Treatment of ischemic conditions, hypoxic conditions, conditions related to hypoxia-induction factor, or conditions related to reactive oxygen species with oxygen-containing liquids

Abstract

To provide an effective method for treating ischemia, hypoxia, and other related conditions.SOLUTION: There is provided a method of treating a condition related to ischemia, hypoxia, a hypoxia-induction factor, or reactive oxygen species, the method comprising delivering an oxygen-containing liquid to a mammal suffering from the condition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 16 / 727,764, filed December 26, 2019, which is a continuation-in-part of U.S. Patent Application No. 16 / 371,398 (now U.S. Patent No. 6,227,764), filed April 1, 2019. Both of these prior applications are incorporated herein by reference in their entireties. [Background technology]

[0002] There is a continuing need for effective methods of treating ischemic conditions and other conditions associated with hypoxia. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] U.S. Patent No. 10,561,682 [Patent Document 2] U.S. Patent No. 8,802,049 [Non-patent literature]

[0004] [Non-Patent Document 1] Remington's Pharmacology, 16th ed., E. W. Martin (Mack Publishing, Easton, PA, 1980) Summary of the Invention [Means for solving the problem]

[0005] The present disclosure relates to the use of oxygen-containing liquids to treat conditions associated with ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species alterations, cancer, and other conditions.

[0006] Some embodiments include a method of treating an ocular condition comprising administering or delivering an oxygen-containing liquid to the eye of a mammal suffering from the ocular condition. [Brief explanation of the drawings]

[0007] [Figure 1] Scotopic b-wave response in the eyes of ischemic rabbits treated with hyperbaric oxygen solution compared with controls. [Figure 2] VEGF levels in retinal pigment epithelial (RPE) cells exposed to hypoxia and treated with hyperbaric oxygen solution. [Figure 3] HIF levels in RPE cells exposed to hypoxia and treated with hyperbaric oxygen solution. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present disclosure relates to a method of treating an ischemic condition, such as an ocular ischemic condition, other condition associated with hypoxia, or condition associated with reactive oxygen species, comprising administering or delivering an oxygen-containing liquid to a mammal, such as a human, for said treatment of the condition.

[0009] The terms "treat" or "treatment" broadly include any type of therapeutic activity, including the diagnosis, cure, mitigation, or prevention of disease in humans or other animals, or any activity that otherwise affects the structure or any function of the body of a human or other animal.

[0010] The oxygen-containing liquid may be any liquid composition containing oxygen or a compound that provides oxygen tension to a liquid and is suitable for therapeutic use in mammals, including humans. The oxygen-containing liquid may be aqueous, based on a suitable organic solvent, or 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, etc. For many routes of administration, such as injection, it may be important that the oxygen-containing liquid be sterile.

[0011] In some embodiments, rather than being administered directly, the oxygen-containing liquid can be generated within the target tissue by inserting an implant or drug delivery device into or near the target tissue, which can provide long-term delivery of the oxygen-containing liquid. For example, the implant can include a biodegradable or bioerodible polymer with components of the oxygenated composition dispersed within the polymer. As the polymer degrades or erodes, the components of the oxygenated composition mix in the aqueous environment of the tissue into which the implant is inserted, and an oxygen-containing liquid is generated at or near the target tissue. The implant or device can be administered by any of the routes described above, including intravenously (e.g., by injection), intravitreally (e.g., by injection), or subretinal (e.g., by injection). The oxygen-containing liquid can also be generated by other types of solid devices, such as punctal plugs and contact lenses, that contain components of the oxygenated composition and gradually diffuse from the device. Alternatively, the punctal plugs or contact lenses can be biodegradable or bioerodible.

