TW202327630A - Methods of treating conditions responsive to nitric oxide therapy - Google Patents

Abstract

Compositions and methods of treating conditions in a subject that are responsive to nitric oxide (NO) treatment are disclosed and described. Such compositions can include a combination of a nitric oxide releasing compound, an acidifying agent, and a carrier in amounts that release from about 1 ppm*min/mL to about 500 ppm*min/mL NO based on 1 mL of the composition when measured by releasing NO from the composition for a period of 30 minutes into a flow of substantially inert carrier gas at a flow rate of 1 liter per minute and a pressure of 1 atmosphere, coupled to a chemiluminescence detector.

Description

Method of treating a condition responsive to nitric oxide therapy

This invention relates to methods of treating conditions responsive to nitric oxide therapy.

background

Nitric oxide (NO) is a diatomic molecule comprising one nitrogen atom and one oxygen atom. The NO molecule is very unstable and has a free radical-like nature. NO is readily oxidized to nitrogen dioxide (NO ₂ ). Accordingly, NO may be difficult to produce and store or use in controlled quantities. In the human body, nitric oxide can be produced by nitric oxide synthase (NOS). Many physiological and pathological processes in the body may involve NO. For example, low levels of NO in the blood can promote vasodilation to prevent ischemic injury, can aid in wound healing, and can be a potent antimicrobial agent. Conversely, high levels of NO in the blood may lead to tissue toxicity and may lead to inflammatory conditions such as septic shock, diabetes and arthritis.

According to one embodiment of the present invention, a method of treating a condition responsive to nitric oxide (NO) therapy in an individual is provided, comprising: administering a volume of nitric oxide releasing solution (NORS), which provides a A therapeutically effective amount of NO to an administration site of the individual for a therapeutic period, wherein the NORS comprises a nitric oxide releasing compound and an acidifying agent, wherein when coupled to a chemiluminescent detector, release of NO from the NORS to The NORS is from about 1 ppm*min/mL to about 500 ppm*min based on 1 mL of the NORS when measured at a flow rate of 1 liter per minute and a substantially inert carrier gas flow of 1 atmosphere for a period of 30 minutes /mL releases NO.

According to another embodiment of the present invention, a composition for treating a condition responsive to nitric oxide (NO) therapy is specifically provided, the composition comprising a nitric oxide releasing solution (NORS), wherein the NORS comprises a Nitric oxide releasing compounds and acidifying agents, wherein when quantified by chemiluminescence detectors are measured by the release of NO from NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes , the NORS releases NO in an amount from about 1 ppm*min/mL to about 500 ppm*min/mL based on 1 mL of the NORS.

According to another embodiment of the present invention, the use of the above-mentioned composition in the preparation of medicines for treating diseases responsive to nitric oxide (NO) treatment is specifically proposed, comprising: adding a therapeutically effective amount of the composition administered to individuals.

According to another embodiment of the present invention, a composition is specifically provided, comprising: a combination of a nitric oxide releasing compound, an acidulant and a carrier in an amount such that when coupled to a chemiluminescence detector, the composition releases When measured at a flow rate of 1 liter per minute and a substantially inert carrier gas flow at 1 atmosphere for a period of 30 minutes, the composition released from about 1 ppm*min/mL to About 500 ppm*min/mL of Nitric Oxide (NO).

Description of the implementation

Although the following detailed description contains many details for purposes of illustration, those of ordinary skill in the art will understand that many changes and modifications to the following details may be made and are considered to be included in the present disclosure. Accordingly, the following embodiments are set forth without any loss of generality and without imposing limitation on any of the claims set forth. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

In this written description, the singular forms "a, an" and "the" provide explicit support for plural elements unless the context clearly dictates otherwise. Thus, for example, reference to "a particle" includes a plurality of particles.

In this application, "comprises, comprising", "containing (containing)" and "having" etc. may have the meanings assigned to them in U.S. Patent Law and may mean "includes, including), etc., and are generally interpreted as open-ended terms. The term "consisting of, consists of" is a closed term, and only includes components, structures, steps, etc. that are clearly listed together with such terms, and content that complies with US patent laws. "Consisting essentially of, consists essentially of" has the meaning usually assigned to it by US patent law. In particular, such terms are generally closed terms, but it is permissible to include additional items, materials, components, steps or elements that do not materially affect the basic and novel characteristics or functions of the related item. For example, trace elements that occur in a composition but do not affect the nature or properties of the composition are permitted if they appear with the phrase "consisting essentially of" even if they are not explicitly listed in the list of items following such term. When open-ended terms such as "comprises" or "comprises" are used in this written description, it is understood that there is also direct support for the phrases "consisting essentially of" and "consisting of" as expressly stated and vice versa .

The terms "first", "second", "third", "fourth", etc., in the description and claims, if any, are used to distinguish similar elements and not necessarily to describe specific sequence or timing. It is to be understood that any terms so used are interchangeable under appropriate circumstances such that the embodiments described herein are, for example, capable of operation in sequences other than those illustrated or otherwise described herein. Similarly, if a method is described as comprising a series of steps, the order in which the steps are presented is not necessarily the only order in which the steps may be performed, and some of the steps may be omitted and/or not described herein. Certain other steps may be added to this method.

The words "in one embodiment" or "in an aspect" appearing in this case do not necessarily refer to the same embodiment or aspect.

As used herein, "individual" refers to a mammal that may benefit from NORS or NO administration. In one aspect, the mammal can be a human.

As used herein, the terms "treat, treatment or treating" when used in connection with administration of NORS or NO, including compositions and dosage forms thereof, refer to administration to asymptomatic or symptomatic individuals. In other words, "treat, treatment or treating" can reduce, ameliorate or eliminate symptoms associated with a condition occurring in an individual, or can be prophylactic (ie, prevent or reduce the occurrence of symptoms in an individual). Such prophylactic treatment can also be referred to as prophylaxis of the condition.

As used herein, the terms "formulation" and "composition" are used interchangeably to refer to a mixture of two or more compounds, elements or molecules. In some aspects, the terms "formulation" and "composition" may be used to refer to a mixture of one or more active agents and a carrier or other excipient. Compositions can assume almost any physical state, including solids, liquids (ie, solutions), or gases. Also, the term "dosage form" may include one or more formulations or compositions presented in a form for administration to a subject. In one embodiment, the composition may be a solution for releasing NO.

A "kit" may refer to a package or container comprising a composition or dosage form together with instructions for administering or administering the composition or dosage form according to a given regimen or within specified time and dosage parameters to treat one or more particular indications. For example, a kit may include a specified volume or amount of a NORS composition or components thereof together with a set of instructions for proper administration of NORS to an individual to treat a given condition, such as an indication. Instructions may include directions for a single type of administration or indication, or directions for multiple types of administration or indications. In addition, the amounts and forms of the NORS compositions in the kit can be adapted for single administration to treat a single indication, multiple administrations to create a regimen for one indication, or single or multiple administrations for multiple indications disease. For example, a composition or dosage form of a NORS composition may be provided in a kit, together with instructions for administering the dosage form in terms of amounts and volumes, which dosage form is suitable for treating a plurality of indications, such as a skin disorder, such as acne, or a wound Healing, or respiratory therapy, or to further improve immunity in the sinus and throat area.

As used in this case, "NORS" means a nitric oxide (NO) releasing solution, composition or substance that includes acidified nitrites capable of releasing NO. In one aspect, the NO released from the NORS can be a gas. NORS can be in various physical forms such as liquid, cream, gel or others.

As used in this case, "nitric oxide releasing compound" and "nitric oxide releasing agent" are used interchangeably, and it should be understood that reference to one term in this written description provides express support for the other. Such terms refer to a compound, agent or molecule that, when reacted with another compound or agent, such as an acid, can liberate nitric oxide. Nitric oxide (NO) can be emitted as a gas such as gNO. Also, the term "nitrite" as used in this written description may be used to refer generically to "nitric oxide releasing compounds" or "nitric oxide releasing agents" or may specifically refer to _NO2 compounds as conventionally known in the chemical arts And express support for terms that are used interchangeably is included herein.

As used herein, "therapeutic agent" refers to an agent that, when administered to an individual in an appropriate or effective amount, can have a beneficial or positive effect on the individual. In one aspect, NO can be a therapeutic agent. In another aspect, therapeutic agents may include physiologically active non-NORS agents such as antibiotics, antihistamines, antivirals, antimicrobials, biomolecules such as siRNA, cDNA, steroids, vasodilators, vascular Tonic agents, analgesics, anti-inflammatory agents, etc. In some aspects, therapeutic agent is used interchangeably with "active agent" or "drug."

As used in this case, an "effective amount" of an agent is an amount sufficient to accomplish the particular task or function for which the agent is intended. A "therapeutically effective amount" of a composition, drug, or agent is a non-toxic but sufficient amount of the composition, drug, or agent to achieve a therapeutic effect in the treatment or prevention of a condition for which the composition, drug, or agent is known to be effective. result. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Thus, an "effective amount" or "therapeutically effective amount" may in some cases depend on such biological factors. Furthermore, while the achievement of a therapeutic effect may be measured by a physician, veterinarian, or other qualified medical practitioner using assessments known in the art, it is recognized that individual differences and responses to treatment may make the achievement of a therapeutic effect somewhat Subjective judgment. The determination of an effective or therapeutically effective amount is well within the general knowledge in the fields of pharmaceutical science and medicine. See, eg, Meiner and Tonascia, "Clinical Trials: Design, Conduct, and Analysis," Monographs in Epidemiology and Biostatistics, Vol. 8 (1986).

As used herein, a "dosage regimen" or "regimen", such as "therapeutic regimen" or "prophylactic regimen" means how, when, how much and for how long an amount of a composition can or should be administered to an individual, To achieve the desired treatment or effect.

As used herein, the terms "release" and "release rate" are used interchangeably to refer to, or the rate at which, a substance, including but not limited to a therapeutic agent, such as NO, is expelled or released from a dosage form or composition containing the substance. In one embodiment, the therapeutic agent can be released in vitro. In another aspect, the therapeutic agent can be released in vivo.

As used in this case, "immediate release" or "immediate release" are used interchangeably and refer to the immediate or near-immediate (i.e., uninhibited or unrestricted) release of an agent or substance, including therapeutic agents, such as NO.

As used herein, the term "controlled release" refers to the non-immediate release of an agent or substance, including therapeutic agents such as NO, from a composition or formulation. Examples of specific types of controlled release include, but are not limited to, extended or sustained release and delayed release. Any number of control mechanisms or components can be used to create a controlled release effect, including formulation ingredients or constituents, formulation properties or states such as pH, the environment in which the formulation is placed, or a combination of ingredients of the formulation and the environment in which the formulation is placed . In one embodiment, extended release may include releasing the therapeutic agent at a level sufficient to provide a therapeutic effect or treatment for a specified or intended period of time that is not immediate.

As used herein, the term "modulation" refers to any change, ie, increase, decrease, etc., of a biological state.

As used in this case, the units "parts per million", "ppm", "parts per billion", "ppb", etc. are based on volume when used to describe a gaseous mixture. Accordingly, a part per million is equivalent to one part by volume in a million parts by volume.

As used in this case, expressions such as "increased", "decreased", "better", "worse", "higher", "lower", "enhanced", "improved", " Comparative terms such as "maximize", "minimize", etc. refer to comparisons in the surrounding or adjacent area, in a similar location, in a single device or composition or in multiple similar devices or compositions, in a group or Other devices, components, compositions, biological responses, biological states, or activities in a class, across groups or classes, or compared to original (e.g., untreated) or baseline states or states known from prior art The property of a different device, component, composition, biological reaction, biological state, or activity that can be measured. For example, a composition that "increases" an immune response provides an elevated level of response in an individual compared to a previous time point, e.g., a baseline level (such as before treatment), or differs from earlier treatment use ( such as lower doses).

As used in this case, the term "substantially" refers to the complete or near-complete scale or degree of an action, character, quality, state, structure, item or result. For example, an object that is "substantially" enclosed means that the object is either completely enclosed or nearly completely enclosed. In some cases, the exact degree of tolerance from absolute perfection may depend on the specific context. In general, however, proximity to completion will have the same overall result as achieving absolute and total completion. The use of "substantially" when used in a negative sense applies equally to the complete or almost complete absence of an action, characteristic, quality, state, structure, item or result. For example, a composition that is "substantially free" of particles is either completely free of particles, or so nearly completely free of particles that the effect is the same as having no particles at all. In other words, a composition that is "substantially free" of an ingredient or element may still actually contain that item, as long as there is no measurable effect of that item.

As used herein, the term "about" is used to provide flexibility in the endpoints of a numerical range by providing that a given value can be "a little above" or "a little below" the endpoint. Unless otherwise stated, use of the term "about" in reference to a particular number or numerical range should also be understood as providing support for such numerical term or range in the absence of the term "about". For example, for convenience and brevity, a numerical range of "about 50 ml to about 80 ml" should also be understood to provide support for a range of "50 ml to 80 ml". Also, it should be understood that in this specification, even when the term "about" is used, support for actual numerical values is provided. For example, reference to "about" 30 should be read as providing support not only for values slightly above and slightly below 30, but also for the actual value of 30.

As used herein, multiple items, structural elements, constituent elements and/or materials may be presented in a common listing for convenience. However, these lists should be read as if each member of the list was individually identified as a separate and unique member. Thus, no individual member of such list should be construed as de facto equivalent to any remaining member of the same list solely based on their presentation in a common group without indications to the contrary.

