhaled Nitric Oxide for Premature Infants with Severe Respiratory Failure," NEngl J Med,2005; 353:13-22). Petit et al found that administration of inhaled NO using an existing compressed gas delivery system would dilute the NO with oxygen enriched air prior to delivery to the patient, resulting in the production of NO ₂ (Petit et al, "The Pathophysiological of Nitrogen Dioxide During Inhaled Nitric Oxide Therapy," ASAIO Journal,2017,63 (1): 7-13). Petit et al also noted that NO inhaled by the patient ₂ Protective antioxidants within Epithelial Lining Fluid (ELF) can oxidize and cause extracellular damage to the airways, which can lead to oedema, bronchoconstriction, and a 1 second loss of forced exhalation. Exposure to low concentrations of NO is known to the toxic substances and disease registry (Agency for Toxic Substances and Disease Registry) ₂ Gas may initially cause mild shortness of breath, but after hours to days, bronchospasm and pulmonary oedema may occur in the contactor. Exposure to higher concentrations >10 ppm) NO ₂ Gases may cause immediate reactions in the subject, including coughing, fatigue, nausea, choking, headache, abdominal pain, and dyspnea. Pulmonary edema may occur after an asymptomatic period of 3 to 30 hours, with anxiety, confusion, somnolence, and loss of consciousness. If a person is exposed to a higher concentration of NO ₂ Fortunately, bronchiolitis obliterans may appear after several weeks. Inhalation of extremely high concentration>50 ppm) can rapidly lead to burns, cramps, swelling of throat tissue, upper airway obstruction, and even death. Therefore, there is also a need for more safetyIs provided.

Disclosure of Invention

The present disclosure relates to compositions, kits, and methods relating to the generation of NO gas for NO inhalation therapy. In one aspect, a method of generating NO gas for NO inhalation therapy includes combining a nitrate anion source and an elemental metal in an acidic solution in a vessel capable of containing a liquid and a gaseous component, thereby generating NO gas. In another aspect, a method of safely generating NO gas for NO inhalation therapy includes combining a nitrite anion source and an elemental metal in an acidic solution in a vessel capable of containing a liquid and a gaseous component, thereby generating NO gas. In certain embodiments, the method further comprises administering NO gas to the subject via a container capable of containing liquid and gas components, e.g., wherein the container capable of containing liquid and gas components is a water tube. In some aspects, administering NO gas to the subject via a container capable of containing liquid and gaseous components includes inhalation by the subject from a water line. In certain embodiments, the water conduit is connected to a respirator. Subjects administered NO gas suffer from dyspnea, migraine, have oxygen saturation levels below 95, are seeking improved athletic performance, are seeking increased endurance, or are seeking improved psychological performance.

The elemental metal is selected from: 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 0.1 to 6.9, for example 2 to 4. In certain embodiments, the method further comprises dissolving the acid powder in a solvent (e.g., water) to produce an acidic solution. In some aspects, the acid powder is citric acid, malic acid, or fumaric acid. In a particular embodiment, the acidic solution is prepared by dissolving the acid powder in 1ml to 10000ml of water.

In some aspects of the method of generating NO gas for NO inhalation therapy, the nitrate anion source is nitrate or a plant source of nitrate. In these embodiments, an effective amount of nitrate anionsThe sub-source and an effective amount of elemental metal are combined in an acidic solution to produce an effective amount of NO gas, wherein the effective amount of elemental metal is from 1mg to 2000mg and the effective amount of nitrate anion source provides from 30mg to 4000mg of nitrate anions. In certain embodiments, an effective amount of the nitrate anion source and an effective amount of the elemental metal are combined in an acid 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 a nitrate anion source and an effective amount of elemental metal are combined in an acid solution to produce at least 5ppm of NO gas and 1000ppm of H ₂ And (3) gas. In some embodiments, the gas component produced by combining the nitrate anion source and the elemental metal in an acidic solution further comprises a nitroxyl gas.

In some aspects of the method of generating NO gas for NO inhalation therapy, the nitrite anion source is nitrite or a plant source of nitrite. In these embodiments, an effective amount of a source of nitrite anions and an effective amount of elemental metal are combined in an acidic solution to produce an effective amount of NO gas, the effective amount of elemental metal being from 1mg to 2000mg, the effective amount of nitrite anion source providing from 1mg to 1000mg of nitrite anions. In certain embodiments, an effective amount of the nitrite anion source and an effective amount of the elemental metal are combined in an acid 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 a nitrate anion source and an effective amount of elemental metal are combined in an acid solution to produce at least 5ppm of NO gas and 1000ppm of H ₂ And (3) gas. In some embodiments, the gas component produced by combining the nitrate anion source and the elemental metal in an acidic solution further comprises a nitroxyl gas.

The above method of generating NO gas for NO inhalation therapy does not generate unsafe levels of NO ₂ And (3) gas. For example, NO generated by combining a nitrite anion source and an elemental metal in an acidic solution ₂ The level of gas is no more than 10ppm, no more than 5ppm, or no more than 2ppm. In some embodiments, the gas produced by combining the nitrite anion source and the elemental metal in an acidic solutionThe bulk component not containing any NO ₂ And (3) gas.

The compositions described herein in connection with generating NO gas for NO inhalation therapy comprise a nitrite source and elemental metal. In some aspects, the composition comprises an acid. The elemental metal in the composition is selected from: 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 technetium, 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 aspects, the nitrite source in the composition is a nitrite, such as sodium nitrite or potassium nitrite. In other aspects, the nitrite source in the composition is a plant source of nitrite normalized to nitrite content, such as beet root powder.

In some aspects, the composition is in the form of a capsule, cachet, pill, tablet, powder, granule, pellet (pellet), bead, microparticle (granule), lozenge, troche, lozenge (patch), solution, elixir, syrup, tincture, suspension, emulsion, mouthwash, spray, drop, ointment, cream, gel, paste, transdermal patch, suppository, pessary, cream, gel, paste, foam, and combinations thereof. The composition may further comprise acceptable additives and/or acceptable carriers. The acceptable additive may be selected from at least one of the following: solubilizers, enzyme inhibitors, anticoagulants, defoamers, antioxidants, colorants, coolants, cryoprotectants, hydrogen bonding agents, flavoring agents, plasticizers, preservatives, sweeteners and thickeners. The acceptable carrier may be selected from at least one of the following: excipients, lubricants, binders, disintegrants, diluents, extenders, solvents, suspending agents, dissolution aids, isotonic agents, buffers, soothing agents and amphiphilic lipid delivery systems. In some aspects, the composition is in a form suitable for oral administration. In other aspects, the composition is in a form suitable for inhalation of gases generated upon contact with the acidified solvent.

In some aspects, the composition comprises an effective amount of nitrite to produce a therapeutic effect, and an effective amount of elemental metal to prevent or reduce nitrite toxicity. The therapeutic effect of nitrite may be to reduce blood pressure or to treat and/or alleviate symptoms of respiratory diseases. The respiratory disease may be an infection with coronavirus, influenza virus, respiratory syncytial virus, streptococcus pneumoniae (Streptococcus pneumoniae), haemophilus influenzae type b (Haemophilus influenzae type b), pneumospore bacteria (Pneumocystis jiroveci), fungi or protozoa. In certain embodiments of the therapeutic composition, the effective amount of nitrite is 1 to 1000mg and the effective amount of elemental metal is 1 to 10000mg. In other embodiments, the effective amount of nitrite is from 5 to 200mg and the effective amount of elemental metal is from 5 to 1000mg. In a particular embodiment of the therapeutic composition, the effective amount of nitrite is from 30 to 100mg and the effective amount of elemental metal is from 10 to 400mg.

In a particular embodiment of the therapeutic composition, the nitrite source is packaged in a capsule, cachet, pill, tablet, powder, granule, pellet, bead, microparticle, lozenge or troche; the elemental metal is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, microparticles, lozenges, or troches. In another embodiment, the nitrite source is packaged in a capsule, cachet, pill, tablet, powder, granule, pellet, bead, microparticle, lozenge or troche; the elemental metal is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, microparticles, lozenges or lozenges; the acid is packaged separately from the nitrite source and the elemental metal. In some aspects, the nitrite source, elemental metal, and acid are in solid form. In a particular embodiment, the nitrite source and the elemental metal are packaged together, for example, in a capsule, a cachet, a pill, or a tablet.