[0012] The oxygen-containing liquid may have a higher oxygen partial pressure than plain water, for example, at room temperature (e.g., 23°C) or body temperature (e.g., 37°C), and the oxygen-containing liquid may have an oxygen tension, i.e., at least 120 mmHg, at least 140 mmHg, at least 145 mmHg, at least 150 mmHg, at least 155 mmHg, at least 160 mmHg, at least 165 mmHg, at least 170 mmHg, up to 180 mmHg, up to 200 mmHg, up to about 250 mmHg, up to about 300 mmHg, up to about 350 mmHg, up to about 400 mmHg, up to about 4 50mmHg, maximum approximately 500mmHg, approximately 120-500mmHg, approximately 20-40mmHg, approximately 40-60mmHg, approximately 60-80mmHg, approximately 80-100mmHg, approximately 100-120mmHg, approximately 120-140mmHg, approximately 140-145mmHg, approximately 145-150mmHg, approximately 150-155mmHg, approximately 155-160mmHg, approximately 160-165mmHg, approximately 165-170mmHg, approximately 170-175mmHg, approximately 175-180mmHg, approximately 140-150mmHg, approximately 150-160mmHg, approximately 160-170mmHg, approximately 17 0-180mmHg, 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 260-270mm Hg, about 270-280mmHg, about 280-290mmHg, about 290-300mmHg, about 300-320mmHg, about 320-340mmHg, about 340-360mmHg, about 360-380mmHg, about 380-400mmHg, about 400-420mmHg, about 420 -440mmHg, approximately 440-460mmHg, approximately 460-480mmHg, approximately 480-500mmHg, approximately 140-160mmHg, approximately 160-180mmHg, approximately 180-200mmHg, approximately 160-200mmHg, approximately 200-250mmHg, approximately 250-300mmHg, approximately 300-350mmHg, approximately 350-400mmHg, approximately 400-450mmHg, approximately 450-500mmHg, approximately 140-200mmHg, approximately 200-300mmHg, approximately 300-400mmHg, approximately 400-500mmHg, 500-750mmHg, 750-1,The oxygen pressure may be 1,000 mmHg, 1,000-1,250 mmHg, 1,250-1,500 mmHg, about 175 mmHg, or any pressure within a range bounded by any of these values. In some embodiments, the oxygen-containing liquid is a hyperbaric oxygen solution (e.g., Examples 1-3 below).

[0013] While there are many ways to add oxygen to a liquid, some oxygen-containing liquids may contain an oxygenated composition, such as a compound or combination of compounds, that releases oxygen gas, for example, by chemical reaction or chemical decomposition. Suitable oxygenated compositions may include metal oxides (e.g., CaO, MgO), metal hydroxides (e.g., Ca(OH)2, Mg(OH)2), peroxides (e.g., hydrogen peroxide or organic peroxides), or combinations thereof. Other components may be added to increase or decrease the rate of oxygen release, depending on specific needs. For example, faster oxygen release may result in higher oxygen tension. On the other hand, slower oxygen release may result in longer, more consistent, or more sustained oxygen tension. Examples of suitable oxygenated compositions are described in U.S. Patent No. 6,249,999, which is incorporated herein by reference in its entirety. One useful oxygenated composition comprises about 20-30% Ca(OH), about 10-15% HO, about 0.5-5% sodium acetate, about 0.5-5% KHPO, and about 1-20% carrageenan, based on the total weight of the oxygen-containing liquid. In some embodiments, the total amount of oxygen atoms present in all metal oxides, hydroxides, and peroxides present in the oxygen-containing liquid is about 20-70%, about 20-50%, about 50-70%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-90%, or about 80-95% of the total weight of the oxygen-containing liquid.

[0014] As noted above, components of these oxygenated compositions, such as metal oxides, metal hydroxides, and / or peroxides, can be dispersed in bioerodible or biodegradable polymers such as silicone-based polymers, polyesters, polyorthoesters, polyphosphoesters, polycarbonates, polyanhydrides, polyphosphazenes, polyoxalates, poly(amino acids), polyhydroxyalkanoates, polyethylene glycols, polyvinyl acetates, polyhydroxy acids, polyanhydrides, or copolymers or blends thereof (e.g., copolymers of lactic acid and glycolic acid).