Concentrations, amounts, and other numerical data may be expressed or presented in this case in a range format. It should be understood that such range formats are used merely for convenience and brevity, and should therefore be construed flexibly to include not only the values expressly recited as limitations of the range, but also all individual values or subranges subsumed within that range, as if each value Same as subranges are all explicitly referenced. As an illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited value of about 1 to about 5, but also include individual values and subranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and subranges such as from 1-3, from 2-4, and from 3-5, etc., as well as individually 1, 2, 3, 4 and 5, and further include decimal or fractional values, such as 1.8, 2.3, 3.7, and 4.2.

The same principle applies to ranges reciting only one numerical value as a minimum or maximum. Moreover, such interpretations should apply regardless of the breadth of the scope or the characteristics described.

Reference throughout this specification to an "embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation. Thus, appearances of the phrase "in an embodiment" in various places throughout this specification do not necessarily refer to the same implementation.

Reference will now be made in detail to the preferred embodiments of the present invention. While the invention will be described in conjunction with preferred embodiments, it will be understood that it is not intended to limit the invention to those preferred embodiments. On the contrary, it is intended to cover alternatives, changes, modifications and equivalents, which may be included within the spirit and scope of the invention as defined by the appended claims. Example implementation

The following provides a preliminary overview of embodiments of the invention, followed by a more detailed description of specific embodiments. This preliminary overview is intended to help readers understand technical concepts more quickly, but it is not intended to identify its key or essential features, nor is it intended to limit the scope of claimed subject matter.

The present disclosure describes several methods and compositions useful in the treatment of conditions responsive to NO therapy. The methods and compositions are useful in the treatment of several specific indications. Such indications include but are not limited to wounds, skin infections, fungal infections, respiratory infections, bacterial infections, viral infections, athlete's foot, onychomycosis, flu, sinusitis, throat infections, acne, diabetic foot ulcers, Warts, common cold, respiratory fusion virus, coronavirus, etc. In some embodiments, NORS can be administered to provide NO gas that can kill and/or inactivate pathogens, such as fungi, bacteria, and viruses. In additional embodiments, NO gas may provide additional therapeutic benefits.

In certain embodiments, a method of treating a condition responsive to nitric oxide (NO) therapy in an individual may comprise administering a volume of a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of NO to the individual The site of administration for a treatment period. In other words, NO gas may contact the administration site during the treatment time course. In some cases, the site of administration can be a location on or within the body of an individual. In certain embodiments, the site of administration may be the site of disease. In further embodiments, the site of administration can be a mucous membrane, such as an area of an individual's nasal passages, sinuses, mouth, throat, lungs, or elsewhere in the respiratory system. In yet further embodiments, the site of administration may be an area of skin of the individual, the foot of the individual, or a nail of the individual, such as a toenail or a fingernail.

Moreover, NORS can take any number of administration forms depending on its intended use. In one embodiment, the NORS may be a spray, such as a nasal spray, sinus spray, throat spray, topical spray for the skin, and the like. In another embodiment, the NORS can be a mouthwash or a solution for gargling. In additional embodiments, NORS may be a sinus wash. In another embodiment, the NORS may be a liquid bath for immersion at the site of administration, such as a foot bath. In yet another embodiment, NORS can be soaked onto a cloth or substrate for use as a wipe. In yet another embodiment, NORS can be an aerosol. In other embodiments, NORS can be a gel or a cream. Almost any form suitable for administration to a particular designated site can be used.

In some embodiments, NORS can provide extended release of gaseous nitric oxide (gNO) when administered to a site. "Prolonged release" means that an effective amount of NO gas is released from a formulation at a controlled rate such that a therapeutically beneficial level (but below a toxic level) of gNO is maintained for an extended period of time. Specific examples of various NORS, including extended release NORS, can be found in US Patent No. 9,730,956, which is hereby incorporated by reference. Prolonged release of NORS is beneficial because a solution can be administered to a site for a short period of time and release of NO from the solution continues after administration.

The NORS described in this case may include a solution of nitrite and acid. In certain embodiments, when nitrite and acid are mixed in saline or water having a pH of less than 4.0, the solution becomes active and exhibits increased or enhanced nitric oxide gas over an extended period of time generation level. In one embodiment, the pH of the active state of the nitric oxide releasing solution is between a pH of about 1.0 and a pH of about 4.0. In another embodiment, the pH of the active state of the nitric oxide releasing solution is between a pH of about 3.0 and a pH of about 4.0. In one embodiment, the pH is about 3.2. In another embodiment, the pH is about 3.6. In another embodiment, the pH is about 3.7. In one embodiment, the pH is about 4.0. In another embodiment, the pH is below about 4.0. Because the nitric oxide releasing solution of the present invention is inactive until the acid in the liquid interacts with the nitrite, the nitrite solution can be pre-prepared, transported and conditioned for use in its resting state (pH greater than 4.0) for administration without producing any appreciable nitric oxide gas or without losing its ability to produce effective amounts of nitric oxide gas. Then, when the user is ready to deliver or administer the solution for treating a human subject, the solution can be activated by adding acid (to drive the pH below 4.0) immediately prior to administration to the human subject, thereby enabling The amount of nitric oxide gas generated by solution administration of the dose is maximized.

In one embodiment, the pH of the solution can be lowered by adding at least one acidulant to the solution. The introduction of an acidifying agent drives the reaction of the solution in the direction of the reactants, thus lowering the pH (producing more acid), which in turn produces more nitric oxide gas.

For example, by introducing sodium nitrite (or other nitrite) into a saline solution, nitric oxide gas will be generated very slowly, but in undetectable amounts (measured by chemiluminescence analysis (ppb sensitivity) ). The rate of NO production from the solution increased as the pH decreased, especially when the pH decreased below 4.0. NO is produced according to the following equilibrium equation: Thus, an acidifying agent such as an acid may donate H ⁺ to nitrite (NO ₂ ⁻ ). The more H ⁺ present, the faster the reaction towards _HNO2 , and the more NO will be produced.

In one embodiment, the nitric oxide releasing solution comprises at least one nitric oxide releasing compound, such as nitrite, a nitrite salt, or a metal nitrite. In one embodiment, the solution is a saline based solution. In one embodiment, the nitric oxide releasing compound is nitrite, salts thereof, and any combination thereof. Non-limiting examples of nitrites include nitrites such as sodium nitrite, potassium nitrite, magnesium nitrite, barium nitrite and calcium nitrite, mixed salts of nitrites such as nitrite orotate Salts, nitrites such as amyl nitrite, metal nitrites such as silver or copper nitrite. In one embodiment, the nitric oxide releasing compound is selected from the group consisting of sodium nitrite and potassium nitrite, and any combination thereof. In another embodiment, the nitric oxide releasing compound is sodium nitrite. In one embodiment, the solution consists of sodium nitrite dissolved in saline solution. In another embodiment, the solution consists of potassium nitrite dissolved in saline solution.

In one embodiment, the concentration of nitrite in the solution may be from about 0.1% w/v to about 1.5% w/v. In another embodiment, the concentration of nitrite may be between 0.07% w/v and about 0.5% w/v. In one embodiment, the concentration of nitrite in the solution is not greater than about 0.5% w/v. In another embodiment, the concentration of nitrite in the solution is not greater than about 0.8% w/v. In another embodiment, the concentration of nitrite in the solution is not greater than about 1% w/v. In yet another embodiment, the concentration of nitrite in the solution is between about 0.07-0.5% w/v. In another embodiment, the concentration of nitrite in the solution is from about 0.2% to about 0.4% w/v. In yet another embodiment, the concentration of nitrite in the solution is from about 0.4% to about 0.7% w/v. In another embodiment, the concentration of nitrite in the solution is from about 0.7% to about 0.9% w/v. In yet another embodiment, the concentration of nitrite in the solution is from about 0.9% to about 1.3% w/v. As used herein, the term "w/v" means (weight of solute in grams/volume of solution in milliliters) x 100%.

The solutions according to the invention may also contain at least one acidifying agent. As described elsewhere in this case, the addition of at least one acidulant to the solutions of the present invention helps to increase NO production. The present invention contemplates any acidulant that provides increased NO production. In one embodiment, the acidulant is an acid. In some embodiments, the acid may be a weak acid. In other embodiments, the acid may be a strong acid. In further embodiments, the acid may include a mixture of strong and weak acids. In yet further embodiments, the acid may be an organic acid. In other embodiments, the acid may be a mineral acid. In further embodiments, the acid may include a combination of organic and inorganic acids. Non-limiting examples of acids include ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, and phosphoric acid. In one embodiment, the acid is selected from the group consisting of ascorbic acid, citric acid, malic acid, hydrochloric acid, and sulfuric acid, and any combination thereof. In one embodiment, the acid is citric acid.

As noted above, the amount of acidulant present in the solution affects the rate of the reaction that produces NO. In some embodiments, the amount of acidulant is from about 0.1% to about 4% w/v. In one embodiment, the amount of acidulant is not greater than about 0.5% w/v. In another embodiment, the amount of acidulant is about 0.5% w/v. In another embodiment, the amount of acidulant is about 0.2% w/v. In one embodiment, the amount of acidulant is about 0.07% w/v. In another embodiment, the amount of acidulant is between about 0.07-0.5% w/v. In yet another embodiment, the amount of acidulant is from about 0.2% to about 0.4% w/v. In another embodiment, the amount of acidulant is from about 0.4% to about 0.7% w/v. In another embodiment, the amount of acidulant is from about 0.7% to about 0.9%. In yet another embodiment, the amount of acidulant is from about 0.9% to about 1.3% w/v. In another embodiment, the amount of acidulant is from about 1.3% to about 2% w/v. In another embodiment, the amount of acidulant is from about 2% to about 3% w/v. In yet another embodiment, the amount of acidulant is from about 3% to about 4% w/v.

As mentioned above, NO gas can be unstable and has a relatively short half-life. Thus, in some embodiments, NO gas is available for a limited time after NO is released from the NORS. In various embodiments, NORS can be a two-part composition. In certain embodiments, NORS can be prepared just prior to administration to the site by administering the acidifying agent to the resting solution. For example, as described elsewhere herein, administration of an acidulant to the resting solution causes the pH of the resting solution to decrease, thereby activating the nitric oxide releasing solution to be administered to the treatment site. Nitric Oxide Release Solutions provide extended production of nitric oxide. In one embodiment, the nitric oxide releasing solution generates nitric oxide for a period of time between 1 minute and 24 hours. In one embodiment, the nitric oxide releasing solution generates nitric oxide for a period of time between 10 minutes and 45 minutes. In one embodiment, the nitric oxide releasing solution produces nitric oxide for at least 15 minutes. In one embodiment, the nitric oxide releasing solution produces nitric oxide for at least 30 minutes. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 1 hour. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 4 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 8 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 12 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 24 hours. Thus, the administered nitric oxide releasing solution provides continuous delivery of nitric oxide to the treatment site of the individual.

In certain embodiments, the rate at which NORS produces NO varies over time. For example, NORS can be prepared by mixing an acidifying agent with a resting solution, and NORS can immediately start releasing NO gas at a specific rate. In some cases, the reaction to form NO gas may have an initial acceleration period during which the rate of NO production may increase to a peak rate. After the peak rate, the rate of NO production decreases over time until eventually the reaction is substantially complete. The initial rate of NO production, the peak of NO production, and the timing of the decline in the rate of NO production can vary depending on the formulation of NORS.

In some embodiments, the amount of NO produced by NORS can be measured and quantified using the methods and apparatus described in U.S. Patent Application Serial No. 16/541,084, published as U.S. Patent Application Publication No. Incorporated by reference into this case. In one embodiment, the NO produced by the NORS can be measured by releasing NO from the NORS into the carrier gas flow. The NO concentration in the carrier gas can then be quantified using a NO gas detector. Any suitable detector type can be used, such as chemiluminescent detectors, electrochemical detectors, fluorescent detectors, mass spectrometers or others. In certain embodiments, the NO detector can be a chemiluminescent detector. Chemiluminescence is an analytical technique that generally involves the emission of light as a result of a chemical reaction. More specifically, the decay of a molecule in an excited state to a lower energy state results in the emission of light, which can be detected by a chemiluminescence analyzer/detector. For example, nitric oxide (NO) can react with ozone ( _O3 ) to produce excited NO, which then decays to a lower energy state and emits electromagnetic radiation that can be detected optoelectronically. In some embodiments, the detector can measure the concentration of NO gas in the carrier gas flow. Concentration units may be, for example, parts per million (ppm) or parts per billion (ppb). In a certain embodiment, the detector can be a Sievers™ Nitric Oxide Analyzer 280i or a Zysense™ Nitric Oxide Analyzer 280i available from Zysense (USA).

When measuring NO released by NORS, several parameters can be adjusted. For example, the flow rate and pressure of the carrier gas can be adjusted. While the rate of NO production by NORS remains constant, increasing the flow rate of the carrier gas results in a decrease in the NO concentration measured by the detector because NO is mixed with a larger volume of carrier gas. Conversely, reducing the flow rate of the carrier gas may have the opposite effect. In some embodiments, the flow rate of the carrier gas may be from about 0.025 liters per minute (L/min) to about 10 L/min. In certain embodiments, standard flow rates can be selected so that the NO release rates of different NORS formulations can be compared to each other. In one embodiment, the flow rate may be 1 L/min. In other embodiments, the flow rate may be 0.5 L/min, 2 L/min, 3 L/min, or 5 L/min.

Additionally, in some embodiments, the carrier gas may be selected from gases that are inert to NO. In some embodiments, the carrier gas may be free or substantially free of oxygen or other reactive gas species. In further embodiments, the carrier gas may include nitrogen, noble gases, helium, argon, neon, krypton, xenon, radon, or combinations thereof.

