CN118076343A - Treatment of vesicant exposure - Google Patents

Abstract

The present disclosure relates to the use of an oxygen-containing liquid as a countermeasure against a vesicant.

Description

Treatment of vesicant exposure

Cross Reference to Related Applications

The present application claims priority from U.S. provisional patent application Ser. No. 63/223,421, issued on Ser. No. 2021, 7, 19, 3, 2022, 16, and U.S. provisional patent application Ser. No. 63/320,625, issued on 6, 2022, 6, all of which are incorporated herein by reference in their entirety.

Disclosure of Invention

The present disclosure relates to the use of an oxygen-containing liquid as a countermeasure against a vesicant or for treating exposure to a vesicant.

The present disclosure relates to the use of oxygenated liquids for treating conditions associated with ischemia, hypoxia, VEGF, HIF, reactive oxygen species or electrochemical changes, cancer and other conditions.

The present disclosure relates to the use of an oxygen-containing liquid for cytoprotection or for preventing pathogen and/or hypoxia-induced cell damage.

The present disclosure also relates to the use of an oxygenated liquid for oxygenating blood (e.g., blood in humans) in the absence of a ventilator.

Some embodiments include a method of treating an ocular disorder comprising administering or delivering an oxygenated liquid to the eye of a mammal having an ocular disorder.

Brief description of the drawings

Fig. 1 depicts the scotopic b-wave response of ischemic rabbit eyes subjected to hyperbaric oxygen solution treatment compared to control.

Fig. 2 depicts VEGF levels in Retinal Pigment Epithelial (RPE) cells exposed to hypoxic conditions and treated with a hyperbaric oxygen solution.

FIG. 3 depicts HIF levels in RPE cells exposed to hypoxic conditions and treated with a high pressure oxygen solution.

Fig. 5 depicts two possible embodiments of nanoparticles containing an oxygen-containing liquid.

Fig. 6 depicts an embodiment of nanoparticles containing an oxygen-containing liquid and further dispersed within the oxygen-containing liquid.

Detailed Description

In some embodiments, the oxygenated liquid further comprises an immune system enhancer.

References herein to "oxygenated liquid" include administration of an actual oxygenated liquid, or another form that can generate oxygen in a liquid within a human or animal body, including compositions, forms, delivery systems, and the like described herein.

For the treatment of any of the conditions described herein, the oxygen-containing liquid may contain chromium (e.g., a chromium complex, a chromium-containing compound, a chromium ion, or a chromium ion). Or chromium (e.g., chromium complexes, chromium-containing compounds, chromium ions, or chromium ions) may be used in solid or liquid dosage forms (e.g., aqueous liquids or dispersions) for treating any of the conditions described herein.

In some embodiments, the oxygenated liquid may be used with diseased animal or human cells (e.g., cancerous human cells) for diagnosis, study, or treatment of infection.

In some embodiments, the oxygenated liquid may be delivered by a pump (e.g., a pump similar to the pump used to deliver insulin).

In some embodiments, the oxygen-containing liquid may be used as a countermeasure against a vesicant (e.g., distilled mustard gas, sulfur mustard gas, nitrogen mustard gas, sesquimustard gas, lewis gas, ammonium oxide, sulfur oxide, phosgene oxime, etc.).

In some embodiments, the oxygenated liquid may be used to prevent or reduce the likelihood of infection after exposure, or to prevent or reduce the severity of post-exposure symptoms.

In some embodiments, the oxygen-containing liquid may be used with a diagnostic agent. For example, the oxygenated liquid may be labeled (e.g., with a fluorescent label) to detect early hypoxic regions that may be prone to develop disease (e.g., cancer).

In some embodiments, the oxygenated liquid (including aqueous oxygenated liquid and/or oxygenated hydrogel) may be administered in combination with Sup>A corneal collagen crosslink including Sup>A corneal collagen crosslink with riboflavin and/or UV-Sup>A. In some embodiments, the patient with corneal collagen crosslinking is treated with the oxygen-containing liquid for at least 1 day, at least 1 week, or at least 2 weeks after performing the surgery.

In some embodiments, the oxygenated liquid may be used to modulate (modulate) VEGF. In some embodiments, the oxygen-containing liquid may be used to modulate inflammatory mediators.

In some embodiments, the oxygenated liquid is delivered via a drip-less delivery method (e.g., anterior chamber), through punctal delivery, or intravitreal, hydrogel plug, implant, or sub-tenon's capsule (subtenon) injection.

In some embodiments, the oxygen-containing liquid is a hydrogel.

In some embodiments, the oxygenated liquid is used to improve cell healing and/or to modulate/normalize vascular and cellular functions. In some embodiments, the oxygenated liquid is used to stop or slow vascular leakage. In some embodiments, the nanoparticle comprising an oxygen-containing liquid is used to treat cancer or ischemic eye disorders.

In some embodiments, the oxygen-containing liquid may be contained in particles, such as nanoparticles or microparticles (or microparticles). In some embodiments, the oxygen-containing liquid may be contained within a drug delivery device. In some embodiments, the means for releasing the oxygenated liquid may be constructed from nanoparticles or other structures containing the oxygenated liquid. In some embodiments, such devices may be prepared using a 3D printer, which may be used to fabricate scaffolds or oxygenated microfibers.

The present disclosure relates to methods of treating ischemic conditions (e.g., ocular ischemic conditions, other conditions related to hypoxia, or conditions related to reactive oxygen species) comprising administering or delivering an oxygenated liquid to a mammal (e.g., a human) for treatment of the conditions. The oxygenated liquid may be used alone or in combination with other drugs or therapeutic agents, such as hypoxia-inducible factor 1 (HIF-1) inhibitors (e.g., ulipristine (eudistidine)).

The term "treatment" or "treatment" broadly includes any type of therapeutic activity, including diagnosis, cure, alleviation or prevention of a disease in a human or other animal, or any activity that otherwise affects the structure or any function of the human or other animal's body.

The oxygen-containing liquid may be any liquid composition comprising oxygen, or a compound that provides oxygen pressure to a liquid, or a liquid that provides oxygen to mammalian cells or tissues, suitable for use in mammals (including humans) for therapeutic purposes. The oxygen-containing liquid may be aqueous or may be based on a suitable organic solvent or may be a combination of aqueous and organic solvents. The liquid may be in the form of a solution or a multiphase liquid, such as a suspension, colloid, emulsion, shear-thinning gel, or the like. For many routes of administration (e.g., injection), it may be important that the oxygen-containing liquid be sterile.

The oxygenated liquid may be formulated for any desired delivery route including, but not limited to, parenteral, suppository, intravenous, intradermal (e.g., intradermal injection), subcutaneous, oral, inhalation, metered dose inhaler (metered dose inhaler, MDI), transdermal, patch, drop, topical delivery route to the eye (e.g., eye drops for delivery to the anterior segment of the eye or eye drops for delivery to the posterior segment of the eye) or skin, transmucosal, rectal, intravaginal, intraperitoneal, intramuscular, intralesional, intranasal, subcutaneous (e.g., subcutaneous injection), buccal, intraocular injection, intravitreal injection, subretinal injection, intrathecal injection (e.g., directly into the heart), and the like. The term "injection" includes injection of a pharmaceutical composition, insertion of an implant or drug delivery device, and other types of injections.

In some embodiments, rather than direct administration, the oxygenated liquid may be generated in the target tissue by insertion of an implant or drug delivery device into or near the target tissue, which may provide for long-term delivery of the oxygenated liquid. For example, the implant may comprise a biodegradable or bioerodible polymer having components of the oxygenating composition dispersed in the polymer. As the polymer degrades or erodes, the components of the oxygenated composition will mix in the aqueous environment of the tissue into which the implant is inserted, thereby generating an oxygenated liquid at or near the tissue to be targeted. The implant or device may be administered by any of the routes described above, including intravenous (e.g., by injection), intravitreal (e.g., by injection), or subretinal (e.g., by injection). The oxygenated liquid may also be generated by other types of solid devices (e.g., punctal plugs and contact lenses containing components of the oxygenated composition) that gradually diffuse out of the device. Or the punctal plugs or contact lenses can be biodegradable or bioerodible.