[0015] The oxygen-containing liquid may be formulated for any desired route of delivery, including, but not limited to, parenteral, suppository, intravenous, intradermal (e.g., intradermal injection), subcutaneous, oral, inhalation, transdermal, topical to the eye (e.g., eye drops for delivery to the anterior of the eye or eye drops for delivery to the posterior of the eye), or topical to the skin, transmucosal, rectal, intravaginal, intraperitoneal, intramuscular, intralesional, intranasal, subcutaneous (e.g., subcutaneous injection), buccal, intraocular injection, intravitreal injection, subretinal injection, intrathecal injection (e.g., direct injection into the heart), etc. The term "injection" includes injection of a pharmaceutical composition, insertion of an implant or drug delivery device, as well as other types of injections.

[0016] Suitable additives for use in oxygen-containing liquids may include, for example, one or more carriers, binders, fillers, vehicles, isotonicity agents, buffers, disintegrants, surfactants, dispersing or suspending aids, thickening or emulsifying agents, preservatives, lubricants, etc., or combinations thereof, tailored to the particular dosage form desired. Non-Patent Document 1 discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. This document is incorporated herein by reference in its entirety.

[0017] In addition to the solvent, oxygen, and / or oxygenated composition, liquid dosage forms for IV injection (e.g., intraocular, subretinal, intrathecal, direct injection into the heart), topical (e.g., to the eye), or oral administration to mammals, including humans, may contain bulking agents (e.g., mannitol, lactose, sucrose, trehalose, sorbitol, glucose, raffinose, glycine, histidine, polyvinylpyrrolidone, etc.), tonicity agents (e.g., dextrose, glycerin, mannitol, sodium chloride, etc.), buffers (e.g., acetic acid, e.g., acetic acid, Preservatives (e.g., phenol, m-cresol, parabens such as methylparaben, propylparaben, butylparaben, myristyl gamma-picolinium chloride, benzalkonium chloride, etc.), preservatives (e.g., 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, etc.), preservatives (e.g., phenol, m-cresol, parabens such as methylparaben, propylparaben, butylparaben, myristyl gamma-picolinium chloride, benzalkonium chloride, etc.), preservatives (e.g., phenol, m-cresol, parabens such as methylparaben, propylparaben, butylparaben ... Benzethonium chloride, benzyl alcohol, 2-phenoxyethanol, chlorobutanol, thimerosal, phenylmercury salts, etc.), surfactants (e.g., polyoxyethylene sorbitan monooleate or Tween 80, sorbitan monooleate polyoxyethylene sorbitan monolaurate or Tween 20, lecithin, polyoxyethylene-polyoxypropylene copolymers, etc.), solvents (e.g., propylene glycol, glycerin, ethanol, polyethylene glycol, sorbitan The composition may contain additives such as ethanol, dimethylacetamide, Cremophor EL, benzyl benzoate, castor oil, cottonseed oil, N-methyl-2-pyrrolidone, PEG, PEG300, PEG400, PEG600, PEG600, PEG3350, PEG400, poppy seed oil, propylene glycol, safflower oil, vegetable oil, etc.), chelating agents (calcium disodium EDTA, disodium EDTA, sodium EDTA, calcium versetamide sodium, cartelidol, DTPA, etc.), or other additives.

[0018] Liquid dosage forms comprising oxygen-containing liquids for IV injection (e.g., intraocular injection, subretinal injection, etc.), topical (e.g., to the eye), or oral administration to mammals, including humans, can have any suitable pH, such as, for example, 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, etc., or any pH within a range bounded by any of these values.

[0019] For many routes of administration, the formulation may be hypertonic or hyperosmolar, e.g., having a tonicity or osmolality greater than about 290 mOsm / L (e.g., about 290-600 mOsm / L, about 290-400 mOsm / L, about 400-500 mOsm / L, or about 500-600 mOsm / L), or isotonic or iso-osmolar, e.g., having a tonicity or osmolality that approximates the tonicity or osmolality of the body tissue to which it is administered (e.g., about 290 mOsm / L, about 250-350 mOsm / L, about 300-400 mOsm / L, about 400-500 mOsm / L, or about 500-600 mOsm / L). It may be useful for the oxygen-containing fluid to be hypotonic or hypoosmolar, e.g., have a tonicity or osmolality of less than about 290 mOsm / L (e.g., about 150-290 mOsm / L, about 150-200 mOsm / L, about 200-290 mOsm / L, about 200-250 mOsm / L, or about 250-290 mOsm / L).