In further embodiments, the amount of NO gas produced over time can be quantified by measuring the concentration of NO gas at different points in time and then multiplying the concentration by the amount of time that the NO concentration was produced. At a given carrier gas flow rate, the concentration of NO gas in the carrier gas can be proportional to the rate at which NO gas is produced from the NORS. For example, if NORS produces a sufficient amount of NO gas at a concentration of 100 ppm, and the concentration remains stable at 100 ppm for 30 minutes, the total amount of NO produced can be quantified by multiplying 100 ppm by 30 minutes to give 3,000 ppm *min. Assuming that the carrier gas flow rate is known, the unit "ppm*min" can correspond to the actual amount of NO produced.

In practice, NORS formulations may often produce NO at continuously varying rates. Therefore, it is impossible for NORS to produce NO at a steady concentration of 100 ppm within 30 minutes. To accurately quantify the amount of NO gas produced, the NO concentration in the carrier gas can be measured at multiple time points. These measurements form a plot of concentration data points over time. By integrating the area under the curve (AUC) the total amount of NO in ppm*min can be determined. In other embodiments, the units used may be different, such as different measures of concentration and different measures of time. For example, other examples of units may include ppb*min or ppb*s or ppb*hr, for example. AUC can be calculated by integrating the curve of the concentration data points using numerical integration methods, such as multiplying each concentration data point by the time interval between the data points, and then taking the sum of the products. In various embodiments, the time interval between data points may be any suitable period of time, for example from 1/1000th of a second up to a minute or longer. A smaller time interval between measurements can generate a larger number of data points and, in some embodiments, can provide a more accurate AUC. In certain embodiments, the measurements can be made using a computer connected to the NO detector, and the computer can be programmed to calculate the AUC.

In certain embodiments, the concentration of NO produced by NORS can be measured following standard procedures. Standard methods can also be used to calculate various metrics such as ppm*min amount of NO produced or peak NO concentration or others over a set period of time. Different NORS formulations can be compared to each other by quantifying the NO produced by the different NORS formulations using the same standard method. In a particular embodiment, a volume of NORS can be introduced into the sample chamber. Any volume of NORS can be used. In some embodiments, the volume can be 1 mL, 2 mL, 3 mL, 5 mL, or another fraction. In some examples, the sample chamber can be made of materials that are inert to NO. In other embodiments, the sample chamber may have a lining that is inert to NO. A carrier gas may flow through the sample chamber at a fixed flow rate. In one embodiment, the flow rate may be 1 L/min at standard temperature and pressure. In another embodiment, the carrier gas can be nitrogen. NORS releases NO into the flowing carrier gas, and the mixture of carrier gas and NO gas can leave the sample chamber through the outlet. A chemiluminescent detector can be connected to the carrier gas stream mixed with NO from the outlet. A chemiluminescent detector measures the NO concentration in a gas mixture. Measurements may be taken at specified time intervals, such as once per minute, once per second, once every 1/10 of a second, or another time interval. These measurements are recorded as data points over a 30-minute period. AUC can be calculated from the data points. This amount can be in ppm*min, which can represent the total amount of NO gas released by the NORS sample within 30 minutes. In another embodiment, the amount of NO released from a single milliliter of NORS can be calculated in units of ppm*min/mL. Assuming that the volume of NORS introduced into the sample chamber is 1 mL, the AUC is the same value in ppm*min/mL. If a larger volume of NORS is used, eg 5 mL, the AUC can be divided by the number of mL used to give the NO release in ppm*min/mL.

Using the same measurement procedure, the peak NO concentration was found by taking the maximum measured value returned by the chemiluminescence detector. In some embodiments, the chemiluminescence detector can return measurements in ppm. Accordingly, the peak NO concentration may be the highest instantaneous value in ppm measured during 30 minutes.

In some embodiments, 1 mL of NORS can release a desired amount of NO gas when measured at a carrier gas flow rate of 1 L/min at a pressure of 1 atm as described above over the course of 30 minutes. In certain embodiments, the amount of NO released by NORS may be from about 1 ppm*min/mL to about 500 ppm*min/mL. In other embodiments, the amount of NO can be from about 1 ppm*min/mL to about 100 ppm*min/mL, or from about 1 ppm*min/mL to about 60 ppm*min/mL, or from about 5 ppm*min/mL to about 100 ppm*min/mL, or from about 10 ppm*min/mL to about 100 ppm*min/mL, or from about 20 ppm*min/mL to about 100 ppm*min/mL. In another example, as described above, when using 1 mL of NORS to release NO gas at 1 atm into a carrier gas of 1 L/min for 30 minutes, NORS can release peak concentrations from about 0.1 ppm/mL to About 20 ppm/mL of NO gas. In certain specific embodiments, the peak concentration of NO released from 1 mL of NORS can be from about 0.3 ppm/mL to about 15 ppm/mL or from about 0.5 ppm/mL to about 12 ppm/mL.

NORS can be administered in a variety of forms. NORS can be administered as a liquid, spray, vapor, droplets, mist, gargle, douche, aerosol, gel, cream, or any form that releases nitric oxide from solution. In one embodiment, NORS is administered as a spray. The amount of nitric oxide releasing solution administered or the volume administered can be varied to optimize the time course of nitric oxide production and delivery. In one embodiment, the amount of nitric oxide releasing solution administered is between about 0.1 mL and 5000 mL. In another embodiment, the amount of nitric oxide releasing solution administered is between about 10 mL and 1000 mL. In additional embodiments, the amount of NORS administered may be from about 0.1 mL to about 1 mL, or from about 0.1 mL to about 2 mL, or from about 0.1 mL to about 5 mL, or from about 0.5 mL to about 1 mL, or from about 0.5 mL to about 2 mL, or from about 5 mL to about 500 mL, or from about 100 mL to about 300 mL, or from about 500 mL to about 5,000 mL. Certain types of NORS formulations can be administered in relatively large quantities, eg, formulations for bathing, washing, and the like. Other types of NORS formulations are available in smaller volumes, such as gels or creams applied to small topical areas, or nasal sprays. Certain types of NORS formulations may be used in medium volumes, such as mouthwashes, sinus washes, and the like.

As mentioned above, when the total dose of NORS was measured by releasing NO from NORS into the carrier gas flow at 1 L/min and 1 atm for 30 min, the total amount of NO released could be quantified in units of ppm*min. In some embodiments, the amount of NO released from a dose of NORS can be from about 10 ppm*min to about 75,000 ppm*min. In additional embodiments, depending on the dosage volume and formulation of NORS, the amount of NO can be from about 25,000 ppm*min to about 75,000 ppm*min, or from about 10 ppm*min to about 100 ppm*min, or from about From about 20 ppm*min to about 100 ppm*min, or from about 50 ppm*min to about 200 ppm*min, or from about 100 ppm*min to about 500 ppm*min, or from about 1,000 ppm*min to about 10,000 ppm *min. In additional embodiments, a dose of NORS releases the peak NO concentration during the 30 minute measurement period. The peak concentration can be from about 1 ppm to about 25,000 ppm, or from about 2 ppm to about 10 ppm, or from about 2 ppm to about 20 ppm, or from about 20 ppm to about 100 ppm, or from about 100 ppm to about 200 ppm, or from about 200 ppm to about 500 ppm, or from about 1,000 ppm to about 5,000 ppm, or from about 15,000 ppm to about 25,000 ppm.

In certain embodiments, the nitric oxide releasing solution is administered directly to the upper airway of the individual. For example, in one embodiment, a nitric oxide releasing solution is nebulized into the upper airway of an individual. The solution may be administered to the upper airway of an individual hourly, daily, weekly, biweekly, monthly, bimonthly, yearly, and any and all ranges in between, to treat the individual. In one embodiment, the solution is nebulized once a week. In another embodiment, the solution is sprayed once a week for four consecutive weeks. The nitric oxide releasing solution provides prolonged nitric oxide production, thereby providing continuous delivery of therapeutic nitric oxide to an individual with an upper respiratory tract infection.

The time course of administration of the nitric oxide releasing solution to an individual can be varied to optimize delivery. In one embodiment, the nitric oxide releasing solution is administered over a period of less than 5 seconds. In another embodiment, the nitric oxide releasing solution is administered over a period of about 5 seconds. In another embodiment, the nitric oxide releasing solution is administered over a period of about 30 seconds. In another embodiment, the nitric oxide releasing solution is administered over a period of from about 1 minute to about 20 minutes. The nitric oxide releasing solution may also be administered according to a dosing regimen, which may include a single dose or multiple doses given at specific times. In some embodiments, several doses may be administered at a frequency of from about once a day to about 5 times a day, or from about once a day to about every 50 days, or from about once a day to about once a week.

It should be noted that the period of time over which a dose of NORS is administered to an individual may be different than the period of time used to measure the concentration of NO gas released from NORS to characterize the NORS formulation. As noted above, in some embodiments, standard procedures can be used to characterize NORS formulations and quantify the amount of NO gas released by NORS. Standard procedures may entail measuring NO release over a period of time, such as 30 minutes. However, when a NORS formulation is administered to an individual, the timing of administering a dose of NORS can vary. Similarly, the volume of NORS administered to an individual may differ from the volume used in the measurement procedure used to quantify the amount of NO released from NORS. Accordingly, the amount of NO actually delivered to the individual may differ from the amount released during standard measurement procedures.

Treatment of respiratory disease by the present invention involves delivering a nitric oxide releasing solution into the upper airway of the individual to be treated. For example, in certain embodiments, the nitric oxide releasing solution may be injected, nebulized, inhaled, or dripped into the airways of an individual. The nitric oxide releasing solution may be administered to the respiratory tract of the individual through the nasal or oral cavity of the individual. In one embodiment, the nitric oxide releasing solution is nebulized into the upper airway of the individual. In one embodiment, the solution is administered to a subject intranasally. In one embodiment, the solution is administered to the sinuses. The nitric oxide releasing solution provides prolonged nitric oxide production, thereby providing continuous delivery of therapeutic nitric oxide to the upper airway of an individual.

In other embodiments, the individual's skin may be treated by applying a nitric oxide releasing solution to an area of skin. The nitric oxide releasing solution may be in the form of a liquid bath, spray, cream, gel, or other form that can be applied to the skin. In certain embodiments, the skin of the foot may be treated by applying a nitric oxide releasing solution to the skin of the foot. In additional embodiments, the fingernails or toenails and surrounding skin may be treated by applying a nitric oxide releasing solution to the fingernails, toenails or surrounding skin. In various embodiments, specific doses of nitric oxide can be provided to specific administration sites. Nitric oxide can be provided by a nitric oxide releasing solution formulated to provide this specific dose of nitric oxide.

In one embodiment, NORS can be used to treat Acrophyllus. Athlete's foot can be treated by administering NORS formulated to provide a therapeutically effective amount of NO for treating Athlete's foot. In some embodiments, NO may be provided to the administration site on the subject's foot. In a particular embodiment, NORS may be in the form of a liquid solution. The liquid solution can be used as a foot bath. The individual's feet may be immersed or submerged in the foot bath for a treatment period.

In certain embodiments, the NORS used to treat Hong Kong foot can release a specific amount of NO gas when measured by releasing NO gas into an inert carrier gas flow with a flow rate of 1 L/min and a pressure of 1 atm. A period of 30 minutes. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 25,000 ppm*min to about 75,000 ppm*min. In further embodiments, the amount of NO released from a single milliliter of NORS may be from about 5 ppm*min/mL to about 15 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 500 mL to about 10,000 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 5,000 ppm to about 20,000 ppm.

NORS can be formulated to provide a therapeutic amount of NO for treating Athlete's foot. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, the method of treating Athlete's foot can comprise administering NORS according to a dosing regimen of soaking the foot in a foot bath containing NORS for 30 minutes. In additional embodiments, the dosing regimen may include soaking the feet in a foot bath every 4 days.

In another embodiment, NORS can be used to treat onychomycosis. Onychomycosis can be treated by administering NORS formulated to provide a therapeutically effective amount of NO for the treatment of onychomycosis. In some embodiments, NO may be provided to the individual's toenail or fingernail at the site of administration. In a particular embodiment, NORS may be in the form of a liquid solution, gel or cream. Liquid solutions, gels or creams can be applied to the individual's nails for a treatment period.

In certain embodiments, NORS for the treatment of onychomycosis releases a specific amount of NO gas when measured by releasing NO gas into an inert carrier gas flow at a flow rate of 1 L/min and a pressure of 1 atm. A period of 30 minutes. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 25 ppm*min to about 75 ppm*min. In further embodiments, the amount of NO released from a single milliliter of NORS may be from about 25 ppm*min/mL to about 75 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 0.1 mL to about 2 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 5 ppm to about 20 ppm.

NORS can be formulated to provide therapeutic amounts of NO for the treatment of onychomycosis. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, the method of treating onychomycosis may comprise administering NORS for a period of 5 to 30 days according to a dosage regimen of administering NORS to the nail daily.

In another embodiment, NORS can be used to treat influenza. Influenza can be treated by administering NORS formulated to provide a therapeutically effective amount of NO for treating influenza. In some embodiments, NO may be provided to the site of administration in the individual's nasal cavity. In a particular embodiment, NORS may be in the form of a nasal spray. The nasal spray can be administered to the nasal cavity of an individual for a treatment period.

In certain embodiments, NORS used to treat influenza releases specific amounts of NO gas up to 30 when measured by releasing NO gas into an inert carrier gas flow at a flow rate of 1 L/min and a pressure of 1 atm. minutes for a period of time. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 1 ppm*min to about 15 ppm*min or from about 5 ppm*min to about 10 ppm*min. In further embodiments, the amount of NO released from a single milliliter of NORS may be from about 2 ppm*min/mL to about 30 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 0.1 mL to about 2 mL or from about 0.1 mL to about 1 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 0.5 ppm to about 5 ppm.

NORS can be formulated to provide therapeutic amounts of NO for the treatment of influenza. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, methods of treating influenza can comprise administering NORS according to an on-demand nasal spray dosing regimen.