The kits for safely administering NO gas to a patient described herein comprise a nitrite or nitrate source; elemental metal, wherein the nitrite source and/or nitrate source is packaged with the elemental metal; an acid; and for combining nitrite source, elemental metal and acid to produce NO gas without producing NO ₂ Instructions for administration of the gas and the generated NO gas to the patient. In some embodiments, the kit further comprises a container, such as a water tube, capable of containing liquid and gaseous components. In some aspects, the nitrite or nitrate source in the kit is a salt, such as nitrite or nitrate. Exemplary salts include sodium nitrite, potassium nitrite, sodium nitrate, potassium nitrate. The elemental metal in the kit is selected from: 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 technetium, 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.

Methods of administering inhaled nitric oxide gas with reduced toxicity to a subject are also disclosed. In some aspects, the reduced toxicity is manifested as reduced lung injury compared to the amount of lung injury that occurs by administration of the same concentration of NO gas itself, or the subject's blood methemoglobin level is NO more than 2%. The method comprises administering nitric oxide gas to a subject and hydrogen gas to the subject. In certain embodiments, the method further comprises administering a nitroxyl gas to the subject. In some aspects, methods of therapeutically administering an inhaled NO gas are described, comprising co-administering to a subject an effective amount of hydrogen gas with NO gas. An effective amount of hydrogen is in the direction ofSufficient to reduce or prevent NO during the administration of NO gas by a subject ₂ The amount formed. In some aspects, the effective amount of hydrogen is at least 1000ppm. In certain embodiments, the method comprises mixing the elemental metal with a nitrate source and/or a nitrite source in an acidified solvent, thereby generating NO gas and an effective amount of hydrogen gas and administering to a subject via inhalation.

Thus, methods of reducing inhaled NO toxicity are described, comprising inhaling NO and an effective amount of hydrogen to reduce NO toxicity (e.g., an increase in nitrotyrosine levels in lung tissue damage or in tissues exposed to NO). Thus, a composition comprising nitric oxide gas and hydrogen gas is described. In some aspects, nitrite toxicity is manifested as the occurrence of methemoglobinemia. Methods of preventing and/or treating methemoglobin in a subject are also described. The method comprises administering an effective amount of hydrogen to the subject via inhalation.

For a composition comprising nitric oxide gas and hydrogen gas, the concentration of the gas is at least 1ppm nitric oxide gas and at least 5ppm hydrogen gas. In a particular embodiment, the composition comprises 1 to 10000ppm hydrogen and 1 to 500ppm nitric oxide gas. In a composition comprising nitric oxide gas and hydrogen gas, the concentration of hydrogen gas does not lead to the formation of liquid water.

In another aspect, methods of preventing and/or treating methemoglobin in a subject (e.g., methemoglobin caused by inhaled NO therapy, administration of nitrite, or administration of nitrate) are disclosed. The method comprises orally administering to the subject an effective amount of an elemental metal. In certain embodiments, the method further comprises orally administering an acid to the subject, wherein the elemental metal and the acid are ingested together. In some aspects, the method comprises orally administering an amount of elemental metal and an acid effective to produce hydrogen in the stomach. Practice of the disclosed methods of preventing and/or treating methemoglobinemia reduces NO exhibited by a subject ₂ Toxicity induced, such as lung and/or airway inflammation, reduced lung function, worsening cough, worsening wheezing, increased asthma attacks or greater likelihood of emergency and hospitalization. In one place In some aspects, the subject does not exhibit NO after oral administration of the elemental metal and/or acid ₂ Toxicity induced.

Drawings

Figure 1 depicts various pathways by which NO acts in the lung.

Figure 2 depicts the quantitative analysis of nitric oxide in the presence of atmospheric concentration of nitrogen dioxide.

FIG. 3 depicts, in an exemplary embodiment, administration of NO and H to an ICU patient connected to a ventilator ₂ Gases, where NO and H ₂ Applied through an air valve inlet, which is typically used for insertion of nebulized drug.

Fig. 4 depicts an exemplary apparatus that may be used to cost-effectively produce a combination of NO, HNO, and hydrogen. The device comprises three compartments, wherein the top compartment contains an acidified water (preferably acidified with citric acid) solution, the middle compartment contains the SpO2 composition, and the bottom compartment is a mixing chamber, wherein the acidified water in the top compartment will drop into the mixing chamber, where it will mix with the SpO2 composition that drops from the middle compartment into the mixing chamber.

Detailed Description

Detailed aspects and applications of the present disclosure are described in the following technical detailed description. Unless specifically indicated, the words and phrases in the specification and claims are intended to be given the plain, ordinary and accustomed meanings known to those of ordinary skill in the applicable arts.

In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of various aspects of the present disclosure. However, it will be understood by those skilled in the relevant art that embodiments of the technology disclosed herein may be practiced without these specific details. It should be noted that there are many different and alternative configurations, devices, and techniques to which the disclosed techniques may be applied. The full scope of the technology disclosed herein is not limited to the embodiments described below.

The singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a step" includes reference to one or more of such steps.

As used herein, the term "about" refers to a deviation of no more than 5% of a given value, for example, a deviation of 3%, 2%, 1%, 0.5% or 0.1% of a given value.

As used herein, the term "acceptable" is a phrase used in its broadest sense to describe the ingredients of the composition that meet the food and drug administration (Food and Drug Administration, FDA) standards, the united states pharmacopeia (United States Pharmacopeia, USP) standards, the united states department of agriculture (US Department of Agriculture, USDA) food grade material standards, standards commonly accepted by the nutritional supplement industry, industry standards, plant standards, or any personally established standard. These criteria may describe an acceptable range in terms of ingredients of the composition, such as edibility, toxicity, pharmacological effects, or any other aspects of the chemical, composition, or formulation used to implement the composition.

As used herein, the term "composition" refers to a mixture of ingredients or components, as well as a combination of capsules comprising different ingredients or components. Thus, in certain embodiments, the composition comprises individual capsules packaged together and intended for administration together.

As used herein, the term "elemental metal" refers to the neutral charge state of the metal element, in other words, the metal in elemental form and in non-salt form or in charged form (exemplary salt forms and charged forms include oxides, hydroxides, carbonates, chlorides, lactates, citrates, aspartate, glycinates, and gluconate of the metal). Thus, as used herein, elemental metal and salts of the same metal are different components. The presence of metal salts does not suffice for the description of the composition comprising elemental metals and vice versa. For example, a composition consisting of magnesium citrate is not a composition comprising elemental magnesium, although there is any description of magnesium citrate providing a certain 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, nickel, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technetium, 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.

As used herein, the term "SpO2 composition" refers to a composition comprising nitrate and/or nitrite anions and elemental metal. In some aspects, the composition is in powder form. Thus, the composition may be referred to as "SpO2 powder".

The present disclosure relates to the discovery that acids, elemental metals, and nitrate anions combine in solution to produce breathable Nitric Oxide (NO) gas, as verified by NO sensors. Nitroxyl gases are also formed and may contribute to the surprising therapeutic benefits of the formulation. Formation of nitroxyl radicals was confirmed by introducing the gas mixture into the closed chamber of a vial of an ammonia solution containing nitrosyl, thereby forming copper-iron-ketone with a characteristic pale yellow colour. It has surprisingly been found that the generated NO gas can be administered to a subject, e.g. via a water line, and that such administration of NO improves alertness, energy level, cures headache/migraine and improves athletic performance, as demonstrated by increased strength and endurance. Thus, disclosed herein are methods of administering NO gas to a subject in need thereof.

Surprisingly, the described method of generating NO gas does not lead to the generation of NO at concentrations up to 40ppm ₂ Gas, while at higher NO concentrations, NO is produced ₂ The gas was much lower than the amounts described in the various studies. Thus, in some embodiments, the subject in need of NO gas is a subject in need of treatment for a respiratory disorder. In certain aspects, the subject exhibits at least one symptom selected from shortness of breath, respiratory problems, chest pain, lung inflammation, and reduced oxygen saturation. In some embodiments, the respiratory disease is caused by an infection, e.g., coronavirus, influenza virus, respiratory syncytial virus, pneumoniaInfection with streptococcus, haemophilus influenzae type b (Hib) and/or pneumospore bacteria. In particular embodiments, a subject in need of treatment for a respiratory disease is diagnosed with pneumonia or severe acute respiratory syndrome caused by a coronavirus, e.g., an alpha coronavirus selected from 299E and NL63 or a beta coronavirus selected from OC43, HKU1, MERS-CoV, SARS-CoV or SARS-CoV-2. In some other aspects, the subject has a disorder selected from the group consisting of: post-coronavirus-19 disease (covd-19) hypoxia, acute Respiratory Distress Syndrome (ARDS), post-ARDS hypoxia, pneumonia, chronic Obstructive Pulmonary Disease (COPD), mesothelioma, anemia, asthma, interstitial lung disease, pulmonary embolism, lung collapse, congenital heart defects or disease, pulmonary oedema, altitude reactions, low respiratory frequency, pulmonary fibrosis, sleep apnea, gastrointestinal infections, helicobacter pylori infections and respiratory tract infections.