[0020] The oxygen-containing liquid can also potentially be delivered in a nanoparticle, nanoemulsion, microemulsion, microsome, liposome, or lysosomal delivery system. For example, the oxygen-containing liquid can be contained within a reverse micelle, or within a nanoparticle, nanoemulsion, microemulsion, microsome, liposome, or lysosome.

[0021] In addition to the above, it may be desirable for orally administered liquids to contain sweeteners such as sucrose or saccharin, or flavoring agents such as peppermint, methyl salicylate, orange flavoring, and the like.

[0022] For creams, gels, ointments and the like, it may be desirable to include thickening agents such as polyethylene glycol, polyacrylic acid, cetyl alcohol, stearyl alcohol, carnauba wax, stearic acid, hydroxyethylcellulose, guar gum, locust bean gum, xanthan gum, gelatin, silica, bentonite, aluminum magnesium stearate and the like.

[0023] The liquid dosage form containing the oxygen-containing liquid can be part of a pharmaceutical product, which includes the oxygen-containing liquid, an oxygen sensor, and a drug-dispensing device. In some embodiments, the oxygen-containing liquid can be dispensed only if the oxygen-containing liquid has a desired oxygen tension, such as the oxygen tensions described above.

[0024] While any suitable oxygen sensor can be used, the High Performance Microsensor available from Unisense is an example of a useful oxygen sensor.

[0025] Any suitable drug dispensing device may be used, such as a syringe or other form of injection device, a droplet dispensing device, or the like.

[0026] Hypoxia, ischemia, and reactive metabolites contribute to the development and progression of many diseases. A common denominator that leads to the inhibition of tissue repair is tissue hypoxia.

[0027] Enhanced delivery of oxygen to tissues can provide adjunctive and direct treatment in a wide variety of disease states.

[0028] Tissue hypoxia is low tissue oxygen levels and is usually associated with circulatory disorders. Tissue hypoxia, ischemic and reactive metabolic products contribute to the development and exacerbation of many diseases.

[0029] In some embodiments, administration or delivery of an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with alterations in ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species, such as an ocular condition associated with alterations in ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species, results in a decrease in hypoxia-inducible factor (HIF) levels in the ischemic tissue (e.g., ocular tissue) 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 even more, compared to the HIF levels in the ischemic tissue (e.g., ocular tissue) immediately prior to administration of the oxygen-containing fluid.

[0030] In some embodiments, administering or delivering an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with alterations in ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species, such as an ocular condition associated with alterations in ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species, results in a reduction in HIF levels in the ischemic tissue (e.g., ocular tissue) to 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 HIF levels in the non-ischemic tissue (e.g., the contralateral eye).

[0031] In some embodiments, a decrease in tissue HIF levels may be observed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 2 months, 3 months, 4 months, 6 months, 1 year, or longer.

[0032] In some embodiments, the reduction in tissue HIF levels 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.

[0033] The administration or delivery of oxygen-containing fluids, such as hyperbaric oxygen-containing fluids, to mammals can be used to treat any type of ischemic condition, such as wounds, vascular disorders, malignancies, arthritis, atherosclerotic plaque, cancer, tumors, burns, inflammatory conditions including inflammation of neural tissue (e.g., concussion), and the like.

[0034] In some embodiments, the ischemic condition is an ocular condition such as diabetic retinopathy, macular degeneration, macular edema, diabetic macular edema, glaucoma, sickle eye disease, ocular inflammation, hypertensive retinopathy, ocular ischemic syndrome, branch retinal vein occlusion, branch retinal artery occlusion, central retinal vein occlusion, central retinal artery occlusion, retinal detachment, penetrating ocular injury, traumatic optic neuropathy, optic neuritis, inflammatory ocular conditions, etc. In some embodiments, the ocular ischemic condition is diabetic retinopathy.