In another embodiment, NORS can be used to treat respiratory viral infections. Respiratory viral infections, such as the common cold, respiratory fusion viruses, and coronaviruses, can be treated by administering NORS formulated to provide a therapeutically effective amount of NO for the treatment of respiratory viral infections. In some embodiments, NO may be provided to the site of administration in the individual's nasal cavity. In a particular embodiment, NORS may be in the form of a nasal spray. The nasal spray can be administered to the nasal cavity of an individual for a treatment period.

In certain embodiments, NORS for the treatment of respiratory viral infections releases a specified amount of NO gas when measured by releasing NO gas into an inert carrier gas flow at a flow rate of 1 L/min and a pressure of 1 atm for a period of up to 30 minutes. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 1 ppm*min to about 15 ppm*min or from about 5 ppm*min to about 10 ppm*min. In further embodiments, the amount of NO released from a single milliliter of NORS may be from about 2 ppm*min/mL to about 30 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 0.1 mL to about 2 mL or from about 0.1 mL to about 1 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 0.5 ppm to about 5 ppm.

NORS can be formulated to provide therapeutic amounts of NO for the treatment of respiratory viral infections. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, the method of treating a respiratory viral infection can comprise administering NORS according to an on-demand nasal spray dosing regimen.

In another embodiment, NORS can be used to treat sinusitis. Sinusitis can be treated by administering NORS formulated to provide a therapeutically effective amount of NO for treating sinusitis. In some embodiments, NO may be provided to the site of administration in the sinus cavity of the individual. In a particular embodiment, NORS may be in the form of a liquid lavage or irrigation solution. In certain embodiments, the liquid lavage or irrigation solution can have a volume of about 240 mL or less.

In certain embodiments, NORS for the treatment of sinusitis can release a specified amount of NO gas when measured by releasing NO gas into an inert carrier gas flow at a flow rate of 1 L/min and a pressure of 1 atm. A period of 30 minutes. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 100 ppm*min to about 5,000 ppm*min, or from about 100 ppm*min to about 500 ppm*min, or from about 500 ppm*min to About 2,000 ppm*min or from about 2,000 to about 5,000 ppm*min. In further embodiments, the amount of NO released from a single milliliter of NORS may be from about 0.5 ppm*min/mL to about 30 ppm*min/mL, or from about 1 ppm*min/mL to about 4 ppm*min/mL , or from about 4 ppm*min/mL to about 10 ppm*min/mL or from about 10 ppm*min/mL to about 30 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 150 mL to about 300 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 50 ppm to about 1,500 ppm.

NORS can be formulated to provide therapeutic amounts of NO for the treatment of sinusitis. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, methods of treating influenza may comprise administering NORS according to a dosing regimen of administering NORS daily for a period of about 10 to about 50 days.

In another embodiment, NORS can be used to treat throat infections. Throat infections can be treated by administering NORS formulated to provide a therapeutically effective amount of NO for treating throat infections. In some embodiments, NO may be provided to the administration site in the throat of an individual. In a particular embodiment, NORS may be in the form of a liquid gargle solution. The solution may be swished by the individual for a treatment period.

In certain embodiments, NORS used to treat throat infections can release a specific amount of NO gas when measured by releasing NO gas into an inert carrier gas flow at a flow rate of 1 L/min and a pressure of 1 atm. A period of 30 minutes. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 200 ppm*min to about 800 ppm*min or from about 400 ppm*min to about 600 ppm*min. In further embodiments, the amount of NO released from a single milliliter of NORS may be from about 10 ppm*min/mL to about 40 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 5 mL to about 40 mL or from about 10 mL to about 30 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 100 ppm to about 200 ppm.

NORS can be formulated to provide therapeutic amounts of NO for the treatment of throat infections. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, the method of treating a throat infection can comprise administering NORS according to a regimen of administering NORS 1 to 3 times per day for a period of about 1 to about 5 days.

In another embodiment, NORS can be used to treat acne. Acne can be treated by administering NORS formulated to provide a therapeutically effective amount of NO for treating acne. In some embodiments, NO may be provided to an administration site located on an area of the individual's skin. In a particular embodiment, NORS may be in the form of a gel or cream. NORS can be applied to the skin of an individual for a treatment period.

In certain embodiments, NORS for the treatment of acne can release specific amounts of NO gas up to 30 when measured by releasing NO gas into an inert carrier gas flow at a flow rate of 1 L/min and a pressure of 1 atm. minutes for a period of time. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 10 ppm*min to about 60 ppm*min or from about 20 ppm*min to about 60 ppm*min. In further embodiments, the amount of NO released from a single milliliter of NORS may be from about 5 ppm*min/mL to about 30 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 1 mL to about 5 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 5 ppm to about 20 ppm.

NORS can be formulated to provide therapeutic amounts of NO for treating acne. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, the method of treating acne may comprise administering NORS according to a regimen of applying NORS to the skin from 1 to 3 times per day for a period of about 10 days to about 50 days.

In another embodiment, NORS can be used to treat diabetic foot ulcers. Diabetic foot ulcers can be treated by administering NORS formulated to provide a therapeutically effective amount of NO for treating diabetic foot ulcers. In some embodiments, NO may be provided to the administration site on the subject's foot. In a particular embodiment, NORS may be in the form of a liquid solution or gel in a foot bath. NORS can be administered to an individual's foot for a treatment period.

In certain embodiments, NORS for the treatment of diabetic foot ulcers releases specific amounts of NO gas when measured by releasing NO gas into an inert carrier gas flow at a flow rate of 1 L/min and a pressure of 1 atm A period of time of up to 30 minutes. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 100 ppm*min to about 75,000 ppm*min or from about 100 ppm*min to about 400 ppm*min or from about 25,000 ppm*min to about 75,000 ppm*min. In further embodiments, the amount of NO released from a dose of NORS may be from about 5 ppm*min/mL to about 80 ppm*min/mL or from about 10 ppm*min/mL to about 60 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 5 mL to about 10,000 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 50 ppm to about 20,000 ppm.

NORS can be formulated to provide therapeutic amounts of NO for the treatment of diabetic foot ulcers. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, a method of treating a diabetic foot ulcer may comprise administering NORS according to a regimen of administering NORS to the foot of an individual from 1 to 3 times per day for a period of about 10 to about 30 days.

In another embodiment, NORS can be used to treat warts. Warts can be treated by administering NORS formulated to provide a therapeutically effective amount of NO for the treatment of influenza. In some embodiments, NO may be provided to an administration site located on an area of the individual's skin. In a particular embodiment, NORS may be in the form of a gel or a liquid solution. NORS can be applied to the skin of an individual for a treatment period.

In certain embodiments, NORS used to treat warts can release specific amounts of NO gas up to 30 when measured by releasing NO gas into an inert carrier gas flow at a flow rate of 1 L/min and a pressure of 1 atm. minutes for a period of time. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 20 ppm*min to about 400 ppm*min or from about 20 ppm*min to about 80 ppm*min or from about 200 ppm*min to about 400 ppm*min. In further embodiments, the amount of NO released from a single milliliter of NORS may be from about 10 ppm*min/mL to about 60 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 0.5 mL to about 10 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 1 ppm to about 60 ppm.

NORS can be formulated to provide a therapeutic amount of NO for treating warts. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, the method of treating warts may comprise administering NORS according to a regimen of applying NORS to the skin from 1 to 3 times per day for a period of about 1 day to about 10 days.

In another embodiment, NORS can be used to disinfect the skin of an individual. The skin can be disinfected by administering NORS formulated to provide a therapeutically effective amount of NO for disinfecting the skin. In some embodiments, NO may be provided to an administration site located on an area of the individual's skin. In a particular embodiment, NORS may be in the form of a gel or cream. NORS can be applied to the skin of an individual for a treatment period.

In certain embodiments, NORS used to disinfect skin can release specific amounts of NO gas up to 30 when measured by releasing NO gas into an inert carrier gas flow at a flow rate of 1 L/min and a pressure of 1 atm. minutes for a period of time. The NO concentration in the carrier gas can be measured periodically using a chemiluminescent detector that measures the concentration in ppm. The total amount of NO released during the 30 min period was found by calculating the area under the curve (AUC) of the NO concentration measurements. In some embodiments, the amount of NO released from a dose of NORS can be from about 450 ppm*min to about 750 ppm*min. In further embodiments, the amount of NO released from a single milliliter of NORS may be from about 5 ppm*min/mL to about 25 ppm*min/mL. In yet other embodiments, the volume of a dose of NORS can be from about 50 mL to about 20 mL. In additional embodiments, a dose of NORS can deliver peak NO concentrations from about 1 ppm to about 20 ppm.

NORS can be formulated to provide therapeutic amounts of NO for disinfecting the skin. In certain embodiments, NORS may include nitrites and acidulants. In some embodiments, NORS can include nitrite at a concentration of from about 0.1 g/L to about 20 g/L, in terms of grams of nitrite in one liter of NORS. In additional embodiments, the NORS may include an acidulant at a concentration of from about 0.1 g/L to about 60 g/L.

In certain embodiments, the method of disinfecting skin may comprise administering NORS according to a regimen of applying NORS to the skin from 1 to 3 times per day for a period of about 10 days to about 20 days.

As noted above, in various embodiments, NORS can be prepared in various forms depending on the particular indication and method of treatment. Some forms of NORS that can be prepared include liquid solutions such as water and saline solutions, gargles, liquid baths, liquid douches, liquid rinses, sprays such as nasal or throat sprays, sinus rinses, gels , cream, foam, ointment, lotion, paste, emulsion, aerosol, etc. In various forms, NORS compositions may include combinations of the above components. In certain embodiments, NORS may include nitrite and acidulants, water, and optional additional ingredients, such as inactive ingredients. Nitrite and acidulant may be included in the desired amount to produce the desired amount of NO gas. Various inactive ingredients can include stabilizers, carriers, preservatives, emollients, adjuvants, and the like.

In some embodiments, NORS can be prepared as a liquid solution. As noted above, liquid solutions can take a variety of specific forms, such as aqueous solutions, saline solutions, gargles, liquid baths, liquid douches, liquid rinses, sprays, sinus rinses, and the like. In certain embodiments, NORS can be prepared by mixing nitrite and an acidulant in water. Nitrite and acidulant may be included in the desired amount to produce the desired amount of NO gas. Examples of nitrites and acidulants are described above, along with exemplary amounts of these ingredients. In some embodiments, NORS in liquid solution form may also include stabilizers, carriers, preservatives, emollients, adjuvants, or combinations thereof.

In embodiments that include a stabilizer, the stabilizer may be included in an amount of from about 0.1 wt% to about 50 wt% of the total weight of the NORS. In other embodiments, the amount of stabilizer can be from about 1 wt% to about 50 wt%, or from about 1 wt% to about 30 wt%, or from about 1 wt% to about 15 wt%, or from about 1 wt% to about 15 wt%. About 1 wt% to about 8 wt%. In certain embodiments, stabilizers may include oxygen scavengers, lipids, synthetic polymers, natural polymers, copolymers, or combinations thereof.

In additional embodiments, NORS in liquid solution form may include a carrier, which may include water, including deionized and/or deoxygenated water, surfactants, polymers, or combinations thereof. Surfactants may include lipophilic surfactants and hydrophilic surfactants. In some embodiments, lipophilic surfactants may include monoglycerides, diglycerides of fatty acids, such as glyceryl monolinoleate (e.g., Maisine® 35-1), monoglycerides of caprylic acid, capric acid, and glycerol Reaction mixtures of diesters (e.g. Capmul® MCM), glyceryl monooleate, alcohols or polyols with various natural and/or hydrogenated oils, e.g. PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated Castor Oil, PEG-6 Corn Oil (eg Labrafil® M 2125 CS), PEG-6 Sweet Almond Oil (eg Labrafil® M 1966 CS), PEG-6 Almond Oil (eg Labrafil® M 1944 CS), PEG-6 Olive Oil (e.g. Labrafil® M 1980 CS), PEG-6 peanut oil (e.g. Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil (e.g. Labrafil®. M 2130 BS), PEG-6 palm kernel oil (e.g. Labrafil® M 2130 CS), PEG-6 Triolein (e.g. Labrafil® M 2735 CS), PEG-8 Corn Oil (e.g. Labrafil® WL 2609 BS), PEG-20 Corn Glycerides (e.g. Crovol® M40), PEG-20 Almond glycerides (e.g. Crovol® A40), lipophilic polyoxyethylene polyoxypropylene block copolymers (e.g. Pluronic® L92, L101, L121, etc.); propylene glycol fatty acid esters, e.g. propylene glycol monolaurate (e.g. Lauroglycol FCC) , Propylene Glycol Ricinoleate (such as Propymuls), Propylene Glycol Monooleate (such as Myverol P-O6), Propylene Glycol Dicaprylate/Dicaprate (such as Captex® 200) and Propylene Glycol Dicaprylate ( e.g. Captex® 800), Propylene Glycol Mono-Caprylate (e.g. Capryol® 90); Propylene Glycol Oleate (e.g. Lutrol OP2000); Propylene Glycol Myristate; Propylene Glycol Monostearate; Propylene Glycol Hydroxystearate; Propylene Glycol Ricinoleate; Propylene Glycol Isostearate; Propylene Glycol Mono-Oleate; Propylene Glycol Dicaprylate/Dicaprate; Propylene Glycol Dicaprylate; Propylene Glycol Caprylate-Caprate; Propylene Glycol Dilaurate Propylene Glycol Distearate; Propylene Glycol Dicaprylate; Propylene Glycol Dicaprate; Mixtures of Propylene Glycol Esters and Glycerides, for example a mixture consisting of Propylene Glycol and Glycerin Oleate (e.g. Arlacel® 186); Sterols and Steroids Alcohol derivatives, such as cholesterol, myosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soy sterol, PEG-10 soy sterol, PEG-20 soy sterol, etc.; glyceryl palm stearate , glyceryl stearate, glyceryl distearate, glyceryl monostearate or combinations thereof; sorbitan fatty acid esters such as sorbitan monolaurate (eg Arlacel 20), sorbitol Anhydride monopalmitate (such as Span-40), sorbitan monooleate (such as Span-80), sorbitan monostearate and sorbitan tristearate, sorbitol Sorbitan Monolaurate, Sorbitan Monopalmitate, Sorbitan Monooleate, Sorbitan Trioleate, Sorbitan Sesquioleate, Sorbitan Tristearate esters, sorbitan monoisostearate, sorbitan sesquistearate, etc.; fatty acids such as capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid, menthol, menthol Derivatives, lecithin, phosphatidylcholine, bile salts, etc. and mixtures thereof.