In other embodiments, the subject in need of NO gas is a subject who would benefit from increased NO levels, e.g., a subject seeking to improve athletic performance, increase energy levels or endurance, improve health, and treat migraine.

A method of administering NO gas to a subject in need thereof includes combining a nitrate anion source and/or a nitrite anion source and an elemental metal in an acidic solution in a container (e.g., a water line) capable of containing a liquid and a gas component, wherein NO gas is generated, and administering NO gas to the subject via the container capable of containing the liquid and the gas component. In some aspects, the reaction also produces nitroxyl gas and hydrogen. In some embodiments, the pH of the acid solution is from 0.1 to 6.9. In a preferred embodiment, the pH of the acid solution is from 2 to 4. NO gas is administered to the subject through an inhalation water tube or some other suitable container that allows inhalation of the gaseous components capable of holding the liquid and gaseous components. In certain embodiments, the method comprises combining a therapeutically effective amount of nitrate anions and a therapeutically effective amount of elemental metal in an acidic solution in a water line, wherein a therapeutically effective amount of NO gas is produced. In some aspects, the therapeutically effective amount of elemental metal and the therapeutically effective amount of nitrate anions are 1mg to 2000mg and 30mg to 4000mg, respectively. In a particular embodiment, the molar ratio of nitrate anions to the therapeutically effective amount of elemental metal is 1:1.

The element metal is alkaline earth metal, alkali metal or transition metal. Elemental metals are not found in nature because of their reactivity. Instead, they exist in the form of ores that contain mixtures of various metal compounds (e.g., salts and oxides). Thus, complex extraction and purification using physicochemical methods are required 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, nickel, elemental copper, elemental zinc, elemental yttrium, elemental zirconium, elemental niobium, elemental molybdenum, elemental technetium, 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: elemental magnesium, elemental calcium, elemental lithium, elemental zinc, and elemental iron. In some embodiments, the combination of elemental metals is administered to the subject. Thus, in some aspects, a composition administered to a subject comprises more than one elemental metal. The elemental metal may be in any form, such as powder or granules. Changing the size and surface area of the elemental metal can be used to affect the rate of reaction between the metal and nitrate and acid. It has thus been found that smaller metal particle sizes result in a faster reaction, producing a larger amount of NO in a shorter time.

In some aspects, nitrate anions (NO ₃ ^- ) Nitrate (e.g., creatine nitrate, arginine nitrate, carnitine nitrate, n-acetyl carnitine nitrate, citrulline nitrate, betaine nitrate, and proline nitrate) of amino acid or amino acid derivative as source, inorganic nitrate (e.g., magnesium nitrate, sodium nitrate, potassium nitrate, calcium nitrate, and lithium nitrate, or their mixed salts, co-saltsCrystal preparations and hydrates), or natural nitrate sources. For natural nitrate sources, nitrate has been concentrated and/or separated from natural sources (e.g., plant nitrate sources). Examples of natural nitrate sources include, but are not limited to, beet juice powder, concentrated beet juice powder, celery powder, spinach and red spinach extract, and amaranth extract. In a preferred embodiment, the nitrate content of the natural nitrate source is normalized to provide a sufficient amount of nitrate. In some aspects, the composition comprises more than one nitrate anion source.

In some aspects, nitrite anions (NO ₂ ^- ) The source is nitrite (e.g., creatine nitrite, arginine nitrite, carnitine nitrite, n-acetyl carnitine nitrite, citrulline nitrite, betaine nitrite and proline nitrite) of an amino acid or amino acid derivative, inorganic nitrite (e.g., magnesium nitrite, sodium nitrite, potassium nitrite, calcium nitrite and lithium nitrite, or mixed salts, co-crystal formulations and hydrates thereof) or natural nitrite source. For natural nitrite sources, nitrite may be concentrated and/or isolated from natural sources (e.g., plant nitrite sources).

In some embodiments, the elemental metal and nitrate and/or nitrite anions are included in a system for sustained release of NO. For example, the system may be a time release system (e.g., diffusion system, dissolution system, permeation system, and ion exchange resin), a floatation system, a bioadhesive system, or a matrix system in which contact with an acid or acid solution is controlled. In other embodiments, the metal and nitrate may be released into the acid solution in a continuous manner using mechanical or electronic methods to achieve sustained NO gas release. In a particular embodiment, the system for sustained release of NO described herein comprises three compartments fluidly connected (see e.g. fig. 4). The top compartment contains an acidified water (preferably acidified with citric acid) solution, the middle compartment contains the SpO2 composition, and the bottom compartment is a mixing chamber, wherein the acidified water in the top compartment will drip into the mixing chamber and mix with the SpO2 composition that drips from the middle compartment into the mixing chamber. The device can control the reaction rate of the acidified water and the SpO2 compositionCan easily regulate NO, HNO and H applied to patients ₂ Is a combination of the amounts of (a) and (b). 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 adjusting the heat in the mixing chamber (e.g., with a heating element with a built-in thermostat (increasing the heat increases the reaction rate)). Similar protocols can be used for administration of NO/H to non-ICU patients using the respiratory system in a home or hospital setting ₂ The only difference is that instead of using an endotracheal tube, the patient must wear a mask or similar device to deliver the gas.

In an exemplary embodiment, NO/H may be administered to a patient connected to the ventilator through an air valve inlet commonly used for insertion of aerosolized medicament ₂ And (3) gas. NO/H ₂ The gas may be generated by the apparatus of fig. 4. Similar protocols can be used for administration of NO/H to non-ICU patients using the respiratory system in a home or hospital setting ₂ The only difference is that the patient must wear a mask, cannula or similar device to deliver the gas, rather than use an endotracheal tube (see figure 3).

Thus, disclosed herein are kits for safely administering NO gas to a patient. The kit comprises a nitrite source or nitrate source; an elemental metal, wherein the nitrite and/or nitrate source is packaged with the elemental metal; an acid; and for combining nitrite source, elemental metal and acid to produce NO gas without producing NO ₂ Instructions for administration of the gas and the generated NO gas to the patient. In some embodiments, the kit further comprises a container, such as a water tube, capable of containing liquid and gaseous components. In some aspects, the nitrite or nitrate source in the kit is a salt, such as nitrite or nitrate. Exemplary salts include sodium nitrite, potassium nitrite, sodium nitrate, potassium nitrate. The elemental metal in the kit is selected from: 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 technetium, 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 method includes providing the acid in powder form and mixing with nitrate or nitrite anions and/or elemental metal prior to dissolution in the solvent, thereby generating NO gas. The acid in powder form may be, for example, citric acid, malic acid or fumaric acid. In a preferred embodiment, the solvent used is water, as it is safe, non-toxic and readily available. However, other protic and/or polar solvents may be used, such as ammonia, ethanol, acetic acid, and the like. The water or solvent need not be pure and other compounds may be dissolved therein, such as fragrances, perfumes, other medicaments and the like. In some embodiments, the acid is a salt of a strong acid with a weak base, which when dissolved in water or some other polar protic solvent, results in the formation of an acidic solution. Thus, the acid may be ammonium chloride, ammonium nitrate or creatine nitrate. In certain embodiments, when nitrate anions are provided as nitrates (e.g., creatine nitrate or proline nitrate) that form with weak bases, the nitrate may serve as a source of acid and nitrate anions.

It should be appreciated that while the general order of adding the ingredients of the formulation is to first produce an acid solution and then to add the elemental metal and nitrate source simultaneously, such order is not required and variations are possible. For example, the step of combining the nitrate anions and the elemental metal in an acidic solution may comprise adding the nitrate source, the powdered acid, and the elemental metal to water simultaneously, or may comprise preparing an aqueous solution of the nitrate source, followed by the addition of the acid and the elemental metal. A key feature of the disclosed method is that the elemental metal cannot be fully reacted with the acid, thereby forming a salt of the elemental metal rather than NO gas. Thus, if elemental magnesium metal is added to the acid solution, and then the nitrate source is added after the reaction is complete (as will be indicated by the magnesium being dissolved in its salt form in the liquid), no nitric oxide gas will be formed.