Any of the therapeutic compositions, dosage forms, drug delivery devices, implants, etc., described herein (e.g., by oral administration, IV (intravenous injection), etc.) may be formulated or designed for timed release, delayed release, controlled release, sustained release, etc., such as by using biodegradable polymers or bioerodible materials. Compositions, dosage forms, drug delivery devices, implants, and the like may provide targeted delivery through both the route and/or location of administration as well as through materials or structural features that include specific environments, chemical properties, chemical activities, biological properties, or biological activities designed to be responsive to the type of cell, tissue, organ, or biological system to be targeted.

Examples of materials having timed release, delayed release, controlled release, sustained release, etc. properties include silica-based materials, or organic biodegradable materials, such as polymers, including poly (D, L-lactic acid) (PLA) and poly (D, L-lactic-co-glycolic acid) or poly (lactic-co-glycolic acid) (PLGA), polyesteramides (PEA, DSM chemical), and Polycaprolactone (PCL); hydrogels such as polyvinyl alcohol (PVA), PEG amine, PEG-N-hydroxysuccinimide ester, and the like; collagen-based materials; acrylic acid and methacrylic acid copolymers and their various esters, such as methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), alkylamine methacrylate copolymers, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polyacrylamide, poly (methacrylic anhydride), and glycidyl methacrylate copolymers; polymerizable quaternary ammonium compounds such as quaternized aminoalkyl esters and aminoalkyl amides of acrylic and methacrylic acid, e.g., beta-methacryloxyethyl trimethylammonium methylsulfate, beta-acryloxypropyl trimethylammonium chloride, trimethylaminomethacrylamide methylsulfate, and the like. The quaternary ammonium atom can also be part of a heterocyclic ring, for example in methacryloyloxyethyl methyl morpholinium chloride or the corresponding piperidinium salt, or it can be linked to an acrylic or methacrylic group through a heteroatom containing group (e.g., a polyethylene glycol ether group). Further suitable polymerizable quaternary ammonium compounds include quaternized vinyl-substituted nitrogen heterocycles such as methyl-vinylpyridinium salts, vinyl esters of quaternized aminocarboxylic acids, styryltrialkyl ammonium salts, and the like. Other polymerizable quaternary ammonium compounds include ethyl methacrylate benzyl dimethyl ammonium chloride (benzyldimethylammoniumethylmethacrylate chloride), ethyl methacrylate diethyl methyl ammonium methyl sulfate and ethyl acrylate diethyl methyl ammonium methyl sulfate (diethylmethylammoniumethyl-ACRYLATE AND-METHACRYLATE METHOSULFATE), methacrylamidopropyl N-trimethyl ammonium chloride (N-trimethylammoniumpropylmethacrylamide chloride), and 2,2-dimethylpropyl 1-methacrylate N-trimethyl ammonium chloride (N-trimethylammonium-2, 2-dimethylpropyl-l-METHACRYLATE CHLORIDE) -.

In some embodiments, a delivery system (e.g., a microparticle or nanoparticle delivery system (e.g., PLGA nanoparticles)) can provide prolonged delivery of an oxygen-containing liquid to a patient. For example, the delivery system may provide oxygen to a target cell, tissue, organ, or system for an extended period of time (e.g., IV nanoparticles containing an oxygen-containing liquid, such as PLGA nanoparticles, may provide oxygen to the blood), for example, for at least about 1 hour, at least about 4 hours, at least about 8 hours, at least about 12 hours, at least about 24 hours, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 2 months, at least 3 months, at least 4 months, at least 6 months, about 1-2 days, about 2-4 days, about 4-7 days, about 1-2 weeks, about 2-4 weeks, about 1-2 months, about 2-4 months, about 4-6 months, or about 1-4 months. In some embodiments, administration of the delivery system may be repeated at intervals of about 4-8 hours, about 8-16 hours, about 16-24 hours, about 1-2 days, about 2-4 days, about 4-7 days, about 1-2 weeks, about 2-4 weeks, about 1-2 months, about 2-4 months, about 4-6 months, or about 1-4 months.

PLGA nanoparticles or microparticles can be administered (e.g., by injection, insertion, or other means) to treat an infection, even in the absence of an oxygenated liquid.

In some embodiments, the delivery system is sterile.

In some embodiments, the oxygenated liquid, or a device or implant that releases or generates the oxygenated liquid in vivo, is administered directly (e.g., by injection, insertion, or other means) to a tissue, organ, or body system affected by the disorder to be treated, such as an organ or system infected with a virus or bacteria, such as the central nervous system, e.g., brain, eye, nerve; cardiopulmonary systems, such as heart, lungs, etc.; liver; a kidney; musculoskeletal system, muscle; endocrine systems, such as the pancreas; the gastrointestinal system, such as the esophagus, stomach, small intestine, large intestine, etc.

The oxygen-containing liquid may have a higher partial pressure of oxygen than ordinary water, or higher partial pressure of oxygen than air at atmospheric pressure, such as at room temperature (e.g., 23 ℃) or body temperature (e.g., 37 ℃) and the oxygen-containing liquid may have at least 120mmHg, at least 140mmHg, at least 145mmHg, at least 150mmHg, at least 155mmHg, at least 160mmHg, at least 165mmHg, at least 170mmHg, at most 180mmHg, at most 200mmHg, at most about 250mmHg, at most about 300mmHg, at most about 350mmHg, at most about 400mmHg, at least about, Up to about 450mmHg, up to about 500mmHg, about 120-500mmHg, about 20-40mmHg, about 40-60mmHg, about 60-80mmHg, about 80-100mmHg, about 100-120mmHg, about 120-140mmHg, about 140-145mmHg, about 145-150mmHg, about 150-155mmHg, about 155-160mmHg, about 160-165mmHg, about 165-170mmHg, about 170-175mmHg, about 175-180mmHg, about, About 140-150mmHg, about 150-160mmHg, about 160-170mmHg, about 170-180mmHg, about 180-190mmHg, about 190-200mmHg, about 200-210mmHg, about 210-220mmHg, about 220-230mmHg, about 230-240mmHg, about 240-250mmHg, about 250-260mmHg, about 260-270mmHg, about 270-280mmHg, about 280-290mmHg, about 290-300mmHg, and, About 300-320mmHg, about 320-340mmHg, about 340-360mmHg, about 360-380mmHg, about 380-400mmHg, about 400-420mmHg, about 420-440mmHg, about 440-460mmHg, about 460-480mmHg, about 480-500mmHg, about 140-160mmHg, about 160-180mmHg, about 180-200mmHg, about 160-200mmHg, about 200-250mmHg, about 250-300mmHg, about, An oxygen pressure of about 300-350mmHg, about 350-400mmHg, about 400-450mmHg, about 450-500mmHg, about 140-200mmHg, about 200-300mmHg, about 300-400mmHg, about 400-500mmHg, 500-750mmHg, 750-1000mmHg, 1000-1250mmHg, 1250-1500mmHg, about 175mmHg, any oxygen pressure within a range defined by any of these values. In some embodiments, the oxygen-containing liquid is a high pressure oxygen solution (e.g., examples 1-3 below).