[0035] 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 sickle cell ophthalmopathy. In some embodiments, the ocular ischemic condition is ocular inflammation. In some embodiments, the condition is hypertensive retinopathy. In some embodiments, the condition is ocular ischemic syndrome. In some embodiments, the condition is retinal vein occlusion. In some embodiments, the condition is an arterial occlusion, such as of the retina. In some embodiments, the condition is branch retinal vein occlusion. In some embodiments, the condition is branch retinal artery occlusion. In some embodiments, the symptom is central retinal vein occlusion. In some embodiments, the symptom is central retinal artery occlusion. In some embodiments, the symptom is retinal detachment. In some embodiments, the symptom is penetrating ocular injury. In some embodiments, the symptom is traumatic optic neuropathy. In some embodiments, the symptom is optic neuritis. In some embodiments, the symptom is an inflammatory ocular condition.

[0036] In some embodiments, the ischemic condition is one in which electrochemistry is altered, such as, for example, heart attack, stroke, neuronal ischemia, central nervous system injury, traumatic brain injury, spinal cord injury, acute and chronic traumatic encephalopathy, immune cytotoxicity, etc. The administration or delivery of oxygen-containing fluids, such as hyperbaric oxygen-containing fluids, may also be useful in treating diseases or conditions related to or caused by sun damage or oxidation.

[0037] In some embodiments, oxygen-containing liquids can be used for the treatment of cancer. For example, oxygen-containing liquids can be administered in combination with chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, and mitotic inhibitors. In some embodiments, co-administration of the chemotherapeutic agent with the oxygen-containing agent can help improve the activity of the chemotherapeutic agent. In some embodiments, the chemotherapeutic agent can be administered in an aqueous solution, for example, intravenously or injected at the site of the cancer. Oxygen-containing liquids may also have other therapeutic effects for the treatment of cancer.

[0038] Other conditions that can be treated with oxygen-containing fluids include anemia, migraines, osteomyelitis, coronavirus infections (such as SARS-CoV-2, which causes COVID-19), viral infections, and bacterial infections.

[0039] The oxygen-containing liquid may also be administered to a mammal undergoing gene therapy and may improve the outcome of the gene therapy. The oxygen-containing liquid may also be administered to a mammal in conjunction with stem cell therapy, such as stem cells of the eye, e.g., the retina, optic nerve, or other ocular structures.

[0040] Oxygen-containing liquids may also be administered to mammals to improve blood oxygenation, which may be measured by transcutaneous oximetry, pulse oximetry, or blood gas measurements.

[0041] Oxygen-containing fluids can also be administered to mammals to improve vitreoretinal oxygenation, retinal oxygenation, subretinal oxygenation, or a combination thereof.

[0042] Improvement in many of the conditions described herein may be measured by optical coherence tomography (OCT), optical coherence tomography angiography, angiography, retinal oximetry, or some other imaging technique. Administering or delivering oxygen-containing fluids, such as hyperbaric oxygen-containing fluids, to mammals may also be used to improve blood oxygen levels and reduce the need for blood transfusions in chronic conditions.

[0043] Administration or delivery of an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with ischemia, hypoxia, alterations in electrochemistry, VEGF, HIF, or reactive oxygen species, such as an ocular condition associated with ischemia, hypoxia, alterations in electrochemistry, VEGF, HIF, or reactive oxygen species, can result in an increase in ERG function of the ischemic tissue. For example, the scotopic b-wave response of the ischemic eye can be about 0-5 mV, about 5-10 mV, about 10-15 mV, about 15-20 mV, about 20-50 mV, about 50-100 mV, or about 100-120 mV.

[0044] In some embodiments, administration or delivery of an oxygen-containing liquid, such as a hyperbaric oxygen-containing liquid, to a mammal suffering from an ocular ischemic condition results in an increase in the scotopic b-wave response of the ischemic eye by at least about 20 mV, at least about 30 mV, at least about 40 mV, at least about 50 mV, at least about 60 mV, at least about 70 mV, at least about 80 mV, at least about 90 mV, at least about 100 mV, or even more, compared to the scotopic b-wave response of the ischemic eye immediately prior to administration of the oxygen-containing liquid.