In other embodiments, the carrier may include a hydrophilic surfactant. Exemplary hydrophilic surfactants may include nonionic surfactants, ionic surfactants, and zwitterionic surfactants. Specifically, hydrophilic surfactants include but are not limited to alcohol oil transesterification products; polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl sulfates, dioctyl sulfosuccinates; polyethylene glycol fatty acids Esters; polyethylene glycol fatty acid monoester and diester mixtures; polysorbate, polyethylene glycol derivatives of tocopherol, etc. It should be noted that combinations of two or more hydrophilic surfactants from the same or different classes fall within the scope of the invention and together may be referred to as hydrophilic surfactants unless expressly stated otherwise. Additional examples of hydrophilic surfactants may include PEG-8 caprylic/capric glyceride, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, PEG-40 Hydrogenated Castor Oil, PEG-35 Castor Oil, Sodium Lauryl Sulfate, Sodium Dicaprylyl Sulfosuccinate, Polyethylene Glycol Fatty Acid Monoester and Diester Blend, Polysorbate 80, Polysorbate 20 , macrogol 1000 tocopheryl succinate, phytosterols, phytosterol fatty acid esters and mixtures thereof.

In some embodiments, surfactants may include sterols and sterol derivatives. In various embodiments, these surfactants can be hydrophilic or lipophilic. Examples of hydrophilic sterol surfactants are lanosterol PEG-24 cholesteryl ether (e.g. Solulan C-24, Amerchol), PEG-30 soy sterol (e.g. Nikkol BPS-30 from Nikko), PEG-25 plant Sterols (eg Nikkol BPSH-25 from Nikko), PEG-30 dihydrocholesterol (eg Nikkol DHC from Nikko). Examples of lipophilic sterol surfactants are cholesterol, myosterol, phytosterols (eg GENEROL series from Henkel), PEG-5 soy sterols (eg Nikkol BPS-S from Nikko), PEG-10 soy sterols Sterols (eg Nikkol BPS-10 from Nikko), PEG-20 soybean sterols (eg Nikkol BPS-20 from Nikko).

In some embodiments, the surfactant may comprise from about 1 wt% to about 20 wt% of the carrier. In other embodiments, the surfactant can be at least 20 wt% of the carrier. In further embodiments, the surfactant may comprise from about 1 wt% to about 10 wt% of the carrier or from about 1 wt% to about 5 wt% of the carrier.

In additional embodiments, NORS liquid solution compositions may include preservatives. Non-limiting examples of preservatives may include ascorbic acid, acetylcysteine, bisulfites, metabisulfites, monothioglycerol, phenol, m-cresol, benzyl alcohol, methylparaben, Propylparaben, Butylparaben, Benzalkonium Chloride, Benzethonium Chloride, Butylated Hydroxytoluene, Myristyl Gamma-Pyridinium Chloride gamma-picolimium chloride), 2-phenoxyethanol, phenylmercuric nitrate, chlorobutanol, thimerosal, tocopherol, etc. or combinations thereof.

In some embodiments, the NORS liquid solution may also include an emollient. Non-limiting examples of emollients may include, but are not limited to, aloe vera, lanolin, urea, petrolatum, shea butter, cocoa butter, mineral oil, paraffin, beeswax, squalene, jojoba oil, coconut oil, Sesame oil, almond oil, cetyl alcohol, stearyl alcohol, olive oil, oleic acid, triethylhexanoin, glycerin, sorbitol, propylene glycol, cyclomethicone, simethicone, etc. or combinations thereof. In certain embodiments, the emollient may be included in an amount of from about 0.1 wt % to about 20 wt % relative to the total weight of the NORS liquid solution. In further embodiments, the emollient may be included in an amount of from about 0.1 wt% to about 10 wt%, or from about 0.1 wt% to about 5 wt%.

In additional embodiments, the NORS liquid solution may also include an adjuvant. Some examples of adjuvants may include analgesic adjuvants, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide, paraffin oil, detergents, plant saponins, cytokines, and combinations thereof. In certain embodiments, the adjuvant may be included in an amount of from about 0.1 wt% to about 20 wt% relative to the total weight of the NORS liquid solution. In further embodiments, adjuvants may be included in amounts of from about 0.1 wt% to about 10 wt%, or from about 0.1 wt% to about 5 wt%.

In other embodiments, the NORS composition may be in the form of a gel, cream, ointment, lotion, liniment, or paste. As with the NORS liquid solution compositions described above, these formulations may also include nitrite and acidulant in amounts necessary to produce the desired amount of NO gas. Additionally, these NORS formulations may also include stabilizers, carriers, preservatives, emollients, adjuvants, or combinations thereof. These ingredients may include the foregoing embodiments in the amounts described above.

In further embodiments, NORS in the form of a gel, cream, ointment, lotion, liniment, or paste may also include a thickener, penetration enhancer, or a combination thereof. In some embodiments, thickeners may include polymers with thickening properties. A non-limiting example of a polymer with thickening properties may include, but is not limited to, a hydrophobically modified cross-linked acrylate copolymer (Carbopol® Ultrez 20). Other polymers with similar properties may also be used. Non-limiting examples of polymers with thickening properties may include PEG-150 Distearate, PEG-7 Glyceryl Cocoate, PEG-200 Hydrogenated Glyceryl Palmitate, PEG-120 Methyl Glucose Dioleate esters, carboxymethylene polymers, carboxyvinyl polymers, acrylates, C10-C30 alkyl acrylate crosspolymers, and combinations thereof. Other exemplary thickeners may include polyacrylic acid (such as Carbopols, for example), gelatin, pectin, tragacanth, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, HPMC, CMC, alginic acid Salt, starch, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyoxyethylene and polyoxypropylene, polyethylene glycol, etc. or combinations thereof. In some embodiments, the amount of stabilizer can be from about 1 wt% to about 20 wt%, or from about 1 wt% to about 10 wt%, or from about 5 wt% to about 20 wt%, based on the total weight of the NORS composition. A portion of 15 wt% was included.

In other embodiments, NORS may include penetration enhancers. Non-limiting examples of penetration enhancers may include, but are not limited to, ethanol, propylene glycol, oleic acid and other fatty acids, azone, terpenes, terpenoids, bile acids, isopropyl myristate, and others Fatty esters, dimethyloxide, N-methyl-2-pyrrolidone and other pyrrolidones, etc., or combinations thereof. In certain embodiments, the amount of penetration enhancer can be from about 0.1 wt% to about 5 wt%, or from about 0.1 wt% to about 3 wt%, or from about 0.1 wt%, based on the total weight of the NORS composition Amounts of up to about 2 wt % are included.

In another embodiment, the NORS composition may also include fumed silica, mica, talc, titanium dioxide, kaolin, aluminum glycinate, ethylenediaminetetraacetic acid, fragrance, colorant or combinations thereof. In some embodiments, these additional ingredients may be included in amounts of from about 1 wt% to about 20 wt%, or from about 1 wt% to about 10 wt%, or from about 1 wt% to about 5 wt%. EXPERIMENTAL EXAMPLES Example 1: No Release Measurements

A series of exemplary nitric oxide releasing solution formulations were prepared. Individual formulations are formulated to treat specific conditions. Conditions to be treated include: Athlete's foot, Onychomycosis, Influenza, Respiratory viral infections such as the common cold, sinusitis, throat infections, acne, diabetic foot ulcers and warts. Example NORS formulated for skin disinfection was also prepared.

Several Example NORS formulations were tested for NO release by measuring the amount of NO gas released from several formulations. The following procedure was used to measure NO gas. 5 mL of the NORS formulation was introduced into the sample chamber with an inner surface inert to NO. Nitrogen was used as carrier gas. Nitrogen gas was flowed into the inlet of the sample chamber and out through the outlet at a flow rate of 1 L/min. This outlet leads to a chemiluminescence detector which measures the NO concentration in the gas stream in ppm. The chemiluminescence detector provided concentration measurements to a computer programmed to record concentration measurements at fixed time intervals over a period of 30 minutes. The period of 30 minutes begins when the NORS sample is introduced into the sample chamber. The computer was also programmed to calculate the area under the curve (AUC) of the concentration data points to find the total amount of NO released in ppm*min. This value is then divided by the volume of 5 mL to find the amount of NO released from a single mL of NORS in ppm*min/mL. The maximum ppm concentration measurement was also chosen as the peak NO concentration occurring during the 30 min period. Divide the measured peak NO concentration by 5 mL to generate the peak NO concentration per 1 mL of NORS formulation. The calculation of the "per milliliter" value is based on the assumption that the amount of NO released is proportional to the volume of NORS in the sample chamber.

Table 1 shows the amount of NO released from example NORS formulations based on a single milliliter of NORS and based on a full dose of NORS, along with example dose volumes and peak NO concentrations. Table 1 sample NO released per 1 mL (ppm*min/mL) NO peak concentration per 1 mL ( ppm/mL) NO released per dose (ppm*min) Dose volume (mL) Hong Kong feet 12.85 3.514 64230 5000 Onychomycosis 52.00 11.034 52 1 influenza 13.23 4.268 6.616 0.5 respiratory virus infection 13.23 4.268 6.616 0.5 Sinusitis A 1.91 0.6 458.4 240 Sinusitis B. 5.46 1.52 1310.4 240 Sinusitis C. 13.23 4.268 3175.7 240 throat infection 23.35 7.12 466.9 20 Acne A 13.23 4.268 26.46 2 Acne B 23.35 7.12 46.69 2 Diabetic foot ulcer A 12.85 3.514 64230 5000 Diabetic foot ulcer B 52.00 11.034 260 5 Wart A 13.23 4.3 66.2 5 Wart B 52.00 11.0 260 5 Skin Disinfection A 13.23 4.3 520 100 Skin Disinfection B 23.35 7.1 660 100 Example 2: Exposure, Safety and Effectiveness of NONS

As depicted in Figure 1, nonclinical pharmacokinetic (PK) and toxicology tests were performed on NO by measuring NONS prevention and NONS treatment compared to native NO and INOmax.

The measured NO concentration in exhaled air was measured under various physiological conditions. The patient population includes adults with routes of administration including exhaled air. The measured NO concentration ranged from 0.02 ppm to 0.1 ppm. The daily exposure duration is about 8 hours per day, as exhalation takes about 1/3 of the total breathing time. Daily NO exposure calculated using the area under the curve (AUC) in ppm*hr ranged from 0.16 to 0.8 ppm*hr. This calculation of daily exposure is based on the lower end of the range of 0.02 ppm for 8 hours and the upper end of the range of 0.1 ppm for 8 hours. Because the exhaled air of a patient population is naturally occurring, exposure levels and safety levels provide a baseline for comparing the exposure, safety, and efficacy of various treatments.

INOmax is a treatment that has been administered to the neonatal patient population by inhalation. NO gas was administered at concentrations ranging from 5 to 20 ppm. Exposure time can be up to 24 hours. Daily NO exposure calculated using AUC in ppm*hr was calculated to range from 120 ppm*hr to 480 ppm*hr based on a dosing range of 5 to 20 ppm and a 24 hour exposure time . The duration of treatment with INOmax can be up to 4 days in Canada and up to 14 days in the United States.

NONS (eg, NORS provided as a nasal spray) can be used as a prophylactic treatment as a nasal spray, which can be administered to adults for a period of 28 days. For each 0.5 mL volume of NONS, the amount of NO concentration administered can be up to a maximum peak NO concentration of 1.5 ppm. Based on six 5-minute treatments, each treatment used a volume of 0.5 mL, with an exposure duration of up to 30 minutes. The maximum total exposure of 5 mL of NONS was measured to be 54 ppm*min, which was calculated to be 5.4 ppm*min for a 0.5 mL treatment volume. Therefore, for each 5-minute treatment, for a 0.5 mL treatment volume, the maximum total exposure is 5.4 ppm*min, which can be calculated by dividing 5.4 ppm*min by 60 min/hr to give 0.1 ppm*hr. For a maximum exposure time of 5 minutes per treatment and 2 treatments a day, the total exposure time was 10 minutes per day. Each treatment provided a NO exposure of 0.1 ppm*hr, so 2 treatments a day resulted in a NO exposure of 0.2 ppm*hr. Therefore, based on an administered concentration of 1.5 ppm and an exposure time of 10 minutes, the daily NO exposure calculated using the AUC in ppm*hr was calculated to be 0.2 ppm*hr.

NONS is available as a nasal spray, which can be administered to adults in 6 divided treatments per day for 7 days. Therefore, as calculated above, for each 5-minute treatment, for a 0.5 mL treatment volume, the maximum total exposure is 5.4 ppm*min, which can be calculated by dividing 5.4 ppm*min by 60 min/hr to give 0.1 ppm *hr. For a maximum exposure time of 5 minutes per treatment and 6 treatments a day, the total exposure time was 30 minutes per day. Each treatment provides a NO exposure of 0.1 ppm*hr, so 6 treatments a day equals a NO exposure of 0.6 ppm*hr. Therefore, based on an administered concentration of 1.5 ppm and an exposure time of 30 minutes, the daily NO exposure calculated using the AUC in ppm*hr was calculated to be 0.6 ppm*hr.