While there may be many ways to add oxygen to the liquid, some oxygenated liquids may contain an oxygenated composition (e.g., a compound or combination of compounds) that releases oxygen, for example, by chemical reaction or chemical degradation. Suitable oxygenating compositions may contain metal oxides (e.g., caO, mgO, etc.), metal hydroxides (e.g., ca (OH) ₂、Mg(OH)₂), peroxides (e.g., hydrogen peroxide or organic peroxides), or combinations thereof. Other ingredients may be added to increase or decrease the oxygen release rate depending on the particular needs. For example, a faster oxygen release may provide a higher oxygen pressure. On the other hand, slower oxygen release may provide longer, more consistent or more sustained oxygen pressure. Examples of suitable oxygenation compositions are described in U.S. patent No. 8,802,049, which is incorporated by reference herein in its entirety. A useful oxygenating composition contains, based on the total weight of the oxygenated liquid, about 20-30% Ca (OH) ₂, about 10-15% H ₂O₂, about 0.5-5% sodium acetate, about 0.5-5% KH ₂PO₄, and about 1-20% carrageenan. In some embodiments, the total amount of oxygen atoms present in all of the metal oxides, metal hydroxides, and peroxides present in the oxygen-containing liquid is from about 20 to about 70%, from about 20 to about 50%, from about 50 to about 70%, from about 20 to about 30%, from about 30 to about 40%, from about 40 to about 50%, from about 50 to about 60%, from about 60 to about 70%, from about 70 to about 90%, or from about 80 to about 95%, based on the total weight of the oxygen-containing liquid.

As noted above, the components of these oxygenating compositions (e.g., metal oxides, metal hydroxides, and/or peroxides) may be dispersed in a bioerodible or biodegradable polymer, such as a silicon-based polymer, polyester, polyorthoester, polyphosphoester, polycarbonate, polyanhydride, polyphosphazene, polyoxalate, poly (amino acid), polyhydroxyalkanoate, polyethylene glycol, polyvinyl acetate, polyhydroxyacid, polyanhydride, or copolymers or blends thereof (e.g., copolymers of lactic acid and glycolic acid).

The components of the oxygenated liquid or oxygenated composition (e.g., metal oxides, metal hydroxides, and/or peroxides) may be lyophilized for oral delivery (e.g., in a tablet, capsule, or other solid oral dosage form), reconstituted or dispersed into a solid or multi-phase (e.g., nanoparticles, nanoemulsions, etc.) drug delivery system or device (e.g., any of the delivery systems or devices described herein). Oral dosage forms comprising an oxygen-containing liquid, or a lyophilized composition, or other compositions that can produce an oxygen-containing liquid in a human or animal body may have an enteric coating.

Suitable excipients for the oxygen-containing liquid may include, for example, one or more carriers, binders, fillers, carriers, tonicity agents, buffers, disintegrants, surfactants, dispersing or suspending aids, thickeners or emulsifiers, preservatives, lubricants and the like or combinations thereof, as appropriate for the particular dosage (form) desired. Remington's Pharmaceutical Sciences, sixteenth edition, e.w. martin (Mack Publishing co., easton, pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for preparing the same. This document is incorporated by reference in its entirety.

In addition to solvents, oxygen and/or oxygenated compositions, liquid dosage forms for IV injection (e.g., intraocular injection, subretinal injection, intrathecal, direct access to the heart), topical (e.g., to the eye), oral administration to mammals (including humans) may contain adjuvants such as compatibilizers (e.g., mannitol, lactose, sucrose, trehalose, sorbitol, glucose, raffinose, glycine, histidine, polyvinylpyrrolidone, etc.), tonicity agents (e.g., dextrose, glycerol, mannitol, sodium chloride, etc.), buffers (e.g., acetates such as sodium acetate, acetic acid, ammonium acetate, ammonium sulfate, ammonium hydroxide, citrate, tartrate, phosphate, triethanolamine, arginine, aspartic acid, benzenesulfonic acid, benzoate, bicarbonate, borate, carbonate, succinate, sulfate, tartrate, tromethamine, diethanolamine, and the like), preservative (e.g., phenol, m-cresol, parabens such as methyl paraben, propyl paraben, butyl paraben, myristyl gamma-methyl pyridine chloride, benzalkonium chloride, benzethonium chloride, benzyl alcohol, 2-phenoxyethanol, chlorobutanol, thimerosal, phenylmercuric salt, and the like), surfactant (e.g., polyoxyethylene sorbitan monooleate or tween 20, lecithin, polyoxyethylene-polyoxypropylene copolymer, and the like), solvent (e.g., propylene glycol, glycerin, ethanol, polyethylene glycol, sorbitol, polyoxyethylene-polyoxypropylene copolymer, and the like), dimethylacetamide, cremophor EL, benzyl benzoate, castor oil, cottonseed oil, N-methyl-2-pyrrolidone, PEG 300, PEG 400, PEG 600, PEG 3350, PEG 400, poppy seed oil, propylene glycol, safflower oil, vegetable oil, and the like), chelating agents (e.g., disodium EDTA calcium ethylenediamine tetraacetate, disodium EDTA, sodium ethylenediamine tetraacetate, sodium vitamin A calcium acetate, calcilyl alcohol, DTPA), or other excipients.

In addition to solvents, oxygen, and/or oxygenated compositions, liquid dosage forms for IV injection (e.g., intraocular injection, subretinal injection, intrathecal, direct access to the heart), topical (e.g., to the eye), or oral administration to mammals (including humans) may contain cyclodextrins, cyclodextrin derivatives, and/or salts thereof, such as naturally occurring cyclodextrins (e.g., α -cyclodextrin, β -cyclodextrin, or γ -cyclodextrin) or synthetic cyclodextrins. Examples include, but are not limited to, (2, 3, 6-tri-O-acetyl) -alpha-cyclodextrin, (2, 3, 6-tri-O-methyl) -alpha-cyclodextrin, (2, 3, 6-tri-O-octyl) -alpha-cyclodextrin, 6-bromo-6-deoxy-alpha-cyclodextrin, 6-iodo-6-deoxy-alpha-cyclodextrin, (6-O-tert-butyl-dimethylsilyl) -alpha-cyclodextrin, butyl-alpha-cyclodextrin, succinyl-alpha-cyclodextrin, (2-hydroxypropyl) -alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin, 6-mono-deoxy-6-mono-amino-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, 6-O-alpha-D-glucosyl-beta-cyclodextrin, 6-O-alpha-maltosyl-beta-cyclodextrin, 6-azido-6-deoxy-beta-cyclodextrin, (2, 3-di-O-acetyl-6-O-sulfo) -beta-cyclodextrin, methyl-beta-cyclodextrin, dimethyl-beta-cyclodextrin (DM beta CD), trimethyl-beta-cyclodextrin (TM beta CD), (2, 3-di-O-methyl-6-O-sulfo) -beta-cyclodextrin, (2, 6-di-O-methyl) -beta-cyclodextrin, (2, 6-di-O-ethyl) -beta-cyclodextrin, (2, 3, 6-tri-O-methyl) -beta-cyclodextrin, (2, 3, 6-tri-O-acetyl) -beta-cyclodextrin, - (2, 3, 6-tri-O-benzoyl) -beta-cyclodextrin, (2, 3, 6-tri-O-ethyl) -beta-cyclodextrin, 6-iodo-6-deoxy-beta-cyclodextrin, 6- (dimethyl-tert-butylsilyl) -6-deoxy-beta-cyclodextrin, 6-bromo-6-deoxy-beta-cyclodextrin, monoacetyl-beta-cyclodextrin, diacetyl-beta-cyclodextrin, triacetyl-beta-cyclodextrin, (3-O-acetyl-2, 6-di-O-methyl) -beta-cyclodextrin, (6-O-maltosyl) -beta-cyclodextrin, (6-O-sulfo) -beta-cyclodextrin, (6-O-tert-butyldimethylsilyl-2, 3-di-O-acetyl) -beta-cyclodextrin, (2, 6-di-O-) ethyl-beta-cyclodextrin, (2-carboxyethyl) -beta-cyclodextrin (CME beta CD), hydroxyethyl-beta-cyclodextrin (HEbeta CD), (2-hydroxypropyl) -beta-cyclodextrin (HP beta CD), (3-hydroxypropyl) -beta-cyclodextrin (3 HP beta CD), (2, 3-hydroxypropyl) -beta-cyclodextrin (DHP beta CD), and, Butyl-beta-cyclodextrin, methyl-beta-cyclodextrin, silyl ((6-O-tert-butyldimethyl) -2,3, -di-O-acetyl) -beta-cyclodextrin, succinyl-beta-cyclodextrin, (2-hydroxyisobutyl) -beta-cyclodextrin, randomly methylated-beta-cyclodextrin, branched-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin (e.g., SBE beta CD, betacyclodextrin,) Carboxymethyl-gamma-cyclodextrin, (2, 3, 6-tri-O-acetyl) -gamma-cyclodextrin, (2, 3, 6-tri-O-methyl) -gamma-cyclodextrin, (2, 6-di-O-pentyl) -gamma-cyclodextrin, 6- (dimethyl-t-butylsilyl) -6-deoxy-gamma-cyclodextrin, 6-bromo-6-deoxy-gamma-cyclodextrin, 6-iodo-6-deoxy-gamma-cyclodextrin, (6-O-t-butyldimethylsilyl) -gamma-cyclodextrin, succinyl-gamma-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, (2-hydroxypropyl) -gamma-cyclodextrin, acetyl-gamma-cyclodextrin, butyl-gamma-cyclodextrin, or a combination thereof.