[0045] In some embodiments, administering or delivering an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, such as an ocular condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, results in an increase in the scotopic b-wave response of the ischemic tissue (e.g., ocular tissue) of at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or even more, compared to the scotopic b-wave response of the ischemic tissue (e.g., ocular tissue) immediately prior to administration of the oxygen-containing fluid.

[0046] In some embodiments, administering or delivering an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, such as an ocular condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, results in a reduction in the scotopic b-wave response of the ischemic tissue (e.g., ocular tissue) to 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., the contralateral eye).

[0047] In some embodiments, improvement in ERG function may be observed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 2 months, 3 months, 4 months, 6 months, 1 year, or longer.

[0048] In some embodiments, administering or delivering an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, such as an ocular condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, results in an increase in the visual acuity of the mammal (e.g., a human) by about 10%, about 20%, about 30%, about 50%, about 70%, about 90%, or to within about 50%, about 40%, about 30%, about 20%, about 10%, about 5%, about 3%, or about 1% of the visual acuity of the normal eye (e.g., the contralateral eye).

[0049] In some embodiments, improved vision may be observed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 2 months, 3 months, 4 months, 6 months, 1 year, or longer.

[0050] In some embodiments, administering or delivering an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, such as an ocular condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, results in a reduction in the retinal thickness of the mammal (e.g., a human) by about 10%, about 20%, about 30%, about 50%, about 70%, about 90%, or to 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., the contralateral eye).

[0051] In some embodiments, improvements in retinal thickness may be observed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 2 months, 3 months, 4 months, 6 months, 1 year or longer.

[0052] In some embodiments, administering or delivering an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, such as an ocular condition associated with ischemia, hypoxia, alterations in VEGF, HIF, electrochemistry, or reactive oxygen species, results in a reduction in neovascularization in the mammal (e.g., a human) by about 10%, about 20%, about 30%, about 50%, about 70%, about 90%, or to within about 50%, about 40%, about 30%, about 20%, about 10%, about 5%, about 3%, or about 1% of the neovascularization in a normal eye (e.g., the contralateral eye).

[0053] In some embodiments, improvement in neovascularization may be observed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 2 months, 3 months, 4 months, 6 months, 1 year, or longer.

[0054] In some embodiments, administering or delivering an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with alterations in ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species, such as an ocular condition associated with alterations in ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species, results in a reduction in vascular endothelial growth factor (VEGF) levels in the ischemic tissue (e.g., ocular tissue) 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 even more, compared to the VEGF levels in the ischemic eye (e.g., ocular tissue) immediately prior to administration of the oxygen-containing fluid.

[0055] In some embodiments, administering or delivering an oxygen-containing fluid, such as a hyperbaric oxygen-containing fluid, to a mammal suffering from a condition associated with ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species alterations, such as an ocular condition associated with ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species alterations, results in a reduction in VEGF levels in the ischemic tissue (e.g., ocular tissue) to 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., the contralateral eye).

[0056] In some embodiments, a decrease in tissue VEGF levels may be observed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 2 months, 3 months, 4 months, 6 months, 1 year, or longer.

[0057] The following embodiments are specifically considered.

[0058] Embodiment 1. A method of treating a mammal suffering from a condition associated with ischemia, hypoxia, electrochemistry, VEGF, HIF, or reactive oxygen species alterations, comprising delivering an oxygen-containing fluid to said mammal suffering from said condition, wherein said treatment produces a therapeutic effect on said condition.

[0059] Embodiment 2. The method of embodiment 1, wherein the condition is ocular and the oxygen-containing liquid is delivered to the eye of the mammal.

[0060] Embodiment 3. The method of embodiment 1 or 2, wherein the oxygen-containing liquid has an oxygen tension greater than 140 mmHg.

[0061] Embodiment 4. The method of embodiment 1, 2, or 3, wherein the oxygen-containing liquid comprises a compound that releases oxygen gas.

[0062] Embodiment 5. The method of embodiment 1, 2, 3, or 4, wherein the oxygen-containing liquid has an osmolality of about 250 mOsm / L to about 350 mOsm / L.

[0063] Embodiment 6. The method of embodiment 1, 2, 3, 4, or 5, wherein the oxygen-containing liquid comprises a metal oxide.