Methods of generating NO gas for NO inhalation therapy do not generate unsafe levels of NO ₂ Gas, thus, the gaseous component produced does not contain NO ₂ And (3) gas. For example, NO generated by combining a nitrite anion source and an elemental metal in an acidic solution ₂ The level of gas is no more than 10ppm, no more than 5ppm, or no more than 2ppm. In some embodiments, the gas component produced by combining the nitrite anion source and the elemental metal in an acidic solution does not comprise any NO ₂ And (3) gas.

The compositions described herein in connection with generating NO gas for NO inhalation therapy comprise nitrite and elemental metal. In some aspects, the composition comprises an acid. The elemental metal in the composition is selected from: 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 technetium, 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 aspects, the nitrite in the composition is a nitrite, such as sodium nitrite or potassium nitrite. In other aspects, the nitrite in the composition is a plant source of nitrite normalized to nitrite content, such as beet root powder.

In some aspects, the composition is in the form of a capsule, cachet, pill, tablet, powder, granule, pellet, bead, microparticle, troche, lozenge, troche, solution, elixir, syrup, tincture, suspension, emulsion, mouthwash, spray, drop, ointment, cream, gel, paste, transdermal patch, suppository, pessary, cream, gel, paste, foam, and combinations thereof. The composition may further comprise acceptable additives and/or acceptable carriers. Acceptable additives may be selected from at least one of the following: solubilizers, enzyme inhibitors, anticoagulants, defoamers, antioxidants, colorants, coolants, cryoprotectants, hydrogen bonding agents, flavoring agents, plasticizers, preservatives, sweeteners and thickeners. The acceptable carrier may be selected from at least one of the following: excipients, lubricants, binders, disintegrants, diluents, extenders, solvents, suspending agents, dissolution aids, isotonic agents, buffers, soothing agents and amphiphilic lipid delivery systems. In some aspects, the composition is in a form suitable for oral administration. In other aspects, the composition is in a form suitable for inhalation of gases generated upon contact with the acidified solvent.

In some aspects, the composition comprises an effective amount of nitrite to produce a therapeutic effect, and an effective amount of elemental metal to prevent or reduce nitrite toxicity. The therapeutic effect of nitrite may be to reduce blood pressure or to treat and/or alleviate symptoms of respiratory diseases. The respiratory disease may be an infection with coronavirus, influenza virus, respiratory syncytial virus, streptococcus pneumoniae, haemophilus influenzae type b, pneumospore bacteria, fungi or protozoa. In certain embodiments of the therapeutic composition, the effective amount of nitrite is 1 to 1000mg and the effective amount of elemental metal is 1 to 10000mg. In other embodiments, the effective amount of nitrite is from 5 to 200mg and the effective amount of elemental metal is from 5 to 1000mg. In a particular embodiment of the therapeutic composition, the effective amount of nitrite is from 30 to 100mg and the effective amount of elemental metal is from 10 to 400mg.

Methemoglobinemia is a condition that can be monitored by a decrease in SpO2 levels and is a side effect associated with inhaled NO therapy (Raut and Maheshwari, "Inhaled nitric oxide, metaglobinemia, and route of release." Saudi J anaesth.2017,11 (3): 364). Surprisingly, it was found that administration of NO gas according to the methods described herein does not lead to the occurrence of methemoglobinemia. The mechanism by which the disclosed method does not cause methemoglobinemia remains to be studied, but the hydrogen product of the reaction of nitrate anions and elemental metals in acidic solutions may have a protective effect. It should be noted that if the method is used to prevent and treat methemoglobinemia, some elemental metals may react with a base such as aluminum to produce hydrogen: 2Al+2NaOH+2H ₂ O→2NaAlO ₂ +3H. For the purposes of the present invention, it is possible to obtain NO gas produced by the reaction of nitrite with acid in a beaker, and H produced by the reaction of metal with a base (e.g. aluminum) to produce hydrogen ₂ And (3) gas.

During the development of the present invention, the main inventors found themselves to be exposed to NO levels above 25ppm for a long period of time (measured using BW BWs-N-Y yellow housing, solo Nitric Oxide (NO) gas detector) multiple times, and NO adverse effects were observed. In fact, his oxygenation level measured by the SpO2 oximeter is always in the range 97 to 100. Thus, also disclosed herein is a method of preventing the occurrence of methemoglobinemia caused by nitrate, nitrite or NO exposure, wherein the method comprises administering hydrogen to a subject exposed to nitrate, nitrite or NO.

In some aspects, describeMethods of administering inhaled nitric oxide gas with reduced toxicity to a subject. In some aspects, the reduced toxicity is manifested as reduced lung injury compared to the amount of lung injury that occurs by administration of the same concentration of NO gas itself. In other aspects, the reduced toxicity is manifested in a subject having a blood methemoglobin level of no more than 2%. In other aspects, methods of reducing inhaled NO toxicity are described that include inhaling NO and an effective amount of hydrogen gas to reduce NO toxicity (e.g., lung tissue damage, increased levels of nitrotyrosine in tissues exposed to NO, occurrence of methemoglobinemia). The method comprises administering nitric oxide gas to a subject and hydrogen gas to the subject. In certain embodiments, the method further comprises administering a nitroxyl gas to the subject. In some aspects, methods of therapeutically administering an inhaled NO gas are described, comprising co-administering to a subject an effective amount of hydrogen gas with NO gas. An effective amount of hydrogen is an amount sufficient to reduce or prevent NO during administration of NO gas to a subject ₂ The amount formed. In some aspects, the effective amount of hydrogen is at least 1000ppm. In certain embodiments, the method comprises mixing elemental metal with nitrate and/or nitrite in an acidified solvent, thereby generating NO gas and an effective amount of hydrogen gas and administering to a subject via inhalation.

Compositions comprising nitric oxide gas and hydrogen gas are also described. The concentration of the gas in the composition is at least 1ppm nitric oxide gas and at least 5ppm hydrogen gas. In a particular embodiment, the composition comprises 1 to 10000ppm hydrogen and 1 to 500ppm nitric oxide gas. In a composition comprising nitric oxide gas and hydrogen gas, the concentration of hydrogen gas does not lead to the formation of liquid water.

Examples

Example 1:

an acid solution was prepared by dissolving 5 grams of citric acid in 100ml of warm water in a 1000ml beaker. Elemental magnesium (200 mg) and potassium nitrate (1000 mg) were added simultaneously to the acid solution. The FeNO of the Niox instrument can measure ambient NO levels and is used to test whether the addition of elemental magnesium and potassium nitrate to an acid solution would form NO gas. NO levels in the room before the experiment were 0. Shortly after the elemental magnesium and potassium nitrate were added to the acid solution, the instrument recorded 200ppb of NO. More NO may be generated because 200bbp is the detection limit of the instrument.

Example 2:

1000mg of citric acid was mixed in a beaker hookah (shaker bong) containing warm water to produce an acid solution. 200mg elemental magnesium and 1000mg potassium nitrate from the pre-filled capsules were poured into a hookah containing an acid solution. A 58 year old male subject with migraine had inhaled the generated gas via a beaker hookah. The subject reported that his headache stopped and breathing was smoother. He also reported that his energy and attention level was improved.

Example 3:

a 39 year old subject reported that his exhaustion time was increased by 5 minutes on the most difficult setup of the exercise bicycle after inhaling the gas generated in the beaker hookah according to the same method described in example 2, as compared to the exhaustion time on the exercise bicycle. In another scenario, the subject reported that the maximum number of push-ups increased by 10 times (the maximum number of push-ups increased from 50 times to 60 times) when he inhaled NO gas generated by the combination of elemental magnesium and potassium nitrate.

Example 4:

to confirm that hydrogen is a by-product of elemental metal in combination with acid, a teaspoon of elemental magnesium powder was added to a vial containing 100ml of water saturated with citric acid. The gas at the top of the vial is flammable.

Example 5:

sodium nitrite is known to be toxic at high levels. Because of its toxicity, its use as a source of NO in therapy is limited to antidotes for cyanide poisoning. The lowest lethal dose calculated was 2.6 grams (Katabami et al, "Severe Methemoglobinemia due to Sodium Nitrite Poisoning", case Reports in Emergency Medicine,2016,Article ID 9013816), but severe methemoglobinemia was reported to occur at much lower doses. After administration of 600mg to adults for the treatment of cyanide poisoning, the methemoglobin level was 58% (va n Heijst et al, "Therapeutic Problems in Cyanide Poisoning," Journal of Toxicology: clinical Toxicology,1987,25 (5): 383-398). Moderate to severe poisoning can lead to cyanosis (skin blushing), confusion, loss of consciousness, seizures, arrhythmias, and death. Because methemoglobinemia cases of subjects who ingest a combination of elemental metal and nitrate sources or inhale gases produced by the combination in an acidic solution are observed to be lacking, it is speculated that exposure to hydrogen and/or zinc/magnesium ions may prevent the occurrence of methemoglobinemia. Methemoglobinemia can be monitored directly by time-consuming blood tests, or indirectly by SpO2 measurements. Because methemoglobin cannot carry O ₂ Thus higher methemoglobin levels will result in lower oxygen saturation levels.