The liquid dosage form comprising the oxygen-containing liquid (e.g., for IV injection (e.g., intraocular injection, subretinal injection, etc.), topical (e.g., to the eye), or oral administration in a mammal (including a human) may have any suitable pH, such as about 2-12, about 2-4, about 4-6, about 6-8, about 8-10, about 10-12, about 6-7, about 7-8, about 8-9, about 6-6.5, about 6.5-7, about 7-7.5, about 7.5-8, about 8-8.5, about 8.5-9, about 7-7.2, about 7.2-7.4, about 7.4-7.6, about 7.6-7.8, about 7.8-8, or any pH within a range defined by any of these values.

For many routes of administration, it may be helpful for the oxygen-containing liquid to be hypertonic or hypertonic (hypertonic or hyperosmolar), such as to have a tonicity or osmolality greater than about 290mOsm/L, such as about 290-600mOsm/L, about 290-400mOsm/L, about 400-500mOsm/L, or about 500-600mOsm/L; isotonic or isotonic (isotonic or isoosmolar), e.g., a tonicity or osmolality approaching that of the body tissue to which it is applied, e.g., about 290mOsm/L, about 250-350mOsm/L, about 250-320mOsm/L, about 270-310mOsm/L, or about 280-300mOsm/L; or hypotonic (hypotonic or hypoosmolar), e.g., with a tonicity or osmolality of less than about 290mOsm/L, e.g., about 150-290mOsm/L, about 150-200mOsm/L, about 200-290mOsm/L, about 200-250mOsm/L, or about 250-290mOsm/L.

The oxygen-containing liquid may also be potentially delivered in a microparticle delivery system, nanoparticle delivery system, nanoemulsion delivery system, microemulsion delivery system, microsomal delivery system, liposome delivery system, or lysosomal delivery system. For example, the oxygen-containing liquid may be contained in reverse micelles or inside nanoparticles, nanoemulsions, microemulsions, microsomes, liposomes or lysosomes. In some embodiments, the oxygen-containing liquid is contained within polymeric nanoparticles (e.g., PLGA nanoparticles). In some embodiments, the delivery system is dispersed within an oxygen-containing liquid for delivery. For example, the nanoparticle, microparticle, liposome, or lysosome can contain an oxygen-containing liquid, and can be further dispersed within the oxygen-containing liquid.

For example, as shown in fig. 5, a polymer 10 (e.g., PLGA) may form an outer solid layer around an oxygen-containing liquid center 20, or a number of smaller liquid nanodroplets or nanoparticles 30 may be encapsulated in a larger solid polymer (e.g., PLGA) host nanoparticle 15.

In some embodiments, the nanoparticles or microparticles comprising the oxygen-containing liquid may also be dispersed within the oxygen-containing liquid. For example, as shown in fig. 6, the polymer 10 (e.g., PLGA) may form an outer solid layer around the oxygenated liquid center 20, and the oxygenated liquid center 20 may be dispersed within the oxygenated liquid 40.

In addition to the above, it may be desirable for the liquid for oral administration to also contain a sweetener, such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For creams, gels, ointments and the like, it may be desirable to include thickeners such as polyethylene glycol, polyacrylic acid, cetyl alcohol, stearyl alcohol, carnauba wax, stearic acid, hydroxyethyl cellulose, guar gum, locust bean gum, xanthan gum, gelatin, silica, bentonite, magnesium aluminum stearate and the like.

The liquid dosage form comprising the oxygen-containing liquid may be part of a pharmaceutical product comprising the oxygen-containing liquid, an oxygen sensor, and a drug dispensing device. In some embodiments, only the oxygen-containing liquid may be dispensed if the oxygen-containing liquid has a desired oxygen pressure (e.g., the oxygen pressures described above).

Although any suitable oxygen sensor may be used, the high performance microsensors available from Unisense are examples of useful oxygen sensors.

Any suitable medicament dispensing device may be used, for example a syringe or other form of injection device, a drop dispensing device.

Hypoxia, ischemia and reactive metabolites can lead to the development and progression of many disease states. Common to the inhibition of tissue repair is tissue hypoxia.

Facilitating oxygen delivery to tissue can lead to adjunct and direct treatment in a wide variety of medical conditions.

Tissue hypoxia is a low tissue oxygen level typically associated with impaired circulation. Tissue hypoxia, ischemia and reactive metabolites lead to the development and exacerbation of many disease states.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid (hyperbaric oxygen-containing liquid)) to a mammal having a disorder associated with ischemia, hypoxia, VEGF, HIF, a reactive oxygen species, or an electrochemical change (e.g., an ocular disorder associated with ischemia, hypoxia, VEGF, HIF, a reactive oxygen species, or an electrochemical change) results in a decrease in HIF levels in a tissue (e.g., ocular tissue) having ischemia by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than hypoxia-inducible factor (Hypoxic Induction Factor, HIF) levels in the tissue (e.g., ocular tissue) having ischemia immediately prior to administration of the oxygenated liquid.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal having a condition associated with ischemia, hypoxia, VEGF, HIF, reactive oxygen species, or electrochemical change (e.g., an ocular condition associated with ischemia, hypoxia, VEGF, HIF, reactive oxygen species, or electrochemical change) results in a decrease in HIF levels in tissue (e.g., ocular tissue) having ischemia such that it is within about 50%, within about 40%, within about 30%, within about 20%, within about 10%, within about 5%, within about 3%, or within about 1% of HIF levels in non-ischemic tissue (e.g., the contralateral eye).

In some embodiments, a decrease in HIF levels in tissue may be observed within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 7 days, within 14 days, within 21 days, within 28 days, within 2 months, within 3 months, within 4 months, within 6 months, within 1 year, or longer.

In some embodiments, the decrease in HIF levels in a tissue may last for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 14 days, at least 21 days, or at least 28 days.

Administration or delivery of an oxygen-containing liquid (e.g., a high pressure oxygen-containing liquid) to a mammal may be used to treat any type of ischemic condition, such as a wound, vascular disease, malignancy, arthritis, atherosclerotic plaque, cancer, tumor, burn, inflammatory condition, including nerve tissue inflammation (e.g., concussion), neuroinflammatory condition, encephalitis, infection-induced encephalitis, brain inflammation, brain infection, other inflammation induced by infection, or other inflammation associated with an inflammation-induced condition, respiratory tract infection, or other condition, such as pneumonia, bronchitis, emphysema, asthma, etc.

In some embodiments, the oxygenated liquid is used to oxygenate blood (e.g., human blood) without the use of a ventilator. For example, the oxygen-containing liquid may be administered intravenously, or by another route, such as by oral administration. Oxygenation of blood may be used to treat any of the conditions described herein.