[0064] Embodiment 7. The method of embodiment 1, 2, 3, 4, 5, or 6, wherein the oxygen-containing liquid comprises a metal hydroxide.

[0065] Embodiment 8. The method of embodiment 1, 2, 3, 4, 5, 6, or 7, wherein the oxygen-containing liquid comprises a peroxide.

[0066] Embodiment 9. The method of embodiment 1, 2, 3, 4, 5, 6, or 8, wherein the oxygen-containing liquid is sterile.

[0067] Embodiment 10. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein said treatment results in improvement of ERG function within 1 week of administering said oxygen-containing liquid to said eye of said mammal.

[0068] Embodiment 11. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein said treatment results in a decrease in VEGF expression within 1 week of administering said oxygen-containing liquid to said eye of said mammal.

[0069] Embodiment 12. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is diabetic retinopathy.

[0070] Embodiment 13 The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is macular degeneration.

[0071] Embodiment 14. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is diabetic macular edema.

[0072] Embodiment 15. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is sickle cell ophthalmopathy.

[0073] Embodiment 16 The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the symptom is ocular inflammation.

[0074] Embodiment 17. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is hypertensive retinopathy.

[0075] Embodiment 18. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is ocular ischemic syndrome.

[0076] Embodiment 19. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is branch retinal vein occlusion.

[0077] Embodiment 20. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is branch retinal artery occlusion.

[0078] 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.

[0079] 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.

[0080] Embodiment 23. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is retinal detachment.

[0081] Embodiment 24. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is penetrating ocular injury.

[0082] 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.

[0083] Embodiment 26. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is optic neuritis.

[0084] Embodiment 27. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, wherein the condition is inflammatory ophthalmopathy.

[0085] Embodiment 28. The method of embodiment 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 infused into a human eye.

[0086] Embodiment 29. The method of embodiment 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 administered topically to a human.

[0087] Embodiment 30. The method of embodiment 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 administered orally to a human.

[0088] Example 1 The effects of hyperbaric oxygen solution on ischemic rabbit eyes were evaluated. Ischemia was induced in six rabbits as follows: A needle was connected to a saline bag, which was elevated to create pressure at the needle opening. The needle was inserted into the rabbit's eye, and intraocular pressure was elevated for 90 minutes, resulting in ischemia in the rabbit's eye. Rabbit 1 was initially untreated, but an intraocular injection of hyperbaric oxygen solution was administered 1 hour after the needle attached to the saline bag was removed. Rabbits 2 and 3 were intraocularly injected with normal saline (oxygen pressure 112.6 mmHg) 20 minutes after the needle attached to the saline bag was removed. Rabbits 4 and 6 were intraocularly injected with hyperbaric oxygen solution (oxygen pressure 175.2 mmHg) 20 minutes after the needle attached to the saline bag was removed. The results are shown in Table 1 and Figure 1.

[0089] [Table 1]

[0090] Example 2 ARPE-19 cells were treated with hyperbaric oxygen solution (oxygen tension 175.2 mmHg) and placed in a hypoxic chamber for 48 hours. Control cells were cultured in the hypoxic chamber without the hyperbaric oxygen solution. Phase-contrast microscopy images show that hypoxic ARPE-19 cells became rounded and exhibited abnormal morphology compared with hyperbaric oxygen-treated hypoxic cells. Control hypoxic cells had 71 rounded cells per high-power field, whereas hypoxic cells treated with hyperbaric oxygen solution had 8 rounded cells per high-power field. It was concluded that hyperbaric oxygen solution appears to protect cells from the typical damage resulting from exposure to hypoxia.

[0091] Example 3 Retinal pigment epithelial cells were exposed to hypoxia for 48 hours. Treatment with hyperbaric oxygen (175.2 mmHg oxygen tension) resulted in a statistically significant decrease in the cellular levels of expressed vascular endothelial growth factor (VEGF) p<0.05 (Figure 2) and HIF (Figure 3).