One inventor ingested a tablet containing 310mg NaNO after overnight fast ₂ Is intended to induce methemoglobinemia, while the other inventor monitors the condition of the test subject inventor. After the first 15 minutes, the subject inventors began to develop undesirable side effects including gastrointestinal discomfort, dizziness, brain fog, confusion, dyspnea, migraine, abnormal palpitations, tachycardia peak 240 beats/minute and low SpO2 levels, with a minimum reading of 91 (at about 25 minutes of the experiment). Table 1 summarizes SpO2 levels and heart rate of the subject inventors during the course of the experiment. SpO2 levels and heart rate readings were recorded as video, as can be found in the following table:

TABLE 1

After a 48 hour rinse period, the test subject inventors prepared 3 capsules, each containing 1000mg of elemental magnesium powder, and 3 other capsules, each containing 1000mg of citric acid. Elemental magnesium powder reacts strongly exothermically with acid. Thus, it is not clear whether such large amounts of elemental magnesium are safe or even tolerable and whether their reaction with toxic amounts of nitrite is tolerable. Regardless, the test subject inventors co-ingest one capsule containing 310mg sodium nitrite and 1000mg elemental magnesium with 2 capsules each containing 1000mg citric acid (as some acid would be consumed by elemental magnesium, the amount of citric acid is doubled compared to the initial dose of the first experiment). After 30 minutes and after 60 minutes, the test subject inventors ingested another 1000mg of elemental magnesium and 1000mg of citric acid in capsule form. The inventors did not experience any of the undesirable side effects of the first experiment. The only side effect noted is dizziness, which he has experienced several times in the past, which is associated with hypotension. His SpO2 level was still higher compared to the first experiment, never below the threshold level of 95%. Table 2 summarizes SpO2 levels and heart rate of the test subject inventors during the second experiment.

TABLE 2

The test subjects the inventors felt completely good at 90 minutes after the experiment. His SpO2 level was 95% to 97%.

Example 6:

nitrogen dioxide is an orange, odorous gas that can be reacted with air by high concentrations of nitric acid (concentrated HNO ₃ Orange NO is continuously precipitated in the open air ₂ Thus called "red fuming nitric acid") and atmospheric oxygen to oxidize Nitric Oxide (NO) (Holleman and Wiberg, inorganic chemistry, academic Press: san Diego, 2001). When nitrogen is released during combustion of the fuel, it combines with oxygen atoms to form NO. NO is further combined with oxygen to form nitrogen dioxide (NO ₂ ). NO is not considered to be harmful to health at typical ambient concentrations, but nitrogen dioxide may be harmful. NO (NO) ₂ Also from nitrite in an acidic solutionAnd decomposing to form the product. When sodium nitrite is used, which is strongly acidic, it can be converted to nitrous acid. Nitrous acid is very unstable and readily breaks down to NO ₂ NO (which can further react with oxygen in the air to become NO ₂ ) And water. Thus, the gaseous products of the reaction of inhaled nitrite with acid in solution are generally considered unsafe because NO is produced ₂ Horizontal. NO (NO) ₂ Is a major problem of the use of NO gas in therapy. Although current NO tanks typically contain 0.1% NO gas in inert nitrogen, NO ₂ The main problem of using NO gas as a therapeutic method remains.

Administration of inhaled Nitric Oxide (NO) with unavoidable nitrogen dioxide (NO) with existing compressed gas delivery systems ₂ ) Is related to the common transport of the same. NO under average atmospheric conditions ₂ The concentration is dominant relative to the concentration of NO (Levaggi et al, "Quantitative analysis of nitric oxide in presence of nitrogen dioxide at atmospheric concentrations," environ. Sci. Technology., 1974,8 (4): 348-350) (see FIG. 2).

In atmospheres with higher oxygen saturation than the atmosphere, for example in people receiving 100% oxygen treatment, the equilibrium is expected to be much higher.

Totapally et al demonstrate that in a mechanical ventilator model designed to mimic NO delivery in humans, NO when it reaches the lungs ₂ The highly toxic concentration of 19.4ppm has been increased. At the same time NO ₂ The level continues to increase while the NO concentration decreases, such that NO+NO ₂ The total concentration of (2) remains unchanged.

NO concentration from proximal port (site 11 of inspiratory circuit) (86.16 +/-0.38 ppm) to pulmonary ripple

The tube (site 4) (70.08+/-0.23 ppm) was significantly reduced (P <.001). NO2 concentration from site

1 (3.25 +/-0.04 ppm) to site 4 (19.4 +/-0.19 ppm) was significantly increased (P <.001). … …

During ventilation with high concentration of NO (80 ppm) and high concentration of oxygen, the concentration of NO2 in the lung is remarkable

Rise above the generally accepted toxic concentrations. (adding emphasis)

(Totapally et al, "Nitric oxide and nitrogen dioxide concentrations during in vitro high-frequency oscillatory ventilation," J Crit Care.1999,14 (3): 141-149).

Even at the proximal end (calculated as nose or throat of human), NO ₂ The levels have also been far above what is considered safe/acceptable (below 2ppm, EPA report number EPA/600/8-91/049aF-cF according to the United states environmental protection agency Nitrogen oxide air quality standards). Most biochemical studies have shown that acute or sub-chronic exposure is in excess of 3160 μg/m ³ The (2 ppm) high level of nitrogen dioxide can have deleterious effects, which is the highest acceptable level recommended by the WHO. For people with airway diseases (e.g. asthma, covd-19, pneumonia, COPD, etc.), NO has to be reduced as much as possible during NO therapy ₂ Horizontal.

Experiment:

into a 700ml glass, 500ml of room temperature (about 20 ℃) water was added. BW WS-D-Y yellow cover, solo Nitrogen dioxide (NO) ₂ ) The gas detector (not wireless) is clamped to the glass rim so that the sensor is as close to the water surface as possible without touching the water. 3000mg of citric acid was dissolved in water to simulate the acidic conditions of the stomach, but any other suitable acidifying substance could be substituted for in order to produce a "clean" NO gas. SpO2max capsules (1200 mg KNO3, 200mg elemental magnesium, 50mg elemental zinc) were dissolved in the solution and the whole process was recorded video. The reaction immediately produces therapeutic concentrations [ ] >20 ppm) of NO and produces beneficial effects on patients and healthy persons. NO was present during the first about 10 minutes of the reaction ₂ Releasing. During the next 20 minutes, small amounts of NO2 (less than 2ppm, in particular less than 1.7 ppm) will be produced. Thus, NO can be applied by applying the reaction product within the first 10 minutes of the reaction, and then re-preparing the reaction mixture when more NO needs to be applied ₂ NO of (c). Of course, different reactant rates and/or reactants may produce a mixture free of any NO for a longer period of time ₂ The "clean" NO gas of the gas is the possibility that the applicant intends to explore adequately. Thus, the described method of administering NO is easier and more robust than current methods of NO gas deliveryHealthy, cheaper and safer.

Example 7:

in developing the described methods for generating NO for a more affordable, efficient and safe source of NO therapy, one of the inventors surprisingly exposes itself both chronically and acutely to NO gas. Upon exposure to a substantial amount of ambient NO (ambient NO>80 ppm) he started to develop methemoglobinemia symptoms and developed pulmonary inflammation, manifested by SpO2 of 85%, dizziness, pulmonary pain and weakness. After symptoms appear, the inventors inhale H ₂ Gas, H ₂ The gas is produced by the reaction of elemental magnesium and citric acid in a glass of water. He also ingests 2000mg of elemental magnesium powder with water and reacts with HCl in the stomach to produce H ₂ And (3) gas.

His condition and SpO2 worsened throughout the day, and at a later time in the evening he was sent to the ER with 45% SpO2 recorded. Hospitals confirmed that NO-induced lung inflammation occurred by the inventors by X-ray and CAT scan. After diagnosis, blood samples were collected from the inventors to measure the methemoglobin level. Surprisingly, although SpO2 of the inventors was 45%, methemoglobin was not detected. Normal methemoglobin fraction is about 1%. During transit he never showed cyanosis (blue skin), which is associated with a methemoglobin content of 3 to 15%. Therefore, the inventors did not receive methemoglobin treatment (intravenous methylene blue).