An oxygen-containing liquid (e.g., a high pressure oxygen-containing liquid) may be used in conjunction with laser therapy or radiation therapy, for example, to enhance therapeutic effects or to assist in therapy-related healing.

Administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal may be used to treat a neurological disorder, such as parkinson's disease.

In some embodiments, the ischemic condition is an ocular condition, such as diabetic retinopathy, macular degeneration, age-related macular degeneration, dry age-related macular degeneration, wet age-related macular degeneration, macular edema, diabetic macular edema, glaucoma, sickle eye disease, ocular inflammation, hypertensive retinopathy, retinopathy of prematurity, ocular ischemic syndrome, retinal branch vein occlusion, retinal branch artery occlusion, central retinal vein occlusion, central retinal artery occlusion, retinal detachment, penetrating eyeball injury, traumatic optic neuropathy, optic neuritis, inflammatory ocular condition, and the like. In some embodiments, the ocular ischemic condition is diabetic retinopathy.

In some embodiments, the ocular ischemic condition is macular degeneration. In some embodiments, the ocular ischemic condition is diabetic macular edema. In some embodiments, the ocular ischemic condition is glaucoma. In some embodiments, the ocular ischemic condition is a sickle cell ocular disease. In some embodiments, the ocular ischemic condition is ocular inflammation. In some embodiments, the disorder is hypertensive retinopathy. In some embodiments, the disorder is ocular ischemic syndrome. In some embodiments, the disorder is retinal vein occlusion. In some embodiments, the disorder is arterial occlusion, e.g., arterial occlusion in the retina. In some embodiments, the disorder is a branch retinal vein occlusion. In some embodiments, the disorder is a retinal branch artery occlusion. In some embodiments, the disorder is central retinal vein occlusion. In some embodiments, the disorder is central retinal artery occlusion. In some embodiments, the disorder is retinal detachment. In some embodiments, the disorder is an eye penetrating injury. In some embodiments, the disorder is traumatic optic neuropathy. In some embodiments, the disorder is optic neuritis. In some embodiments, the disorder is an inflammatory ocular disorder.

In some embodiments, the ischemic condition is a condition in which electrochemistry is altered, such as cardiovascular conditions, heart attacks, strokes, nerve ischemia, central nervous system injury, traumatic brain injury, spinal cord injury, acute and chronic traumatic brain lesions, and immunocytotoxicity. Application or delivery of an oxygen-containing liquid (e.g., a high pressure oxygen-containing liquid) may also be useful in treating diseases or conditions associated with or caused by solar injury or oxidation.

In some embodiments, the oxygen-containing liquid may be used to treat cancer. For example, the oxygenated liquid may be administered in combination with a chemotherapeutic agent (e.g., alkylating agent, antimetabolite, antitumor antibiotic, topoisomerase inhibitor, mitotic inhibitor, etc.). In some embodiments, co-administration of an oxygen-containing liquid with a chemotherapeutic agent may help improve the activity of the radiation therapy or chemotherapeutic agent. For example, oxygen-containing fluids can increase oxygen within cancers and tumors to increase the effectiveness of radiation therapy and/or chemotherapy. The oxygenated liquid may be used to reduce or interrupt tumor growth and/or growth rate. In some embodiments, the chemotherapeutic agent may be administered in an aqueous solution, for example intravenously or injected into the cancer site. The oxygenated liquid may also have other therapeutic effects for the treatment of cancer.

Other conditions that may be treated with the oxygenated liquid include anemia, migraine, refractory osteomyelitis, coronavirus infection (e.g., SARS-CoV-2 leading to COVID-19), viral infection, bacterial infection, fungal infection, etc., such as Enterobacter (Enterobacter), staphylococcus aureus (Staphylococcus Aureus) (including MRSA), methicillin-resistant Staphylococcus aureus (S.Aureus), klebsiella pneumoniae (Klebsiella pneumoniae), actinomyces (Actinomycetes), pseudomonas (Pseudomonas), enterococcus (Enterococcus), fungi, mycobacteria, enterococcus faecium (Enterococcus Facium), staphylococcus aureus, klebsiella pneumoniae (Klebsiella Pneumonia), acinetobacter baumannii (Actinobacter baumanii), pseudomonas aeruginosa (Pseudomonas Aeruginosa), enterobacter, etc.

Arenaviridae (ARENAVIRADAE):

Tacaribe virus

Pickins (Pichinde) virus

Dove (Junin) virus

Lymphocytic virus

Choriomeningitis virus

Bunyaviridae (Bunyaviridae):

Setaria fever Virus

Panama (Punta Toro) virus

LaCrosse Virus

Maporal Virus

Ha Telan De (Heartland) Virus

Severe fever thrombocytopenia syndrome virus

A Luo Puqie (Oropouche) Virus

Flaviviridae (flavoviridae):

dengue virus

West Nile Virus

Yellow fever virus

Japanese encephalitis (Japanese encephalitis) virus

Powassan (Powassan) virus

Zika virus

Wusu figure virus

Togaviridae (Togaviridae):

venezuelan equine encephalitis (Venezuelan equine encephalitis) virus

Eastern equine encephalitis (Eastern equine encephalitis) virus

Western equine encephalitis (Western equine encephalitis) virus

Chikungunya virus

Ma Yaluo (Mayaro) Virus

Picornaviridae (Picornaviridae):

Poliovirus (Poliovirus)

Enterovirus-71

Enterovirus-68

Coxsackie virus (Coxsackie virus) B3

Respiratory viruses:

MERS coronavirus

Influenza A H1N1 virus

Respiratory syncytial virus

Other viruses:

Measles virus

Ebola virus

Lassa virus

Marburg virus

Nipah virus

Human norovirus

Mouse norovirus

HBV

Herpesviridae (Herpesviridae):

Herpes simplex virus-1

Herpes simplex virus-2

Human cytomegalovirus

Murine cytomegalovirus

Guinea pig cytomegalovirus

Varicella zoster virus

Epstein-barr virus

Human herpesvirus-6 b

Human herpesvirus-8

Milk sky virus family (Papovaviridae):

BK virus

JC virus

Papilloma virus (Papillomavirus)

Other viruses:

Adenovirus-5

Vaccinia virus (Vaccinia virus)

Vaccinia virus

Oxygenation of a patient infected with hypoxia can be improved by administering an oxygenated liquid to the patient. It is believed that intravenous oxygen-containing solutions can help the body overcome hypoxia and ameliorate organ damage. Intravenous oxygen delivery is a unique oxygenation method. Intravenous oxygenation will allow for faster recovery and help heal the organ, avoiding the sometimes devastating consequences of hypoxia caused by infection.

As disclosed herein, it has been found that an oxygenated liquid can improve the consequences of retinal hypoxia. In vitro and in vivo studies have met with some degree of success. It has been found that some oxygenated liquids are safe across a variety of cell lines. As described herein, the oxygenated liquid can protect cells in vitro and modulate vascular endothelial growth factor (Vascular Endothelial Growth Factor, VEGF) responses of cells exposed to hypoxic environments (see example 2 below). In addition, as shown in example 1 below, some oxygenated liquids have been demonstrated to promote recovery of cellular function following induction of ischemia.

High oxygen levels may inhibit viral growth. Oxidative conditions in infection may alter gene expression. Hypoxia may directly or indirectly modulate viral responses. Viruses and bacteria may target the hypoxic pathway and glycolytic metabolism. These mechanisms are complex and involve hypoxia-inducible factor (Hypoxic Induction Factor, HIF) pathways and vascular endothelial growth factor (Vascular Endothelial Growth Factor, VEGF) regulation and their relationship to DNA or RNA viruses.

Some patients develop sepsis. One characteristic of sepsis is lactic acidosis. Lactic acidosis can potentially be overcome with intravenous oxygen liquids.