As depicted in the table in FIG. 1 , the safety margins for NONS prevention and NONS treatment compared to INOmax were calculated to be 3.3 to 13 times safer for NONS prevention and NONS treatment, measured as the concentration of NO administered in ppm. The safety margins for NONS prevention and NONS treatment compared to INOmax were calculated to be 57-fold safer for NONS prevention and NONS treatment, as measured by the daily NO exposure time course. The safety margins for NONS prevention and NONS treatment compared to INOmax were calculated to be approximately 600 times safer for NONS prevention and 200 times safer for NONS treatment, as measured using daily NO exposure calculated as AUC in ppm*hr. The duration of treatment for NONS prevention and NONS treatment compared to INOmax can in some cases be shorter and in some cases longer. Example 3a: Pig Infected Wounds

As exemplified in Figures 2a and 2b, a porcine study was conducted to evaluate the antimicrobial activity of nitric oxide releasing solution (NORS) and nitric oxide releasing gel (NORG) compared to untreated control wounds.

Pathogen-free, female, commercially bred Yorkshire crosses with a body weight of approximately 55 kg (+/- 5 kg) are the subject of research. A local thickness wound of 2.0 cm diameter with a custom design was created, as exemplified in Figure 2a. Bacterial mixture inoculum (eg, Clostridium spp., Staphylococcus aureus (ATCC 6538), and Pseudomonas aeruginosa (porcine isolate)) is administered as a sterile douche ball filled with 60 to 80 mL of inoculum and used for submersion Gauze until the gauze is saturated with the bacterial mixture. The gauze strips were covered with a sealant (S.C. Johnson and Sons, Brantford, ON) and left to stand for 1 hour.

Wound healing involves Treatment 1 or Treatment 2. Treatment 1 used NORG in volumes of approximately 2 to 5 mL, which corresponded to exposures of 104 to 210 ppm*min and 52 ppm*min/mL. This NORG treatment was followed by NORS saturated gauze with a volume of 2 to 5 mL, corresponding to 26 to 65 ppm*min and 13 ppm*min/mL. This NORS treatment was followed by covering with a clear occlusive dressing and incubating for 7 hours.

Treatment 2 involved a NORS rinse in a volume of 1 mL, which corresponded to an exposure of 13 ppm*min. This was followed by a volume of NORG of approximately 2 to 5 mL, which corresponded to exposures of 104 to 210 ppm*min and 52 ppm*min/mL. This NORG treatment was followed by NORS saturated gauze with a volume of 2 to 5 mL, corresponding to 26 to 65 ppm*min and 13 ppm*min/mL. This NORS treatment was followed by covering with a clear occlusive dressing and incubating for 7 hours.

The control group involved covering the wound with a sterile, saline-moistened non-adherent dressing (Curad), secured with Transpore tape and incubated for 7 hours.

Figure 2b provides a graph depicting the concentrations (Log CFU/mL) of different bacteria (Clostridium, Staphylococcus aureus, and Pseudomonas aeruginosa) within 7.5 hours of wound treatment with one of the following: NORG alone or rinsed with NORS first , and then clean the resulting graph with NORG.

In the case of Clostridium species, the bacterial concentration was about 7.2 Log CFU/mL in the control group, about 3.8 Log CFU/mL in NORG alone, and about 3.7 Log CFU/mL in the rinse with NORS followed by NORG. These results indicate that NORG alone or NORS followed by NORG significantly reduced the concentration of Clostridium compared to the control group.

In the case of Staphylococcus aureus, the bacterial concentration was approximately 7.2 Log CFU/mL in the control, approximately 3.9 Log CFU/mL in NORG alone, and approximately 4.1 Log CFU/mL in the rinse with NORS followed by NORG. These results indicate that NORG alone or NORS followed by NORG significantly reduced the concentration of S. aureus compared to the control group.

In the case of Pseudomonas aeruginosa, the bacterial concentration was about 6.0 Log CFU/mL in the control group, about 3.5 Log CFU/mL in NORG alone, and about 2.2 Log CFU/mL in the rinse with NORS followed by NORG. These results indicate that NORG alone or NORS followed by NORG significantly reduced the concentration of S. aureus compared to the control group. These results also indicated that treatment with NORS followed by NORG reduced the concentration of S. aureus more than NORG alone. Example 3b: Warts

As exemplified in Figures 3a to 3f, studies were conducted on human subjects to evaluate the effect of nitric oxide releasing solution (NORS) and nitric oxide releasing gel (NORG) on warts. Human subjects' feet developed warts in 3 areas: (a) the underside of the big toe, (b) the underside of the left rear portion of the foot, and (c) a portion of the underside below the big toe. Affected feet were treated with a half-hour NORS foot bath (12.85 ppm*min/mL) a total of three times per week for two weeks. Affected feet were also treated for one week with once-daily NORG (52 ppm*min/mL).

As exemplified in Figure 3a, the wart on the underside of the left posterior part of the foot, which was substantial before treatment, was completely removed 28 days after the start of treatment, as exemplified in Figure 3b. Figures 3c to 3f illustrate the progression of treatment at day 1 (Figure 3c), day 7 (Figure 3d), day 14 (Figure 3e) and day 28 (Figure 3f). These results show that treatment with NORS and NORG can remove warts on the feet within 28 days. Example 3c: Nail Fungus Case Study 3c-1

As exemplified in Figures 4a and 4b, a study was conducted on human subjects to evaluate the effect of nitric oxide releasing solution (NORS) and nitric oxide releasing gel (NORG) on nail fungus. Nail fungus developed on the fingers of the human subject. Affected fingers were treated with 1 mL of NORG (52 ppm*min/mL) daily for a total of 2 weeks.

As exemplified in Figure 4a, the nail fungus covered approximately 1/3 of the fingernails before the start of the treatment and was completely removed 60 days after the start of the treatment, as exemplified in Figure 4b. These results show that treatment with NORS and NORG can remove nail fungus on the nails within 60 days. Case Study 3c-2

As exemplified in Figures 4c to 4h, a study was performed on human subjects to evaluate the effect of nitric oxide releasing solution (NORS) and nitric oxide releasing gel (NORG) on nail fungus on the toes. Nail fungus developed on the toes of the human subject. Affected toes were treated with 1 mL of NORG (52 ppm*min/mL) daily for a total of 3 weeks.

As exemplified in Figure 4c, the nail fungus covered approximately 1/2 of the toenails before the start of the treatment, and was completely removed 9 days after the start of the treatment, as exemplified in Figure 4h. Figures 4c to 4g illustrate the treatment progression at day 1 (Figure 4d), day 21 (Figure 4e), month 2 (Figure 4f) and month 4 (Figure 4g). These results show that treatment with NORS and NORG can remove nail fungus on the fingers within 9 months. Case Study 3c-3.

As exemplified in Figures 4i and 4m, a study was conducted on human subjects to evaluate the effect of nitric oxide releasing solution (NORS) and nitric oxide releasing gel (NORG) on nail fungus on the index and fourth toes. The human instance developed nail fungus on the index and fourth toes. Affected toes were treated with 1 mL of NORG (52 ppm*min/mL) daily for a total of 4 weeks.

As exemplified in Figure 4i, on treatment day 1, nail fungus covered the entire toenails of the index and fourth toes and was completely removed 120 days after the start of treatment, as exemplified in Figure 4m. Figures 4j to 41 illustrate the progression of treatment at day 28 (Figure 4j), day 63 (Figure 4k) and day 77 (Figure 4l). These results show that treatment with NORS and NORG can remove nail fungus on the toes within 120 days. Example implementation

The following examples relate to specific technical implementations and point out specific features, elements or steps that can be used or otherwise combined to achieve such implementations.

In one embodiment, a method of treating a condition responsive to nitric oxide (NO) treatment/therapy in an individual is provided.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise administering a volume of a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of NO to the site of administration in a subject for a therapeutic schedule.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may be NORS which may include nitrite and acidulant. In one embodiment, the NORS, when coupled to a chemiluminescent detector, is measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere of pressure for a period of 30 minutes. NO can be released in an amount from about 0.05 ppm*min to about 500 ppm*min per milliliter of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be NORS, which can release NO in an amount from about 0.05 ppm*min to about 10 ppm*min per mL of NORS. In one embodiment, the volume of NORS can be from about 0.1 mL to about 10,000 mL. In one embodiment, the total volume of NO released by the administered NORS may be from about 0.1 ppm*min to about 3,000 ppm*min.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition which may be a wound, skin infection, fungal infection, respiratory infection, bacterial infection or viral infection.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be Athlete's foot. In one embodiment, a method for treating Athlete's foot is provided. In one embodiment, the site of administration may be the individual's foot. In one embodiment, the NORS can release NO in an amount from about 0.2 ppm*min to about 5 ppm*min per mL of NORS. In one embodiment, the total volume of NO released by the administered NORS may be from about 1,000 ppm*min to about 5,000 ppm*min. In one embodiment, the volume of NORS administered may be from about 500 mL to about 10,000 mL. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 5,000 ppm to about 20,000 ppm.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be onychomycosis. In one embodiment, there is provided a method of treating a condition which may be onychomycosis. In one embodiment, the site of administration may be the nail of an individual. In one embodiment, the NORS can release NO in an amount from about 1 ppm*min to about 2 ppm*min per mL of NORS. In one embodiment, the total volume of NO released by the administered NORS may be from about 1 ppm*min to about 4 ppm*min. In one embodiment, the volume of NORS administered may be from about 0.5 mL to about 2 mL. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 5 ppm to about 30 ppm.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition which may be influenza. In one embodiment, there is provided a method of treating a condition which may be influenza. In one embodiment, a method of treatment can include a site of administration, which can be the nasal cavity of an individual. In one embodiment, the NORS can release NO in an amount from about 0.1 ppm*min to about 10 ppm*min per mL of NORS. In one embodiment, the total amount of NO released by the volume of NORS administered may be from about 5 ppm*min to about 10 ppm*min. In one embodiment, the volume of NORS administered may be from about 0.5 mL to about 1 mL. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 1 ppm to about 4 ppm.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be a respiratory viral infection. In one embodiment, there is provided a method of treating a condition that may be a respiratory viral infection, and the site of administration may be the nasal cavity or lungs of a subject. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 15 ppm*min per mL of NORS. In one embodiment, the total amount of NO released by the volume of NORS administered may be from about 5 ppm*min to about 10 ppm*min. In one embodiment, the volume of NORS administered may be from about 0.5 mL to about 1 mL. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 1 ppm to about 4 ppm.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition which may be sinusitis. In one embodiment, there is provided a method of treating a condition that can be sinusitis, and the site of administration can be a sinus cavity of a subject. In one embodiment, the NORS can release NO in an amount from about 1 ppm*min to about 15 ppm*min per mL of NORS. In one embodiment, the total amount of NO released by the volume of NORS administered may be from about 400 ppm*min to about 3,200 ppm*min. In one embodiment, the volume of NORS administered may be from about 150 mL to about 300 mL. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 100 ppm to about 1,200 ppm.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be a throat infection. In one embodiment, there is provided a method of treating a condition that can be a throat infection, and the site of administration can be the throat of a subject. In one embodiment, the NORS can release NO in an amount from about 15 ppm*min to about 30 ppm*min per mL of NORS. In one embodiment, the total amount of NO released from the administered NORS volume may be from about 400 ppm*min to about 600 ppm*min. In one embodiment, the volume of NORS administered may be from about 10 mL to about 20 mL. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 100 ppm to about 200 ppm.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition which may be acne. In one embodiment, there is provided a method of treating a condition that can be acne, and the site of administration can be an area of skin of an individual. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 30 ppm*min per mL of NORS. In one embodiment, the total volume of NO released by the administered NORS may be from about 10 ppm*min to about 60 ppm*min. In one embodiment, the total amount of NO released by the volume of NORS administered may be from about 20 ppm*min to about 60 ppm*min. In one embodiment, the volume of NORS administered may be from about 1 mL to about 5 mL. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 5 ppm to about 20 ppm.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be a diabetic foot ulcer. In one embodiment, there is provided a method of treating a condition that can be a diabetic foot ulcer, and the site of administration can be the foot of an individual. In one embodiment, the NORS can release NO in an amount from about 5 ppm*min to about 80 ppm*min per mL of NORS. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 60 ppm*min per mL of NORS. In one embodiment, the total volume of NO released by the administered NORS may be from about 100 ppm*min to about 75,000 ppm*min. In one embodiment, the total amount of NO released from the administered NORS volume may be from about 200 ppm*min to about 75,000 ppm*min. In one embodiment, the volume of NORS administered may be from about 5 mL to about 10,000 mL. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 50 ppm to about 20,000 ppm.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be a wart. In one embodiment, there is provided a method of treating a condition that can be a wart, and the site of administration can be an area of skin of an individual. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 60 ppm*min per mL of NORS. In one embodiment, the total amount of NO released from the administered NORS volume may be from about 45 ppm*min to about 75 ppm*min. In one embodiment, the total amount of NO released by the volume of NORS administered may be from about 20 ppm*min to about 400 ppm*min. In one embodiment, the volume of NORS administered may be from about 0.5 mL to about 10 mL. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 1 ppm to about 60 ppm.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may be a NORS that may include at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may include nitrite. In one embodiment, the nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In further embodiments, the acidulant comprises ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may be NORS capable of providing extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may comprise NORS, which may be capable of measuring the amount of NO released by the NORS by: introducing a carrier gas flow through the gas inlet into the sample holding chamber; introducing NORS into the sample holding chamber through the sample inlet to Exposure to a continuous stream of carrier gas; directing the carrier gas and any released NO through the outlet from the sample holding chamber to a NO detector; and quantifying the amount of released NO using the NO detector. In one embodiment, the sample holding chamber can include an inner surface that is inert to NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include as a nasal spray, open container bath for soaking, liquid sinus wash, liquid mouthwash, respiratory inhaler, air NORS administered as a spray, gel, foam, emulsion, liquid solution, cream, or a combination thereof.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may be NORS which may include a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutically acceptable carrier may include water, saline, hydroxyethylcellulose, xanthan gum, or combinations thereof.