Thus, hydrogen inhalation and uptake (via elemental metallic form, in this case magnesium) treats and/or alleviates NO-induced methemoglobinemia. However, the presence of liquid in the inventors' lungs suggests that the concentration of H2 administered must not form liquid water in the lungs.

Example 8:

a flask containing 100ml of 0.1M HCl was placed in a Bel-Art Secador polystyrene Mini drying cabinet (0.31 ft) ³ ) Is a kind of medium. Will contain 1200mg KNO ₃ The contents of one capsule, 200mg of elemental magnesium and 50mg of elemental zinc, and the contents of a second capsule containing 1000mg of citric acid were added to the flask. Placing NO sensor into drying cabinet. Within 10 minutes, the NO level increased from 0ppm to 6.4ppm. Thus, in theory, the average size of the stomach would be one liter and the amount of NO in the stomach would be 56ppm after ingestion of two capsules.

Notably, 1 spoon KNO ₃ The addition to 50ml of 25% HCl did not produce any measurable amount of NO gas.

Example 9:

a100 ml vial containing 100mg NaNO3 and 50mg elemental magnesium was placed into a Bel-Art Secador polystyrene mini drying cabinet (0.31 ft ³ ) Is a kind of medium. Honeywell NO and Honeywell NO ₂ The detector is turned on and placed in a drying cabinet. The vials were filled with 0.1N HCl and the containers were quickly sealed. Within three minutes, the concentration of NO gas exceeds the therapeutic level of 20 ppm. NO is detected ₂ 。

Five minutes after the addition of hydrochloric acid, the NO level reached a level of 31.4ppm, whereas NO ₂ The level was kept below the level of 2ppm which was believed to cause the pest action.

Example 10:

honeywell NO and Honeywell NO ₂ The detector was placed in a Bel-Art Secador polystyrene Mini drying cabinet (0.31 ft) ³ ) Is a kind of medium. Gelatin capsule containing 1000mg of citric acid and KNO containing 1200mg ₃ Gelatin capsules of 200mg elemental (metal) magnesium and 50mg elemental (metal) zinc were added to vials. 100ml of 0.1N HCl (simulating the acidic conditions of the stomach) was added to the vial, and then the door to the drying cabinet was quickly closed. The NO level rose to a concentration of 10.6ppm in 40 minutes, at which time 1ppm of NO was formed ₂ . Thus, the surprising effect of this oral formulation in the treatment of respiratory diseases is not only due to the formation of NO, but also due to the lack of conversion of NO to NO ₂ 。

Example 11:

to further investigate the mechanism behind the unexpected results of examples 9 and 10, hydrogen and oxygen sensors were also combined with NO and NO under the same conditions (same reactants) as example 10 ₂ The sensors are placed together in a drying cabinet.

During the reaction, H ₂ Horizontal levelAnd rapidly rises. After three minutes of HCl addition to the flask, H was detected ₂ The level rises before the NO level rises. About 20 minutes after the reaction was started, H ₂ The concentration reached 1000ppm of the maximum capacity of the sensor. About 50 minutes after the start of the reaction, the NO concentration reached 15ppm, NO ₂ The concentration reached 2ppm.

Surprisingly, the oxygen sensor detects no oxygen loss. In previous experiments, the inventors found that excessive inhalation of H ₂ The gas may cause a decrease in SpO2, possibly due to the reaction of atmospheric oxygen with hydrogen to form water in the lungs. Later experiments demonstrated the hypothesis that high concentrations of hydrogen can react with atmospheric oxygen and form water in the lungs, where adding 10 grams of elemental magnesium to 500ml of water in a vial placed in a desiccating cabinet resulted in O ₂ The level decreases while the humidity level measured by the hydrometer increases. In fact, transparent water drops can be seen on the walls of the drying cabinet.

In view of the results of the present application, exposure to 1000ppm of H is presumed ₂ Is safe but requires further experimentation to explore the safest and most effective proportions of NO, nitrogen and hydrogen.

Example 12:

to further clarify NO, NO ₂ And H ₂ Three experiments were performed in relation to each other and their use for treating patients inhaling or ingesting NO-producing formulations.

For the first experiment, 100ml vials containing 200mg elemental (metallic) magnesium in 100ml 0.1N HCl were combined with the NO, NO used in examples 9 to 11 ₂ And H ₂ The sensors are placed in the same cabinet as used in these embodiments, and the cabinet door is quickly closed. H ₂ The level rose rapidly to over 1000ppm. The vials were placed in a desiccation cabinet and recorded for one hour, NO and NO ₂ Is kept at zero.

For the second experiment, 100mg of NaNO will be contained ₂ And 100ml vials of 100ml 0.1N HCl with NO, NO ₂ And H ₂ The sensors were placed in the same cabinet as used in examples 9 to 11. NO and NO ₂ The level of (2) starts to rise rapidly, NO after two minutes ₂ Levels above 2ppm and no levels above 4.2ppm. H ₂ The level was maintained at 0ppm.

Three minutes after the reaction started, NO ₂ The level exceeded the safety limit of 5ppm while the NO level rose to 13ppm. H ₂ The level was still kept at 0ppm. 30 minutes after the reaction, NO ₂ The level reached 58ppm, which is theoretically high enough that a person would die as soon as a few minutes of inhalation exposure. NO level is almost equal to NO ₂ At a level of about 58ppm. Interestingly, H ₂ The level was raised to 112ppm. The mechanism of the hydrogen generation reaction is not clear (presumably by partial evaporation of HCL gas), but H ₂ Is insufficient to affect the human body and its presence is effective to reduce NO/NO ₂ The ratio has no positive effect.

For the third experiment, two 100ml vials were combined with the NO, NO used in examples 9 to 11 ₂ And H ₂ The sensors are placed in the same cabinet as used in these embodiments. One vial contained 200mg elemental (metal) magnesium in 100ml 0.1N HCl, which proved to rapidly produce H levels in excess of 1000ppm ₂ . Another vial contained 100ml of NaNO in 0.1N HCl at 100mg ₂ . NO/NO by 30 minutes of recording ₂ The ratio was kept approximately at 2:1. 30 minutes after the start of the reaction, the NO level was 44ppm NO, NO ₂ At a level of 22ppm NO ₂ . As in the previous experiments, H ₂ The level rose rapidly to 1000ppm, which is the detection limit of the sensor, and was maintained at that level for a 30 minute recording time. Thus, the coexistence of hydrogen and NO reduces NO ₂ And the safety and effectiveness of NO inhalation can be improved.

Example 13:

a pair of sheep lungs was obtained from Carolina Chemicals. Each lung was inserted into Bel-Art Secador polystyrene Mini drying cabinet (0.31 ft ³ ) To investigate the effect of exposure to different modes of generation of NO. For one lung, NO and its by-product two are produced in the chamber by mixing 200mg sodium nitrite with 100ml water containing 1 gram citric acid Nitrogen oxide. The lungs were exposed to gas for 4 hours. The lungs were sectioned and examined under a microscope, and obvious histopathological lesions (alveolar wall thawing) and changes in tissue color were observed. The experiment was repeated on the second lung, but this time was exposed to KNO by combining 200mg elemental magnesium, 50mg elemental zinc, 1200mg ₃ And 1000mg of citric acid in 100ml of water. After 2 hours, the lungs were removed, sectioned, and examined under a microscope for any histopathological lesions or changes in tissue color. No histopathological damage to the lungs or changes in tissue color were observed.

Example 14:

the size of elemental magnesium affects the effectiveness, safety, and side effect characteristics of the composition to which it is applied.

Multiple replicates of the composition of elemental metal having different mesh sizes were prepared and tested in subjects to determine if the mesh size of the elemental metal would affect the benefits and/or side effects experienced by the subject after ingestion. Table 3 lists the formulations tested.

Table 3. Formulations of elemental metals evaluated in the study.

Different formulations exhibit different effects in alleviating respiratory diseases. In some cases, the subject exhibits side effects, including gastrointestinal disorders, diarrhea, nausea, and vomiting. Adverse reactions of magnesium micropowder formulations are more common than other formulations.

Example 15:

elemental magnesium in various forms is capable of producing H with potassium nitrate ₂ NO and NO ₂ And (3) gas.

An amount of 200mg of elemental magnesium in three forms (and sizes) was used to compare 1200mg of KNO when 100ml of water was added ₃ H produced after mixing with 1000mg of citric acid powder ₂ NO and NO ₂ And (3) generating gas. Immediately after adding 100ml of distilled water at room temperature, a beaker containing magnesium was placedBel-Art Secador polystyrene Mini drying cabinet (0.31 ft) ³ ) Is a kind of medium. At the beginning of the experiment using magnesium powder, particulate magnesium and magnesium beads, H ₂ NO and NO ₂ The sensors are all zero.