The patient's infection may be characterized using parameters measured by blood-gas machines and other devices for measuring oxygen (O ₂), partial pressure of oxygen (PO ₂), partial pressure of carbon dioxide (PCO ₂), lactic acid, pH, electrolytes (e.g., Na⁺、K⁺、Ca^{2 +}、Mg²⁺、HCO₃ ^-、CO₃ ^2-、H₂PO^3-、HPO₃ ^2-、PO₃ ^3-, etc.), and the like. Blood gas machines and other devices may also be used to determine hypoxia and reactive oxygen species (reactive oxygen specie, ROS) in blood, such as superoxide, hydrogen peroxide, hydroxyl radicals, and the like. Measurement indicators of hypoxia, ROS, and electrolyte changes in blood can be used to characterize disease severity, prognosis, and stage (stage). These blood tests can be used as markers in the algorithm, which can influence treatment decisions.

Based on the above criteria, by intravenous administration of an oxygenated liquid, the infection may potentially be treated and/or the severity of the disease may potentially be improved, and/or the progression of the disease may potentially be stopped. Reducing organ damage and correcting hypoxia and lactic acidosis may reduce the severity of the disease and/or stop viral transmission. This will provide the body with a better chance of self-healing. This is especially true under conditions where hypoxia levels may be indicative of disease severity.

Determining viral load can potentially be used as an indication of infection severity. Based on the viral load and the indices of blood gas, blood measurement and hypoxia, infections can potentially be divided into sub-categories/subunits that will then provide guidance for treatment.

The infection may be treated by direct administration of an oxygenated liquid, for example by direct administration of a liquid or a liquid-containing form, such as a gel, cream or liquid phase dispersed in a solid (e.g. biodegradable polymer). Treatment may also be performed by indirect administration of an oxygen-containing liquid, for example by direct administration of a solid or other non-liquid material that forms an oxygen-containing liquid in situ (e.g., in the tissue or organ to be treated, in the gastrointestinal tract, or in another bodily fluid). In some embodiments, the oxygenated liquid is administered by intravenous injection, or by intravenous injection of a solid or other non-liquid material that forms an oxygenated liquid in the patient after intravenous injection.

For the treatment of viral infections, the oxygenated liquid may be used alone or in combination with a vaccine. For some vaccines, oxygenation may help activate the vaccine or increase the efficacy of the vaccine.

Overall, in vivo and in vitro studies of oxygenated liquids have shown that oxygenated liquids can normalize elevated VEGF levels in hypoxic environments, can protect cells exposed to hypoxic environments, have excellent safety in vitro using 3 cell lines, and promote recovery from ischemic injury. Because of this, it is believed that administration of an oxygenated liquid can potentially reduce viral transmission and/or pathogenicity. It is also believed that the administration of an oxygenated liquid can potentially supplement the basic needs of the human body for oxygen, thereby promoting the natural mechanisms of the human body itself to heal. Blood gas measurements (potentially using an algorithm) may be used to determine the severity of the disease before oxygen is needed. Mobile blood-gas machines are available.

The oxygenated liquid may also be administered to a mammal undergoing gene therapy and may improve the outcome of gene therapy. The oxygenated liquid may also be administered to the mammal in combination with treatment of stem cells (e.g., stem cells in the eye, such as the retina, optic nerve, or other ocular structures).

An oxygenated liquid may also be administered to the mammal to improve blood oxygenation. This may be measured by percutaneous oxygen measurement, pulse oximetry or blood gas measurement.

The oxygenated liquid may also be administered to a mammal to improve vitreoretinal oxygenation, retinal oxygenation, subretinal oxygenation, or combinations thereof.

Improvement in many of the disorders described herein may be measured by optical coherence tomography (optical coherent tomography, OCT), optical coherence tomography angiography, retinal oximetry, or some other imaging technique. Administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal may also be used to improve blood oxygen levels in chronic diseases and reduce the need for blood transfusion.

Administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal suffering from a disorder associated with ischemia, hypoxia, VEGF, HIF, reactive oxygen species, or electrochemical changes (e.g., an ocular disorder associated with ischemia, hypoxia, VEGF, HIF, reactive oxygen species, or electrochemical changes) can result in enhanced ERG function of the ischemic tissue. For example, the scotopic b-wave response of an eye with ischemia may be about 0-5mV, about 5-10mV, about 10-15mV, about 15-20mV, about 20-50mV, about 50-100mV, or about 100-120mV.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal having an ocular ischemic disorder results in an increase in the scotopic b-wave response of an eye having ischemia as compared to the scotopic b-wave response of an eye having ischemia immediately prior to administration of the oxygenated liquid of at least about 20mV, at least about 30mV, at least about 40mV, at least about 50mV, at least about 60mV, at least about 70mV, at least about 80mV, at least about 90mV, at least about 100mV, or more.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal having a disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or VEGF change (e.g., an ocular disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or VEGF change) results in an increase in a scotopic b-wave response of a tissue (e.g., ocular tissue) having ischemia by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to a scotopic b-wave response of a tissue (e.g., ocular tissue) having ischemia immediately prior to administration of the oxygenated liquid.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal having a disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or a change in VEGF (e.g., an ocular disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or a change in VEGF) results in an increase in the scotopic b-wave response of tissue (e.g., ocular tissue) having ischemia such that the scotopic b-wave response is within about 50%, within about 40%, within about 30%, within about 20%, within about 10%, within about 5%, within about 3%, or within about 1% of the scotopic b-wave response of normal or non-ischemic tissue (e.g., contralateral eye).

In some embodiments, improvement in ERG function may be observed within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 7 days, within 14 days, within 21 days, within 28 days, within 2 months, within 3 months, within 4 months, within 6 months, within 1 year, or longer.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal having a disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or a change in VEGF (e.g., an ocular disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or a change in VEGF) results in an increase in visual acuity of the mammal (e.g., a human) of about 10%, about 20%, about 30%, about 50%, about 70%, about 90%, or within about 50%, about 40%, about 30%, about 20%, about 10%, about 5%, about 3%, or about 1% of the visual acuity of a normal eye (e.g., a contralateral eye).

In some embodiments, an improvement in visual acuity may be observed within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 7 days, within 14 days, within 21 days, within 28 days, within 2 months, within 3 months, within 4 months, within 6 months, within 1 year, or longer.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal having a disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or a change in VEGF (e.g., an ocular disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or a change in VEGF) results in a reduction in retinal thickness of the mammal (e.g., a human) by about 10%, about 20%, about 30%, about 50%, about 70%, about 90%, or within about 50%, about 40%, about 30%, about 20%, about 10%, about 5%, about 3%, or about 1% of the retinal thickness of a normal eye (e.g., a contralateral eye).

In some embodiments, an improvement in retinal thickness may be observed within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 7 days, within 14 days, within 21 days, within 28 days, within 2 months, within 3 months, within 4 months, within 6 months, within 1 year, or longer.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal having a disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or a change in VEGF (e.g., an ocular disorder associated with ischemia, hypoxia, HIF, electrochemical, reactive oxygen species, or a change in VEGF) results in a reduction in angiogenesis in the mammal (e.g., a human) of about 10%, about 20%, about 30%, about 50%, about 70%, about 90%, or within about 50%, about 40%, about 30%, about 20%, about 10%, about 5%, about 3%, or about 1% of the angiogenesis of a normal eye (e.g., a contralateral eye).

In some embodiments, improvement in angiogenesis may be observed within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 7 days, within 14 days, within 21 days, within 28 days, within 2 months, within 3 months, within 4 months, within 6 months, within 1 year, or longer.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., a high pressure oxygenated liquid) to a mammal having a disorder associated with ischemia, hypoxia, VEGF, HIF, a reactive oxygen species, or an electrochemical change (e.g., an ocular disorder associated with ischemia, hypoxia, VEGF, HIF, a reactive oxygen species, or an electrochemical change) results in a decrease in VEGF levels in tissue (e.g., ocular tissue) having ischemia by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or more compared to vascular endothelial growth factor (Vascular Endothelial Growth Factor, VEGF) levels in tissue (e.g., ocular tissue) having ischemia immediately prior to administration of the oxygenated liquid.