In one embodiment, a composition for treating a condition responsive to nitric oxide (NO) therapy may include a nitric oxide releasing solution (NORS). In one embodiment, a NORS may include at least one NO releasing compound and at least one acidulant. In one embodiment, the NORS, when coupled to a chemiluminescent detector, is measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere of pressure for a period of 30 minutes. NO can be released in an amount from about 0.05 ppm*min to about 500 ppm*min per milliliter of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be formulated to be administered to the foot of an individual to treat Athlete's foot, and the NORS can release NO in an amount from about 10 ppm*min to about 15 ppm*min per mL of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be formulated to be administered to a nail of an individual to treat onychomycosis, and the NORS can release NO in an amount from about 45 ppm*min to about 60 ppm*min per mL of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be formulated to be administered to the nasal cavity of an individual to treat influenza, and the NORS can release NO in an amount from about 10 ppm*min to about 15 ppm*min per mL of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be formulated and administered to the nasal cavity or lungs of an individual to treat respiratory virus infection, and the NORS can release NO from about 10 ppm*min to about 15 ppm*min per mL of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be formulated to be administered to a sinus cavity of an individual for the treatment of sinusitis, and the NORS can release NO in an amount from about 1 ppm*min to about 15 ppm*min per mL of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be formulated to be administered to the throat of an individual to treat a throat infection, and the NORS can release NO in an amount from about 15 ppm*min to about 30 ppm*min per mL of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be formulated to be administered to an area of skin of an individual to treat acne, and the NORS can release NO in an amount from about 10 ppm*min to about 30 ppm*min per mL of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be formulated to be administered to the foot of an individual for the treatment of diabetic foot ulcers, and the NORS can release NO in an amount from about 10 ppm*min to about 60 ppm*min per mL of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition can be formulated to be administered to an individual's skin area to treat warts, and the NORS can release NO in an amount from about 10 ppm*min to about 60 ppm*min per mL of NORS. In one embodiment, the composition can be formulated to be administered to an area of skin of an individual to treat warts, and the NORS can release NO in an amount from about 5 ppm*min to about 80 ppm*min per mL of NORS.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may be a NO releasing compound which may include nitrite. In one embodiment, the nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may include an acidulant. In one embodiment, the acidulant may include ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may be NORS capable of providing extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In some embodiments, the composition can include NORS, wherein the amount of NO released by NORS can be measured by: introducing a carrier gas flow into the sample holding chamber through the gas inlet; introducing NORS into the sample holding chamber through the sample inlet to contact the continuous carrier gas flow; directing the carrier gas and any released NO through the outlet from the sample holding chamber to the NO detector; and quantifying the amount of released NO using the NO detector. In one embodiment, the sample holding chamber can include an inner surface that is inert to NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may be formulated as a nasal spray, open container bath for soaking, liquid sinus wash, liquid mouthwash, respiratory inhaler, aerosol, gel, foam, emulsion , liquid solutions, creams, or combinations thereof.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise compositions. In one embodiment, the composition may include a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutically acceptable carrier may comprise water, saline, hydroxyethylcellulose, xanthan gum, or combinations thereof.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be Athlete's foot. In one embodiment, a method of treating athlete's foot in an individual may comprise administering to the individual's foot a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of nitric oxide (NO) gas for A treatment time course, wherein when measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes to quantify by a chemiluminescence detector, the NORS releases NO in amounts from about 50,000 ppm*min to about 75,000 ppm*min. In one embodiment, the volume of NORS administered may be from about 1,000 mL to about 10,000 mL. In one embodiment, the NORS can release NO in an amount from about 5 ppm*min to about 15 ppm*min per mL of NORS. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 15 ppm*min per mL of NORS. In one embodiment, the NORS can release NO in an amount from about 25 ppm*min to about 500 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 5,000 ppm to about 20,000 ppm. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 15,000 ppm to about 20,000 ppm. In one embodiment, NORS can be administered as a liquid solution in a foot bath. In one embodiment, the method comprises administering NORS according to a dosing regimen of soaking the foot in a foot bath for 30 minutes every 4 days. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be onychomycosis in the nails of an individual. In one embodiment, the method may include administering to the individual's nails a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of nitric oxide (NO) gas for a treatment period, wherein when NORS released from about 45 ppm* when measured by quantification by a chemiluminescence detector in a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes min to about 60 ppm*min of NO. In one embodiment, the volume of NORS administered may be from about 0.5 mL to about 2 mL. In one embodiment, the NORS can release NO in an amount from about 25 ppm*min to about 75 ppm*min per mL of NORS. In one embodiment, the NORS can release NO in an amount from about 45 ppm*min to about 60 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 5 ppm to about 15 ppm. In one embodiment, NORS can be administered as a liquid solution, gel, or cream. In one embodiment, the method may comprise administering NORS according to a regimen of administering NORS to the nail once every 21 days. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may comprise sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition which may be influenza. In one embodiment, a method of treating influenza in an individual may comprise administering to the nasal cavity of the individual a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of nitric oxide (NO) gas for a therapeutically effective amount of nitric oxide (NO) gas. Time course, wherein when measured by the release of NO from a NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes to quantify by a chemiluminescent detector, the NORS NO is released in an amount from about 5 ppm*min to about 10 ppm*min. In one embodiment, the volume of NORS administered may be from about 0.5 mL to about 1 mL. In one embodiment, the NORS can release NO in an amount from about 2 ppm*min to about 15 ppm*min per mL of NORS. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 15 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 1 ppm to about 4 ppm. In one embodiment, NORS can be administered as a nasal spray. In one embodiment, the method may comprise administering NORS according to an on-demand administration of a nasal spray regimen. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be a respiratory viral infection. In one embodiment, a method of treating a respiratory viral infection in an individual may comprise administering a nitric oxide releasing solution (NORS) providing a therapeutically effective amount of nitric oxide (NO) gas to the individual's nasal or The lung reaches a treatment time course as measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes to be quantified by a chemiluminescence detector , the NORS releases NO in an amount from about 5 ppm*min to about 10 ppm*min. In one embodiment, the volume of NORS administered may be from about 0.5 mL to about 1 mL. In one embodiment, the volume of NORS administered may be from about 0.5 mL to about 5 mL. In one embodiment, the NORS can release NO in an amount from about 5 ppm*min to about 15 ppm*min per mL of NORS. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 15 ppm*min per mL of NORS. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 30 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 1 ppm to about 4 ppm. In one embodiment, NORS can be administered as a nasal spray. In one embodiment, the method may comprise administering NORS according to an on-demand administration of a nasal spray regimen. In one embodiment, the respiratory viral infection can be the common cold, respiratory fusion virus or coronavirus. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition which may be sinusitis. In one embodiment, a method of treating sinusitis in an individual may comprise administering to the individual's sinus cavities a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of nitric oxide (NO) gas. A treatment time course, wherein when measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes to quantify by a chemiluminescence detector, the NORS releases NO in amounts from about 400 ppm*min to about 3,200 ppm*min. In one embodiment, the volume of NORS administered may be from about 150 mL to about 300 mL. In one embodiment, the NORS can release NO in an amount from about 1 ppm*min to about 15 ppm*min per mL of NORS. In one embodiment, the NORS can release NO in an amount from about 1 ppm*min to about 30 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 50 ppm to about 500 ppm. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 100 ppm to about 1,200 ppm. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 100 ppm to about 5,000 ppm. In one embodiment, NORS can be administered as a douche, douche, or spray. In one embodiment, the method may comprise administering NORS according to a dosing regimen of administering NORS about every 42 days. In one embodiment, the method may comprise administering NORS according to a dosing regimen of administering NORS daily for a period of about 10 to about 50 days. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be a throat infection. In one embodiment, a method of treating a throat infection in an individual may comprise administering to the individual's throat a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of nitric oxide (NO) gas for one Treatment time course, wherein when measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes to quantify by a chemiluminescence detector, the NORS is to release NO in an amount from about 400 ppm*min to about 600 ppm*min. In one embodiment, the volume of NORS administered may be from about 10 mL to about 20 mL. In one embodiment, the volume of NORS administered may be from about 5 mL to about 40 mL. In one embodiment, the NORS can release NO in an amount from about 15 ppm*min to about 30 ppm*min per mL of NORS. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 40 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 100 ppm to about 200 ppm. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 200 ppm to about 800 ppm. In one embodiment, NORS may be administered as a liquid gargle solution. In one embodiment, the method may comprise administering NORS according to a dosing regimen of gargling for 1.5 minutes every 3 days. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may comprise sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition which may be acne. In one embodiment, a method of treating acne in an individual may comprise administering to an area of the individual's skin a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of nitric oxide (NO) gas for one Treatment time course, wherein when measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes to quantify by a chemiluminescence detector, the NORS is to release NO in an amount from about 20 ppm*min to about 60 ppm*min. In one embodiment, the volume of NORS administered may be from about 1 mL to about 5 mL. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 30 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 5 ppm to about 20 ppm. In one embodiment, NORS can be administered as a cream. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may comprise sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be a diabetic foot ulcer. In one embodiment, a method of treating a diabetic foot ulcer in an individual may comprise administering to the individual's foot a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of nitric oxide (NO) gas. A treatment time course as measured by quantification by chemiluminescent detectors by release of NO from NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes , the NORS releases NO in an amount from about 200 ppm*min to about 75,000 ppm*min. In one embodiment, the volume of NORS administered may be from about 5 mL to about 10,000 mL. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 60 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 50 ppm to about 20,000 ppm. In one embodiment, NORS can be administered as a liquid solution in a foot bath. In one embodiment, the method may comprise administering NORS according to a dosing regimen of soaking the foot in a foot bath for 30 minutes once every 12 days. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may comprise sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be a wart. In one embodiment, a method of treating warts in an individual may comprise administering a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of nitric oxide (NO) gas to an area of the skin of the individual for a period of Treatment time course, wherein when measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes to quantify by a chemiluminescence detector, the NORS is to release NO in an amount from about 45 ppm*min to about 75 ppm*min. In one embodiment, the volume of NORS administered may be from about 0.5 mL to about 10 mL. In one embodiment, the NORS can release NO in an amount from about 10 ppm*min to about 60 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 1 ppm to about 60 ppm. In one embodiment, NORS can be administered as a liquid solution in a bath. In one embodiment, the method may comprise administering NORS according to a dosing regimen of soaking the skin in a bath for 30 minutes every 6 days. In one embodiment, the method may comprise administering NORS according to a regimen of soaking the skin in a bath for 30 minutes daily for a period of about 1 day to about 10 days. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may include a condition that may be skin at risk of infection. In one embodiment, a method of disinfecting the skin of an individual may comprise administering to an area of the individual's skin a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of nitric oxide (NO) gas for a period of Treatment time course, wherein when measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes to quantify by a chemiluminescence detector, the NORS is to release NO in an amount from about 450 ppm*min to about 750 ppm*min. In one embodiment, the volume of NORS administered may be from about 50 mL to about 200 mL. In one embodiment, the NORS can release NO in an amount from about 5 ppm*min to about 25 ppm*min per mL of NORS. In one embodiment, the volume of NORS administered can release peak NO concentrations from about 1 ppm to about 20 ppm. In one embodiment, a NORS may comprise at least one NO releasing compound and at least one acidulant. In one embodiment, the NO releasing compound may comprise nitrite. In one embodiment, the nitrite may be sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite, copper nitrite or a combination thereof. In one embodiment, the acidulant may comprise ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof. In one embodiment, NORS can provide extended release of NO.

In one embodiment, a method of treating a condition responsive to NO treatment/therapy may comprise using the compositions provided herein. In one embodiment, the use of a composition as provided herein in the preparation of a medicine for treating a condition responsive to nitric oxide (NO) treatment may comprise: administering a therapeutically effective amount of the composition to individual. In one embodiment, a composition for treating a condition responsive to nitric oxide (NO) therapy may comprise: administering to a subject a therapeutically effective amount of the composition.

In one embodiment, a composition, such as a nitric oxide releasing composition, is provided.

In one embodiment of the composition, when coupled to a chemiluminescence detector, it is measured by the release of NO from the composition into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere of pressure for a period of 30 minutes. When, the composition comprises the combination of nitric oxide releasing compound, acidulant and carrier, based on 1 mL of the composition, its amount is a nitric oxide releasing compound from about 1 ppm*min/mL to about 500 ppm*min/mL Nitric oxide (NO).

In one embodiment of the composition, the pharmaceutically acceptable carrier comprises water, saline, hydroxyethylcellulose, xanthan gum or a combination thereof.

In one embodiment of the composition, the composition is formulated as a nasal spray, open container bath for soaking, liquid sinus wash, liquid mouthwash, respiratory inhaler, aerosol, gel, foam , emulsion, liquid solution, cream, or a combination thereof.

In one embodiment of the composition, the amount of NO released is from about 1 ppm*min/mL to about 500 ppm*min/mL.