After adding water to KNO containing magnesium powder (60 to 200 mesh size) and 1200mg ₃ And 1000mg of citric acid powder in a beaker for about 90 seconds, the concentration of NO gas was 12.8ppm, NO ₂ The concentration of the gas was 0ppm, H ₂ The concentration of the gas was 142ppm. As the experiment continued, NO and H ₂ The concentration of the gas continues to rise. After adding water to the powder for 2 minutes, the concentration of NO gas was 39.2ppm, H ₂ The concentration of the gas was 435ppm, NO ₂ The concentration of the gas was 0ppm. Such NO and NO ₂ The ratio of (2) is surprising. In NO ₂ NO gas contents up to approximately 40ppm with zero are not known. 5 minutes after the addition of water to the powder, the NO gas reached 49ppm, NO ₂ The gas was increased to 3.0ppm. Hydrogen increased to over 1000ppm (maximum detectable range of the sensor).

In the case of using granular magnesium (about 35 mesh size) and 1200mg KNO ₃ And 1000mg of citric acid powder, NO gas, H after 1 minute of addition of water ₂ Gas, NO ₂ The concentrations of the gases were 3.8ppm, 66ppm and 0ppm, respectively. After 5 minutes from the addition of water, the sensor reads 11.4ppm of NO gas, H ₂ 186ppm of gas, NO ₂ And 0ppm of gas. Thus, compared to magnesium powder, NO and H are produced using particulate magnesium ₂ Much less gas, and in the same time frame, the NO amount was reduced by nearly 4 times.

In the case of magnesium beads (diameter about 5 mm) and 1200mg KNO ₃ And 1000mg of citric acid powder, NO NO gas or NO was generated at 1 minute and 20 seconds from the experiment ₂ And (3) gas. 5 minutes after the addition of water, the sensor reads 16.2ppm NO gas, NO ₂ Gas 0ppm, hydrogen 337ppm.

Our experiments have shown that H is produced in combination using the disclosed methods and compositions ₂ Gas and NO gas reduction and even elimination of NO ₂ And (3) generating gas.

Example 16:

it should also be noted that high concentrations of hydrogen gas form water, which, if inhaled over time, can cause the lungs of the subject to accumulate water, thereby preventing the lungs from absorbing oxygen. This can explain that the inventors inhale H for a long time ₂ The gas is used to combat the low SpO2 that occurs when NO causes methemoglobinemia. In a series of experiments, atmospheric humidity at an ambient temperature of 30 ℃ was combined with H obtained from the formulation ₂ Concentration was compared, the inventors noted that H ₂ The relative humidity increases by 1% for every increase in concentration of about 40ppm (the amount of water vapor present in the air is expressed as a percentage of the amount required for saturation at the same temperature). Relative humidity with H ₂ The results of increasing the concentration and increasing are shown in table 4 below.

Table 4. Effect of hydrogen on atmospheric humidity in closed systems.

Although the sensor reached a limit at 1000ppm, these experiments, as well as any symptoms in which the lungs of all subjects did not develop water (edema), showed 1000ppm of H ₂ The concentration is safe. Suppose H up to 1500ppm ₂ The concentration is also safe and no significant H is present in the lungs of the subject inhaling the gas produced by the composition ₂ O is formed.

Claims

1. A method of generating NO gas for NO inhalation therapy, the method comprising combining a nitrate anion source and an elemental metal in an acidic solution in a vessel capable of containing a liquid and a gaseous component, thereby generating NO gas.

2. The method of claim 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.

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

4. A method according to claim 3, wherein the elemental metal is elemental zinc.

5. The method of claim 1, wherein the nitrate anion source is nitrate.

6. The method of claim 1, wherein the source of nitrate anions is a plant source of nitrate.

7. The method according to claim 1, wherein:

an effective amount of a nitrate anion source and an effective amount of elemental metal are combined in an acidic solution to produce an effective amount of NO gas,

an effective amount of elemental metal of from 1mg to 2000mg, and

an effective amount of the nitrate anion source provides 30mg to 4000mg of nitrate anions.

8. The method of claim 1, where an effective amount of the nitrate anion source and an effective amount of the elemental metal are combined in an acid solution in a ratio of 10:1 to 1:10 to produce an effective amount of NO gas.

9. The method of claim 1, where an effective amount of the nitrate anion source and an effective amount of the elemental metal are combined in an acid solution to produce at least 5ppm NO gas and 1000ppm H ₂ And (3) gas.

10. The method of any one of claims 1 to 9, wherein the pH of the acidic solution is from 0.1 to 6.9.

11. The method of any one of claims 1 to 9, wherein the pH of the acidic solution is from 2 to 4.

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

13. The method of claim 12, wherein the acid powder is citric acid, malic acid, or fumaric acid.

14. The method of claim 12, wherein the solvent is water.

15. The method of claim 15, wherein the acid powder is dissolved in 1ml to 10000ml of water.

16. The method according to any one of claims 1 to 9, wherein the gas component produced by combining the nitrate anion source and the elemental metal in an acidic solution does not contain unsafe levels of NO ₂ And (3) gas.

17. The method according to claim 16, wherein NO is generated by combining a nitrate anion source and an elemental metal in an acidic solution ₂ The level of gas does not exceed 2ppm.

18. The method according to claim 16, wherein NO is generated by combining a nitrate anion source and an elemental metal in an acidic solution ₂ The level of gas does not exceed 5ppm.

19. The method according to claim 16, wherein NO is generated by combining a nitrate anion source and an elemental metal in an acidic solution ₂ The level of gas does not exceed 10ppm.

20. The method of claim 16, wherein the method is performed by treating the sample in an acidic solutionThe gas component produced by combining the nitrate anion source and the elemental metal does not contain any NO ₂ And (3) gas.

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

22. A method of safely generating NO gas for NO inhalation therapy, the method comprising combining a nitrite anion source and elemental metal in an acidic solution in a vessel capable of containing a liquid and a gaseous component, thereby generating NO gas.

23. The method of claim 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.

24. The method of claim 22, wherein the elemental metal is elemental magnesium.

25. The method of claim 22, wherein the elemental metal is elemental zinc.

26. The method according to claim 22, wherein the nitrite anion source is nitrite.

27. The method according to claim 22, wherein the source of nitrite anions is a plant source of nitrite.

28. The method according to claim 22, wherein an effective amount of a source of nitrite anions and an effective amount of elemental metal that provides 1mg to 1000mg of nitrite anions are combined in an acidic solution to produce an effective amount of NO gas.

29. The method according to claim 22, wherein the effective amount of nitrite anion source and the effective amount of elemental metal are combined in an acid solution in a ratio of 10:1 to 1:10 to produce an effective amount of NO gas.

30. The method according to claim 22, wherein an effective amount of nitrite anion source and an effective amount of elemental metal are combined in an acid solution to produce at least 5ppm NO gas and 1000ppm H ₂ And (3) gas.

31. The method of any one of claims 22 to 30, wherein the pH of the acidic solution is from 0.1 to 6.9.

32. The method of any one of claims 22 to 30, wherein the pH of the acidic solution is from 2 to 4.

33. The method of any one of claims 22 to 30, further comprising dissolving an acid powder in a solvent to produce an acidic solution.

34. The method of claim 33, wherein the acid powder is citric acid, malic acid, or fumaric acid.

35. The method of claim 33, wherein the solvent is water.

36. The method of claim 35, wherein the volume of water is 1ml to 10000ml.

37. The method according to any one of claims 22 to 30, wherein the gas component produced by combining the nitrate anion source and the elemental metal in an acidic solution does not contain unsafe levels of NO ₂ And (3) gas.

38. The method according to claim 37,wherein NO is generated by combining a nitrite anion source and an elemental metal in an acidic solution ₂ The level of gas does not exceed 2ppm.

39. The method according to claim 37, wherein NO is generated by combining a nitrite anion source and an elemental metal in an acidic solution ₂ The level of gas does not exceed 5ppm.

40. The method according to claim 37, wherein NO is generated by combining a nitrite anion source and an elemental metal in an acidic solution ₂ The level of gas does not exceed 10ppm.

41. The method according to claim 37, wherein the gas component produced by combining the nitrite anion source and the elemental metal in an acidic solution does not comprise any NO ₂ And (3) gas.