In some embodiments, administration or delivery of an oxygenated liquid (e.g., an oxygenated liquid) to a mammal having a disorder associated with ischemia, hypoxia, VEGF, HIF, reactive oxygen species, or an electrochemical change (e.g., an ocular disorder associated with ischemia, hypoxia, VEGF, HIF, reactive oxygen species, or an electrochemical change) results in a decrease in VEGF levels in tissue (e.g., ocular tissue) having ischemia such that it is within about 50%, within about 40%, within about 30%, within about 20%, within about 10%, within about 5%, within about 3%, or within about 1% of the VEGF levels in normal or non-ischemic tissue (e.g., contralateral eye).

In some embodiments, a decrease in VEGF levels in a tissue may be observed within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 7 days, within 14 days, within 21 days, within 28 days, within 2 months, within 3 months, within 4 months, within 6 months, within 1 year, or longer.

In some embodiments, administration or delivery of an oxygen-containing liquid (e.g., a high pressure oxygen-containing liquid) to a mammal having a disorder associated with ischemia, hypoxia, VEGF, HIF, a reactive oxygen species, or an electrochemical change (e.g., an ocular disorder associated with ischemia, hypoxia, VEGF, HIF, a reactive oxygen species, or an electrochemical change) results in an increase in oxygen level (PO ₂) or SO ₂ of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 50% or more as compared to the original oxygen level (PO ₂) or oxygen saturation (SO ₂). The increase from the original PO ₂ of 50 to 55 levels was a 10% increase. In some embodiments, the SO ₂ is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 50% or more based on 100% saturation. The increase from 50% to 60% is based on 100% saturation, an increase of 10%.

The following embodiments are specifically considered.

Embodiment D-1. A method of detecting an infection or detecting disease progression, the method comprising: obtaining a blood level of a chemical substance in a human in need thereof.

Embodiment D-2. The method of embodiment D-1, wherein the chemical is a gas.

Embodiment D-3. The method of embodiment D-2, wherein the gas is O ₂.

Embodiment D-4. The method of embodiment D-2 or D-3, wherein the gas is CO ₂.

Embodiment D-5. The method of embodiment D-1, D-2, D-3, or D-4, wherein the chemical is lactic acid.

Embodiment D-6. The method of embodiment D-1, D-2, D-3, D-4, or D-5 wherein the chemical is H ⁺、OH^-、H₃O⁺ or a combination thereof, as determined by blood pH.

Embodiment D-7. The method of embodiment D-1, D-2, D-3, D-4, D-5, or D-6 wherein the chemical is an electrolyte.

Embodiment D-8. The method of embodiment D-7, wherein the electrolyte is Na ⁺.

Embodiment D-9. The method of embodiment D-7 or D-8, wherein the electrolyte is K ⁺.

Embodiment D-10. The method of embodiment D-7, D-8, or D-9, wherein the electrolyte is Ca ²⁺.

Embodiment D-11. The method of embodiment D-7, D-8, D-9, or D-10 wherein the electrolyte is Mg ²⁺.

Embodiment D-12. The method of embodiment D-7, D-8, D-9, D-10, or D-11 wherein the electrolyte is HCO ₃ ^-.

Embodiment D-13 the method of embodiment D-7, D-8, D-9, D-10, D-11, or D-12 wherein the electrolyte is CO ₃ ^2-.

Embodiment D-14. The method of embodiment D-7, D-8, D-9, D-10, D-11, D-12, or D-13 wherein the electrolyte is a phosphate species.

Embodiment D-15 the method of embodiment D-7, D-8, D-9, D-10, D-11, D-12, D-13, or D-14 wherein the chemical is a reactive oxygen species.

Embodiment D-16. The method of embodiment D-15, wherein the reactive oxygen species comprises a superoxide.

Embodiment D-17 the method of embodiment D-15 or D-16, wherein the reactive oxygen species comprises hydrogen peroxide.

Embodiment D-18. The method of embodiment D-15, D-16, or D-17, wherein the reactive oxygen species comprises a hydroxyl group.

Embodiment D-19 the virus is treated by administering to the patient a therapy with a chemical substance according to embodiment D-1, D-2, D-3, D-4, D-5, D-6, D-7, D-8, D-9, D-10, D-11, D-12, D-13, D-14, D-15, D-16, D-17 or D-18 described above having a level above a threshold.

Embodiment D-20 the virus is treated by administering to the patient a therapy with a chemical substance according to embodiments D-1, D-2, D-3, D-4, D-5, D-6, D-7, D-8, D-9, D-10, D-11, D-12, D-13, D-14, D-15, D-16, D-17 or D-18 described above having a level above a threshold.

Embodiment D-21. The method of embodiment D-19 or D-20, wherein the treatment comprises administering an oxygenated liquid to the patient.

Embodiment D-22. The method of treatment according to embodiments D-1, D-2, D-3, D-4, D-5, D-6, D-7, D-8, D-9 or D-10, further comprising determining viral load in the human.

Embodiment D-23. A method of detecting a viral infection or detecting disease progression, the method comprising: determining the viral load in said human in need thereof.

Embodiment 1. A method of treating a mammal having a condition associated with ischemia, hypoxia, VEGF, HIF, reactive oxygen species, or electrochemical change, the method comprising delivering an oxygenated liquid to the mammal having the condition, wherein the treatment results in a therapeutic effect on the condition.

Embodiment 2. The method of embodiment 1, wherein the condition is ocular and the oxygenated liquid is delivered to the eye of the mammal.

Embodiment 3. The method of embodiment 1 or 2, wherein the oxygen-containing liquid has an oxygen pressure of greater than 140 mmHg.

Embodiment 4. The method of embodiment 1, 2, or 3, wherein the oxygen-containing liquid contains an oxygen-releasing compound.

Embodiment 5. The method of embodiments 1,2, 3, or 4, wherein the oxygen-containing liquid has an osmolality of about 250mOsm/L to about 350mOsm/L.

Embodiment 6. The method of embodiment 1, 2, 3,4, or 5, wherein the oxygen-containing liquid comprises a metal oxide.

Embodiment 7. The method of embodiments 1,2, 3, 4,5, or 6 wherein the oxygen-containing liquid comprises a metal hydroxide.

Embodiment 8. The method of embodiments 1,2, 3, 4, 5, 6, or 7 wherein the oxygen-containing liquid comprises a peroxide.

Embodiment 9. The method of embodiments 1, 2, 3,4, 5, 6, or 8 wherein the oxygen-containing liquid is sterile.

Embodiment 10. The method of embodiments 1,2, 3, 4, 5,6,7,8, or 9 wherein the treatment results in an improvement in ERG function within 1 week of administering the oxygenated liquid to the eye of the mammal.

Embodiment 11. The method of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the treatment results in reduced VEGF expression within 1 week after administration of the oxygenated liquid to the eye of the mammal.

Embodiment 12. The method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 wherein the disorder is diabetic retinopathy.

Embodiment 13. The method of embodiment 1,2, 3,4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is macular degeneration.

Embodiment 14. The method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the disorder is diabetic macular edema.

Embodiment 15. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 wherein the disorder is a sickle cell eye disease.

Embodiment 16. The method of embodiment 1,2, 3,4, 5, 6, 7, 8, 9, 10, or 11, wherein the disorder is ocular inflammation.

Embodiment 17. The method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the disorder is hypertensive retinopathy.

Embodiment 18. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 wherein the disorder is ocular ischemic syndrome.

Embodiment 19. The method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the disorder is a branch retinal vein occlusion.

Embodiment 20. The method of embodiment 1,2, 3,4, 5,6, 7, 8, 9, 10, or 11 wherein the condition is a branch retinal artery occlusion.

Embodiment 21. The method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 wherein the condition is central retinal vein occlusion.