[0092] As shown in Figure 2, with the addition of 17.5% oxygenated components, VEGF levels in cells exposed to hypoxia (17.5 POI + hypoxia) were lower than HIF levels in cells exposed to hypoxia without treatment (untreated hypoxia) and were comparable to cells not exposed to hypoxia (untreated normoxic).

[0093] HIF levels were analyzed by Western blot analysis. Proteins were extracted from cell cultures, and protein concentrations were measured with a BCA protein assay reagent kit (Pierce, Rockford, IL) according to the manufacturer's protocol.

[0094] As shown in Figure 3, the addition of 12.5% ​​oxygenated components resulted in lower HIF levels in cells exposed to hypoxia (12.5POI+H) than in cells exposed to hypoxia without treatment (UH). Furthermore, the addition of 17.5% oxygenated components further reduced HIF levels in cells exposed to hypoxia (17.5POI+H).

[0095] These results indicate that treatment with hyperbaric oxygen solution normalizes VEGF and HIF levels in cells exposed to hypoxia, returning them to basal levels.

[0096] (Addendum) (Appendix 1) A method for treating a condition associated with ischemia, hypoxia, hypoxia-inducing factors, or reactive oxygen species, comprising delivering an oxygen-containing fluid to a mammal suffering from said condition.

[0097] (Appendix 2) 2. The method of claim 1, wherein the pathology is ocular and the oxygen-containing liquid is delivered to the mammal's eye.

[0098] (Appendix 3) 2. The method of claim 1, wherein the oxygen-containing liquid has an oxygen pressure greater than 140 mmHg.

[0099] (Appendix 4) 2. The method of claim 1, wherein the oxygen-containing liquid comprises a compound that releases oxygen gas.

[0100] (Appendix 5) 2. The method of claim 1, wherein the oxygen-containing liquid has an osmolality of about 250 mOsm / L to about 350 mOsm / L.

[0101] (Appendix 6) 2. The method of claim 1, wherein the oxygen-containing liquid comprises a metal oxide.

[0102] (Appendix 7) 2. The method of claim 1, wherein the oxygen-containing liquid comprises a metal hydroxide.

[0103] (Appendix 8) 2. The method of claim 1, wherein the oxygen-containing liquid comprises a peroxide.

[0104] (Appendix 9) 2. The method of claim 1, wherein the oxygen-containing liquid is sterile.

[0105] (Appendix 10) 3. The method of claim 2, wherein delivering the oxygen-containing liquid to the mammal results in improvement in ERG function within one week of administering the oxygen-containing liquid to the eye of the mammal.

[0106] (Appendix 11) 3. The method of claim 2, wherein delivering the oxygen-containing liquid to the mammal results in a decrease in VEGF expression within one week of administering the oxygen-containing liquid to the eye of the mammal.

[0107] (Appendix 12) 3. The method of claim 2, wherein the condition is diabetic retinopathy.

[0108] (Appendix 13) 3. The method of claim 2, wherein the condition is macular degeneration, diabetic macular edema, sickle cell eye disease, ocular inflammation, hypertensive retinopathy, ocular ischemic syndrome, branch retinal vein occlusion, branch retinal artery occlusion, central retinal vein occlusion, central retinal artery occlusion, or retinal detachment.

[0109] (Appendix 14) 3. The method of claim 2, wherein the condition is penetrating ocular injury.

[0110] (Appendix 15) 3. The method of claim 2, wherein the condition is traumatic optic neuropathy.

[0111] (Appendix 16) 3. The method of claim 2, wherein the condition is optic neuritis.

[0112] (Appendix 17) 3. The method of claim 2, wherein the condition is inflammatory ophthalmopathy.

[0113] (Appendix 18) 3. The method of claim 2, wherein the oxygen-containing liquid is injected into a human eye.

[0114] (Appendix 19) 3. The method of claim 2, wherein the oxygen-containing liquid is administered topically to a human eye.

[0115] (Appendix 20) 2. The method of claim 1, wherein the oxygen-containing liquid is administered orally to a human.

Claims

[Claim 1] A method for treating a condition associated with ischemia, hypoxia, hypoxia-inducing factors, or reactive oxygen species, comprising delivering an oxygen-containing fluid to a mammal suffering from said condition.

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