42. The method according to claims 22 to 30, wherein the gas component produced by combining the nitrite anion source and the elemental metal comprises a nitroxyl gas.

43. The method of any one of claims 1 to 42, further comprising administering NO gas to the subject via a container capable of containing a liquid and a gaseous component.

44. The method of claim 43, wherein the container capable of containing liquid and gaseous components is a water line.

45. The method according to claim 44, wherein administering NO gas to the subject via a container capable of containing liquid and gaseous components comprises inhalation by the subject from a water line.

46. The method of claim 45, wherein the container is connected to a respirator via a conduit.

47. The method of claims 44-46, wherein the subject has dyspnea, has migraine, has an oxygen saturation level of less than 95, is seeking improved athletic performance, is seeking increased endurance, or is seeking improved psychological performance.

48. A method of therapeutically administering an inhaled NO gas, the method comprising co-administering to a subject an effective amount of hydrogen gas with NO gas, wherein the effective amount of hydrogen gas is sufficient to reduce or prevent NO during administration of NO gas to the subject ₂ The amount formed.

49. The method of claim 48, wherein the effective amount of hydrogen is at least 1000ppm.

50. The method of claim 48 or 49, wherein the method comprises mixing the elemental metal with a nitrate source and/or a nitrite source in an acidified solvent, thereby generating NO gas and an effective amount of hydrogen gas and administering to the subject via inhalation.

51. A method of administering inhaled nitric oxide gas with reduced toxicity to a subject, the method comprising:

administering nitric oxide gas to a subject, and

hydrogen is administered to the subject.

52. The method of claim 51, wherein the nitroxyl gas is also administered to the subject.

53. The method of claim 51 or 52, wherein reduced toxicity is manifested as reduced lung injury compared to the amount of lung injury that occurs by administration of the same concentration of NO gas itself.

54. The method of claim 51 or 52, wherein reduced toxicity is manifested as no methemoglobinemia.

55. The method of claim 54, wherein the subject's blood methemoglobin level is no more than 2%.

56. A composition comprising:

A nitrite source; and

elemental metal.

57. The composition of claim 56, wherein said nitrite source is nitrite.

58. The composition of claim 57, wherein the nitrite is sodium nitrite or potassium nitrite.

59. The composition according to claim 56, wherein the nitrite source is a plant source of nitrite normalized to nitrite content.

60. The composition according to claim 59, wherein the plant source of nitrite normalized to nitrite content is fermented beetroot meal.

61. The composition according to claim 56, wherein said 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 technetium, 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.

62. The composition of any one of claims 56 to 61, wherein the composition is in the form of a capsule, cachet, pill, tablet, powder, granule, pellet, bead, microparticle, lozenge, troche, solution, elixir, syrup, tincture, suspension, emulsion, mouthwash, spray, drops, ointment, cream, gel, paste, transdermal patch, suppository, pessary, cream, gel, paste, foam, and combinations thereof.

63. The composition of any one of claims 56 to 61, wherein the composition further comprises an acceptable additive and/or an acceptable carrier.

64. The composition of claim 63, wherein:

the acceptable additive is selected from at least one of the following: solubilizers, enzyme inhibitors, anticoagulants, defoamers, antioxidants, colorants, coolants, cryoprotectants, hydrogen bonding agents, flavoring agents, plasticizers, preservatives, sweeteners and thickeners; and

the acceptable carrier is selected from at least one of the following: excipients, lubricants, binders, disintegrants, diluents, extenders, solvents, suspending agents, dissolution aids, isotonic agents, buffers, soothing agents and amphiphilic lipid delivery systems.

65. The composition according to any one of claims 56 to 61, wherein the composition comprises an effective amount of nitrite to produce a therapeutic effect, and an effective amount of elemental metal to prevent or reduce nitrite toxicity.

66. The composition according to claim 65, wherein nitrite toxicity is manifested as the occurrence of methemoglobinemia.

67. The composition according to claim 65, wherein the therapeutic effect of nitrite is to reduce blood pressure or treat and/or alleviate symptoms of respiratory diseases.

68. The composition of claim 67, wherein the respiratory disease is an infection by coronavirus, influenza virus, respiratory syncytial virus, streptococcus pneumoniae (Streptococcus pneumoniae), haemophilus influenzae type b (Haemophilus influenzae type b), pneumospore bacteria (Pneumocystis jiroveci), fungi, or protozoans.

69. The composition of claim 65, wherein:

an effective amount of nitrite is 1 to 1000mg and an effective amount of elemental metal is 1 to 10000mg;

an effective amount of nitrite of 5 to 200mg and an effective amount of elemental metal of 5 to 1000mg; or (b)

The effective amount of nitrite is 30 to 100mg and the effective amount of elemental metal is 10 to 400mg.

70. The composition of claim 63, wherein the composition is in a form suitable for oral administration.

71. The composition of claim 63, wherein the composition is in a form suitable for inhalation of gases generated upon contact with an acidified solvent.

72. The composition of claim 63, wherein:

the nitrite source is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, microparticles, lozenges or lozenges; and

the elemental metal is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, microparticles, lozenges, or troches.

73. The composition of any one of claims 56 to 61, wherein the composition further comprises an acid.

74. The composition of claim 73, wherein:

the nitrite source is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, microparticles, lozenges or lozenges;

the elemental metal is packaged in capsules, cachets, pills, tablets, powders, granules, pellets, beads, microparticles, lozenges or lozenges; and

The acid is packaged separately from the nitrite source and the elemental metal.

75. The composition of claim 73 wherein the nitrite source, elemental metal and acid are in solid form.

76. The composition of claim 73, wherein the nitrite source and elemental metal are packaged together.

77. The composition of claim 76, wherein the nitrite source and elemental metal are packaged in capsules, cachets, pills, or tablets.

78. A kit for safely administering NO gas to a patient, the kit comprising:

nitrite or nitrate sources;

an elemental metal, wherein the nitrite or nitrate source is packaged with the elemental metal;

an acid; and

for combining nitrite or nitrate, elemental metal and acid to produce NO gas without producing NO ₂ Instructions for administration of the gas and the generated NO gas to the patient.

79. The kit of claim 78, further comprising a container capable of containing liquid and gaseous components.

80. The kit of claim 79, wherein the container capable of containing liquid and gaseous components is a water tube.

81. The kit of any one of claims 78 to 80, wherein the nitrite or nitrate source is nitrite or nitrate.

82. The kit of claim 81, wherein the nitrite salt is sodium nitrite or potassium nitrite.

83. The kit of claim 81, wherein the nitrate salt is sodium nitrate or potassium nitrate.

84. The kit of any one of claims 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 technetium, 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.

85. A composition comprising:

nitric oxide gas; and

hydrogen gas.

86. The composition of claim 85, further comprising a nitroxyl gas.

87. The composition of claim 85 or 86, wherein the concentration of nitric oxide gas is at least 1ppm and the concentration of hydrogen gas is higher than 0.55ppm.

88. The composition of claim 85 or 86, wherein the hydrogen gas is at a concentration of 1 to 10000ppm and the nitric oxide gas is at a concentration of 1 to 500ppm.

89. The composition of claim 85 or 86, wherein the concentration of hydrogen does not result in the formation of liquid water.

90. A method of reducing inhaled NO toxicity, the method comprising inhaling NO and an effective amount of hydrogen to reduce NO toxicity.

91. The method of claim 90, wherein the reduced NO toxicity is lung tissue injury.

92.86 the method of claim 90, wherein the prevented NO toxicity is an increase in nitrotyrosine levels in NO-exposed tissues.

93. A method of preventing and/or treating methemoglobinemia in a subject comprising administering to the subject an effective amount of hydrogen via inhalation.

94. A method of preventing and/or treating methemoglobinemia in a subject comprising orally administering to the subject an effective amount of an elemental metal.

95. The method of claim 94, further comprising orally administering an acid to the subject, wherein the elemental metal and acid are ingested together.

96. The method of claim 95, wherein the elemental metal and acid are in amounts effective to produce hydrogen in the stomach.

97. The method of any one of claims 93-96, wherein the methemoglobinemia is caused by inhaled NO therapy, administration of nitrite or administration of nitrate.

98. The method of any one of claims 93-96, wherein the subject does not exhibit NO ₂ Toxicity induced.

99. The method of any one of claims 93-96, wherein the subject exhibits reduced NO ₂ Toxicity induced.

100. The method of claim 98 or 99, wherein the NO ₂ The toxicity induced is lung and/or airway inflammation, reduced lung function, worsening cough, worsening wheezing, increased asthma attacks, or greater likelihood of emergency and hospitalization.