Embodiment 22. The method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 wherein the condition is central retinal artery occlusion.

Embodiment 23. The method of embodiment 1,2, 3, 4, 5,6, 7, 8, 9, 10, or 11, wherein the condition is retinal detachment.

Embodiment 24. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is an eye penetrating injury.

Embodiment 25. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 wherein the condition is traumatic optic neuropathy.

Embodiment 26. The method of embodiment 1,2, 3,4, 5, 6, 7, 8, 9, 10, or 11, wherein the disorder is optic neuritis.

Embodiment 27. The method of embodiment 1,2,3, 4, 5,6, 7, 8, 9, 10, or 11, wherein the disorder is an inflammatory ocular disorder.

Embodiment 28. The method of embodiments 1, 2,3, 4,5, 6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 wherein the oxygenated liquid is injected into the eye of a human.

Embodiment 29. The method of embodiments 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 wherein the oxygen-containing liquid is topically applied to a human.

Embodiment 30. The method of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 wherein the oxygen-containing liquid is orally administered to a human.

Example 1

The effect of the hyperbaric oxygen solution on ischemic rabbit eyes was evaluated. Ischemia was induced in six rabbits as follows. The needle is connected to a saline bag which is raised to create a pressure at the needle opening. The needle was placed into the rabbit eye and the intraocular pressure of the rabbit eye was allowed to rise for 90 minutes, which resulted in ischemia of the rabbit eye. Rabbit 1 initially received no treatment, but received intraocular injection of hyperbaric oxygen solution one hour after removal of the needle attached to the saline bag. Rabbits 2 to 3 were intraocular injected with physiological saline (oxygen pressure 112.6 mmHg) 20 minutes after removing the needle attached to the saline bag. Rabbits 4 to 6 were injected with a high pressure oxygen solution (oxygen pressure 175.2 mmHg) in the eyes 20 minutes after removing the needle attached to the saline bag. The results are depicted in table 1 and fig. 1.

TABLE 1

Example 2

ARPE-19 cells were treated with a high pressure oxygen solution (oxygen pressure 175.2 mmHg) and placed in an anoxic chamber for 48 hours. Control cells were incubated in an anoxic chamber without the hyperbaric oxygen solution. The phase contrast image shows that hypoxic ARPE-19 cells are rounded and exhibit an abnormal morphology compared to hypoxic cells treated with hyperbaric oxygen. There were 71 circular cells per high power field in control hypoxic cells, as compared to 8 circular cells per high power field in hypoxic cells treated with high pressure oxygen solution. It was concluded that the hyperbaric oxygen solution was shown to protect cells from typical damage caused by exposure to hypoxia.

Example 3

Retinal pigment epithelial cells were exposed to hypoxic conditions for 48 hours. Treatment with hyperbaric oxygen solution (oxygen pressure 175.2 mmHg) resulted in statistically significant reduction in cellular levels of expressed Vascular Endothelial Growth Factor (VEGF) p < 0.05 (fig. 2) and HIF (fig. 3).

As shown in fig. 2, the VEGF level of cells that had been exposed to hypoxic conditions (17.5 POI + hypoxia) with the added 17.5% oxygenation component was lower than the HIF level of untreated cells exposed to hypoxic conditions (untreated hypoxia, UH) and comparable to those that had not been exposed to hypoxic conditions (untreated normoxic).

HIF levels were analyzed by western blot analysis (Western blot analyses). Proteins were extracted from cell cultures and protein concentrations were measured using BCA protein assay kit (Pierce, rockford, IL) according to the manufacturer's protocol.

As shown in FIG. 3, the HIF level of cells exposed to hypoxic conditions (12.5POI+H) with 12.5% of the added oxygenation component was lower than that of untreated cells exposed to hypoxic conditions (UH). In addition, HIF levels were even lower in cells exposed to hypoxic conditions (17.5poi+h) with 17.5% of the oxygenation component added.

These results indicate that treatment with high pressure oxygen solution normalizes VEGF and HIF levels in cells exposed to hypoxic conditions, such that they are similar to basal levels of VEGF and HIF.

Improved blood oxygenation

Example 4

The partial pressure of the oxygen-containing solution was confirmed using a standardized blood gas machine. PO ₂ for the oxygen-containing solution was 182mmHg.

Plasma was taken from a single donor. Oxygen levels in plasma were measured on a standardized blood-gas machine. Plasma was treated with a solution containing oxygen levels measured at 182mmHg (solution = 182mmHg O ₂). Immediately after treatment with the oxygen-containing solution, O ₂ mmHg was measured using a standardized blood gas machine. Measurements were taken ten minutes after administration of the oxygenated solution.

Table 2: plasma oxygen levels

Annotation: the improved average time was observed to be within a few seconds. The greatest change (27.4 mmHg was observed within 10 minutes after application of the solution).

Conclusion: after treatment with the measured oxygen partial pressure increasing solution, the oxygen partial pressure in the single donor plasma increases.

Example 5

Whole venous blood samples were obtained from a single donor. Carbon dioxide levels (pCO ₂), oxygen levels (PO ₂) and oxygen saturation (SO ₂) of whole venous blood were measured on a standardized blood-gas machine. Whole venous blood was treated with a solution containing an oxygen level measured at 182mmHg (solution = 182mmHg O ₂). Immediately after treatment with the oxygen-containing solution, pCO ₂、PO₂、SO₂ was measured using a standardized blood gas machine. Measurements were made ten minutes and 20 minutes after application of the oxygenated solution. At 105 minutes after the first treatment, another treatment with an oxygen-containing solution was added to the whole blood and additional measurements were made. The results are depicted in table 3.

Table 3: oxygen level in whole blood

Conclusion: after treatment of whole venous blood of a single donor with an oxygen-containing solution with PO ₂, the following was observed:

1. The carbon dioxide (pCO ₂) after the treatment was decreased.

2. The oxygen level (PO ₂) after treatment increased.

3. The saturation (SO ₂) after treatment increases.

TABLE 5

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Claims (18)

1. A composition comprising nanoparticles or microparticles, wherein the nanoparticles or microparticles contain an oxygen-containing liquid.

2. The composition of claim 1, wherein the nanoparticle or microparticle comprises poly (lactic-co-glycolic acid).

3. The composition according to claim 1 or 2 for use in the treatment of a condition associated with ischemia or hypoxia.

4. A method of treating a disorder associated with ischemia or hypoxia, the method comprising administering to a human in need thereof the composition of claim 1 or 2, wherein the nanoparticle or microparticle comprises an oxygenated liquid.

5. The method of claim 4, wherein the oxygenated liquid is administered directly to the central nervous system of the human.

6. The method of claim 4, wherein the oxygenated liquid is administered directly to the brain of the human.

7. The method of claim 4, wherein the oxygenated liquid is administered directly to the eye of the human.

8. The method of claim 4, wherein the oxygenated liquid is administered directly to the human cardiopulmonary system.

9. The method of claim 4, wherein the oxygenated liquid is administered directly to the heart of the human.

10. The method of claim 4, wherein the oxygenated liquid is administered directly to the lungs of the human.

11. The method of claim 4, wherein the oxygenated liquid is administered directly to the liver of the human.

12. The method of claim 4, wherein the oxygenated liquid is administered directly to the human kidney.

13. The method of claim 4, wherein the oxygenated liquid is administered directly to the musculoskeletal system of the human.

14. The method of claim 4, wherein the oxygenated liquid is administered directly to the muscles of the human.

15. The method of claim 4, wherein the oxygenated liquid is administered directly to the endocrine system of the human.

16. The method of claim 4, wherein the oxygenated liquid is administered directly to the human pancreas.

17. The method of claim 4, wherein the oxygenated liquid is administered directly to the gastrointestinal system of the human.

18. Use of a composition according to claim 1 or 2 in the manufacture of a medicament for the treatment of a condition associated with ischemia or hypoxia.