While the foregoing embodiments illustrate the principles of the present technology in one or more particular applications, it will be apparent to those skilled in the art that numerous modifications in form, use, and execution details may be made without exercising the inventive capacity. , without departing from the principles and concepts of the technology.

none

Features and advantages of the present disclosure will become apparent from the following detailed description when taken in conjunction with the accompanying drawings, which together illustrate features of the disclosure by way of example; and, in which: FIG. 1 depicts a graph showing differences in exposure between naturally occurring NO breath, INOmax, nitric oxide nitric oxide nasal spray (NONS) prophylaxis, and NONS treatment, according to an embodiment; Figure 2a illustrates the administration of a bacterial mixture to a pig individual according to an embodiment; Figure 2b depicts the concentration of various bacterial types for the control group, nitric oxide releasing gel (NORG) treatment and nitric oxide releasing solution (NORS) + NORG treatment according to the embodiment; Figure 3a illustrates a wart on a foot before initiating treatment according to an embodiment; Figure 3b illustrates regression of warts on feet after treatment according to an embodiment; Figure 3c illustrates warts on the feet at day 1 after initiation of treatment according to the embodiments; Figure 3d illustrates warts on the feet at day 7 after initiation of treatment according to the embodiments; Figure 3e illustrates warts on the feet at day 14 after initiation of treatment according to the embodiments; Figure 3f illustrates warts on the feet at day 28 after initiation of treatment according to embodiments; Figure 4a illustrates nail fungus before initiation of treatment according to an embodiment; Figure 4b illustrates regression of nail fungus after treatment according to an embodiment; Figure 4c illustrates toenail fungus prior to initiation of treatment according to an embodiment; Figure 4d illustrates toenail fungus after 1 day of treatment according to the embodiments; Figure 4e illustrates toenail fungus 3 weeks after initiation of treatment according to the embodiments; Figure 4f illustrates toenail fungus 2 months after initiation of treatment according to an embodiment; Figure 4g illustrates toenail fungus 42 months after initiation of treatment according to an embodiment; Figure 4h illustrates toenail fungus 9 months after initiation of treatment according to an embodiment; Figure 4i illustrates toenail fungus after 1 day of treatment according to an embodiment; Figure 4j illustrates toenail fungus 28 days after initiation of treatment according to an embodiment; Figure 4k illustrates toenail fungus 63 days after initiation of treatment according to an embodiment; Figure 41 illustrates toenail fungus 77 days after initiation of treatment according to an embodiment; and Figure 4m illustrates regression of toenail fungus 120 days after initiation of treatment according to an embodiment.

Reference will now be made to the illustrated exemplary embodiments, and specific terminology will be used in this specification to describe the same. It should be understood, however, that no limitation of the scope of the invention is thereby intended.

Claims (68)

A method of treating a condition responsive to nitric oxide (NO) therapy in an individual comprising: administering a volume of a nitric oxide releasing solution (NORS) that provides a therapeutically effective amount of NO to an administration site in the individual for a therapeutic period, wherein the NORS includes a nitric oxide releasing compound and an acidifying agent, wherein when Coupled to a chemiluminescent detector, the NORS is based on 1 mL when measured by the release of NO from the NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere for a period of 30 minutes The NORS releases NO from about 1 ppm*min/mL to about 500 ppm*min/mL. The method of claim 1, wherein the NORS releases NO in an amount from about 1 ppm*min to about 60 ppm*min per mL of the NORS. The method of claim 1, wherein the volume of the NORS is from about 0.1 mL to about 10,000 mL. The method of claim 1, wherein the total amount of NO released from the volume of NORS administered is from about 6 ppm*min to about 75,000 ppm*min. The method according to claim 1, wherein the condition is wound, skin infection, fungal infection, respiratory tract infection, bacterial infection or viral infection. The method of claim 1, wherein the condition is Athlete's foot and the administration site is the individual's foot, and wherein the NORS is from about 5 ppm*min/mL to about 15 ppm*min based on 1 mL of the NORS /mL releases NO. The method of claim 6, wherein the total amount of NO released from the volume of NORS administered is from about 25,000 ppm*min to about 75,000 ppm*min. The method of claim 6, wherein the volume of NORS administered can be from about 500 mL to about 10,000 mL. The method of claim 6, wherein the volume of NORS administered releases a peak NO concentration from about 5,000 ppm to about 20,000 ppm. The method of claim 1, wherein the condition is onychomycosis and the administration site is the individual's nails, and wherein the NORS is from about 25 ppm*min/mL to about 75 ppm*min/mL based on 1 mL of the NORS The amount of mL releases NO. The method of claim 10, wherein the total amount of NO released from the volume of NORS administered is from about 25 ppm*min to about 75 ppm*min. The method of claim 10, wherein the volume of NORS administered is from about 0.1 mL to about 2 mL. The method of claim 10, wherein the volume of NORS administered releases a peak NO concentration from about 5 ppm to about 30 ppm. The method of claim 1, wherein the condition is influenza and the administration site is the nasal cavity of the individual, and wherein the NORS is from about 2 ppm*min/mL to about 30 ppm*min/mL based on 1 mL of the NORS The amount released NO. The method of claim 14, wherein the total amount of NO released from the volume of NORS administered is from about 1 ppm*min to about 15 ppm*min. The method of claim 14, wherein the volume of NORS administered is from about 0.1 mL to about 2 mL. The method of claim 14, wherein the volume of NORS administered releases a peak NO concentration from about 0.5 ppm to about 5 ppm. The method of claim 1, wherein the condition is a respiratory virus infection and the administration site is the individual's nasal cavity or lungs, and wherein the NORS is from about 2 ppm*min/mL to about 30 ppm based on 1 mL of the NORS *NO released in the amount of min/mL. The method of claim 18, wherein the total amount of NO released from the volume of NORS administered is from about 1 ppm*min to about 15 ppm*min. The method of claim 18, wherein the volume of NORS administered is from about 0.1 mL to about 2 mL. The method of claim 18, wherein the volume of NORS administered releases a peak NO concentration from about 0.5 ppm to about 5 ppm. The method of claim 1, wherein the condition is sinusitis and the administration site is the sinus cavity of the individual, and wherein the NORS is from about 0.5 ppm*min/mL to about 30 ppm*min based on 1 mL of the NORS /mL releases NO. The method of claim 22, wherein the total amount of NO released from the volume of NORS administered is from about 100 ppm*min to about 5,000 ppm*min. The method of claim 22, wherein the volume of NORS administered is from about 150 mL to about 300 mL. The method of claim 22, wherein the volume of NORS administered releases a peak NO concentration from about 50 ppm to about 1,500 ppm. The method of claim 1, wherein the condition is a throat infection and the administration site is the throat of the individual, and wherein the NORS is from about 10 ppm*min/mL to about 40 ppm*min based on 1 mL of the NORS /mL releases NO. The method of claim 26, wherein the total amount of NO released from the volume of NORS administered is from about 200 ppm*min to about 800 ppm*min. The method of claim 26, wherein the volume of NORS administered is from about 5 mL to about 40 mL. The method of claim 26, wherein the volume of NORS administered releases a peak NO concentration from about 100 ppm to about 200 ppm. The method of claim 1, wherein the disorder is acne and the application site is an area of skin of the individual, and wherein the NORS is from about 5 ppm*min/mL to about 30 ppm*min/mL based on 1 mL of the NORS The amount of mL releases NO. The method of claim 30, wherein the total amount of NO released from the volume of NORS administered is from about 10 ppm*min to about 60 ppm*min. The method of claim 30, wherein the volume of NORS administered is from about 1 mL to about 5 mL. The method of claim 30, wherein the volume of NORS administered releases a peak NO concentration from about 5 ppm to about 20 ppm. The method of claim 1, wherein the condition is diabetic foot ulcer and the administration site is the individual's foot, and wherein the NORS is from about 5 ppm*min/mL to about 80 ppm based on 1 mL of the NORS *NO released in the amount of min/mL. The method of claim 34, wherein the total amount of NO released from the volume of NORS administered is from about 100 ppm*min to about 75,000 ppm*min. The method of claim 34, wherein the volume of NORS administered is from about 5 mL to about 10,000 mL. The method of claim 34, wherein the volume of NORS administered releases a peak NO concentration from about 50 ppm to about 20,000 ppm. The method of claim 1, wherein the condition is a wart and the administration site is a skin area of the individual, and wherein the NORS is from about 10 ppm*min/mL to about 60 ppm*min/mL based on 1 mL of the NORS The amount of mL releases NO. The method of claim 38, wherein the total amount of NO released from the volume of NORS administered is from about 20 ppm*min to about 400 ppm*min. The method of claim 38, wherein the volume of NORS administered is from about 0.5 mL to about 10 mL. The method of claim 38, wherein the volume of NORS administered releases a peak NO concentration from about 1 ppm to about 60 ppm. The method of claim 1, wherein the nitric oxide releasing compound comprises sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, silver nitrite , copper nitrite, or combinations thereof. The method of claim 1, wherein the acidulant comprises ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid or a combination thereof. The method of claim 1, wherein the NORS provides an extended release of NO. The method of claim 1, wherein the NORS is administered as a nasal spray, open container bath for soaking, liquid sinus wash, liquid mouthwash, respiratory inhaler, aerosol, gel, foam, emulsion, It can be administered as a liquid solution, a cream, or a combination thereof. The method according to claim 1, wherein the NORS comprises a pharmaceutically acceptable carrier. The method of claim 46, wherein the pharmaceutically acceptable carrier comprises water, saline, hydroxyethyl cellulose, xanthan gum or a combination thereof. A composition for the treatment of a condition responsive to nitric oxide (NO) therapy, the composition comprising a nitric oxide releasing solution (NORS), wherein the NORS comprises a nitric oxide releasing compound and an acidulant, wherein when treated by The release of NO from a NORS into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and a pressure of 1 atmosphere for a period of 30 minutes is measured by quantification by a chemiluminescent detector, based on 1 mL of the NORS NO is released in amounts from about 1 ppm*min/mL to about 500 ppm*min/mL. The composition of claim 48, wherein the composition is formulated to be administered to the individual's feet to treat Hong Kong's foot, and wherein the NORS is based on 1 mL of the NORS from about 5 ppm*min/mL to about 15 NO is released in the amount of ppm*min/mL. The composition of claim 48, wherein the composition is formulated to be administered to the individual's nails to treat onychomycosis, and wherein the NORS is from about 25 ppm*min/mL to about 75 ppm based on 1 mL of the NORS *NO released in the amount of min/mL. The composition of claim 48, wherein the composition is formulated to be administered to the nasal cavity of an individual to treat influenza, and wherein the NORS is from about 2 ppm*min/mL to about 30 ppm* based on 1 mL of the NORS The amount of min/mL releases NO. The composition of claim 48, wherein the composition is formulated to be administered to the nasal cavity or lungs of an individual to treat respiratory viral infections, and wherein the NORS is based on 1 mL of the NORS from about 2 ppm*min/mL to NO is released in an amount of about 30 ppm*min/mL. The composition of claim 48, wherein the composition is formulated to be administered to the sinus cavity of an individual to treat sinusitis, and wherein the NORS is from about 0.5 ppm*min/mL to about 30 ppm based on 1 mL of the NORS *NO released in the amount of min/mL. The composition of claim 48, wherein the composition is formulated to be administered to the throat of an individual to treat a throat infection, and wherein the NORS is from about 10 ppm*min/mL to about 40 ppm* based on 1 mL of the NORS The amount of min/mL releases NO. The composition of claim 48, wherein the composition is formulated to be administered to an individual's skin area to treat acne, and wherein the NORS is from about 5 ppm*min/mL to about 30 ppm* based on 1 mL of the NORS The amount of min/mL releases NO. The composition of claim 48, wherein the composition is formulated to be administered to the individual's feet to treat diabetic foot ulcers, and wherein the NORS is based on 1 mL of the NORS from about 5 ppm*min/mL to about 80 ppm*min/mL releases NO. The composition of claim 48, wherein the composition is formulated to be administered to the skin of an individual to treat warts, and wherein the NORS is from about 10 ppm*min/mL to about 60 ppm* based on 1 mL of the NORS The amount of min/mL releases NO. The composition of claim 48, wherein the nitric oxide releasing compound comprises sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, nitrous acid Silver, copper nitrite, or combinations thereof. The composition of claim 48, wherein the acidulant comprises ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid or combinations thereof. The composition of claim 48, wherein the NORS provides an extended release of NO. The composition of claim 48, wherein the composition is formulated as a nasal spray, open container bath for soaking, liquid sinus wash, liquid mouthwash, respiratory inhaler, aerosol, gel, Foams, emulsions, liquid solutions, creams, or combinations thereof are administered. The composition according to claim 48, wherein the composition further comprises a pharmaceutically acceptable carrier. The composition according to claim 62, wherein the pharmaceutically acceptable carrier comprises water, saline, hydroxyethyl cellulose, xanthan gum or a combination thereof. A use of the composition according to any one of claims 48 to 63 in the preparation of medicines for treating diseases responsive to nitric oxide (NO) treatment, comprising: A therapeutically effective amount of the composition is administered to the individual. A composition comprising: Combination of nitric oxide releasing compound, acidifying agent and carrier in an amount such that when coupled to a chemiluminescence detector, NO is released from the composition into a substantially inert carrier gas flow at a flow rate of 1 liter per minute and 1 atmosphere of pressure The composition releases from about 1 ppm*min/mL to about 500 ppm*min/mL of nitric oxide (NO), based on 1 mL of the composition, when measured over a period of up to 30 minutes. The composition according to claim 65, wherein the pharmaceutically acceptable carrier comprises water, saline, hydroxyethyl cellulose, xanthan gum or a combination thereof. The composition of claim 65, wherein the composition is formulated as a nasal spray, open container bath for soaking, liquid sinus wash, liquid mouthwash, respiratory inhaler, aerosol, gel, Foams, emulsions, liquid solutions, creams, or combinations thereof are administered. The composition of claim 65, wherein the amount of NO released is from about 1 ppm*min/mL to about 500 ppm*min/mL.