CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/040,743, filed on June 18, 2020; which is incorporated by reference herein in its entirety.

GOVERNMENT INTEREST STATEMENT

[0002] This invention was made with government support under W91 INF-17-1-0360 awarded by the Army Research Office. The government has certain rights in the invention.

FIELD OF THE INVENTION

[0003] This disclosure provides methods for treating or preventing nonthyroidal illness syndrome and for immunosuppression using halogen compounds, including those comprising a halogen compound in a reduced form, e.g. halides such as iodide.

BACKGROUND OF THE INVENTION

[0004] Nonthyroidal illness syndrome (NTIS; also known as Euthyroid sick syndrome) is identified by abnormal findings on thyroid function tests that occur in the setting of a nonthyroidal illness (NTI) or injury, without preexisting hypothalamic-pituitary and thyroid gland dysfunction. Such NTIs include, but are not limited to, acute and chronic illness, particularly fasting, starvation, protein-energy undernutrition, severe trauma, myocardial infarction, chronic kidney disease, diabetic ketoacidosis, anorexia nervosa, cirrhosis, thermal injury, and sepsis. Is has been postulated that NTIS results from decreased peripheral conversion of T4 to T3, decreased clearance of rT3 generated from T4, and decreased binding of thyroid hormones to thyroxine-binding globulin (TBG). Proinflammatory cytokines (eg, tumor necrosis factor-alpha, IL-1) may be responsible for some changes.

[0005] Patients with NTIS typically exhibit decreased triiodothyronine (T3) levels, and patients with more severe or prolonged illness also have decreased thyroxine (T4) levels. Serum reverse T3 (rT3) is typically increased. Patients are clinically euthyroid and do not have elevated thyroid-stimulating hormone (TSH) levels. However, interpretation of abnormal thyroid function test results in ill patients may be complicated by the effects of various drugs, including the iodine-rich contrast agents and amiodarone, which impairs the peripheral conversion of T4 to T3, and by drugs such as dopamine and corticosteroids, which decrease pituitary secretion of TSH, resulting in low serum TSH levels and subsequent decreased T4 secretion.

[0006] Patients with NTIS are treated by treatment of the underlying NTI or injury, since treatment with thyroid hormone is not considered appropriate. However, there remains a need in the art to treat NTIS directly. The present disclosure meets this need.

BRIEF SUMMARY OF THE INVENTION

[0007] The present disclosure provides compositions and methods useful in treating or preventing NTIS, e.g., NTIS resulting from a primary injury or disease.

[0008] In one embodiment, the disclosure provides a method for treating, reducing the severity of, or preventing nonthyroidal illness syndrome (NTIS) in a subject in need thereof, comprising providing to the subject an effective amount of a halogen compound, wherein the halogen compound is optionally an iodide, e.g., Nal or KI. In some embodiments, the subject has been diagnosed with NTIS. In some embodiments, the subject displays one or more of the following: TSH > 4.0 uU/mL, > 6.0 uU/mL, > 10.0 uU/mL, or > 15.0 uU/mL; T3 < 100 ng/dL, < 80 ng/dL, < 60 ng/dL, or < 40 ng/dL; and/or T4 < 5.0 ug/dL, < 4.0 ug/dL, < 3.0 ug/dL, < 2.0 ug/dL. In some embodiments, the subject has or is at risk of an illness or injury that causes NTIS. In some embodiments, the halogen compound is provided to the subject prior to, during, or following an illness or injury that causes NTIS. In some embodiments, the halogen compound, e.g., Nal or KI, is provided to the subject at least two hours, at least four hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 2 days, at least 3 days, at least 4 days, or at least one week folloing the illness or injury that resulted in NTIS.

[0009] In particular embodiments of any of the methods disclosed herein, the illness or injury is selected from gastrointestinal diseases, pulmonary diseases, cardiovascular diseases, renal diseases, infiltrative and metabolic disorders, inflammatory conditions, myocardial infarction, starvation or diminished food intake, septicemia, sepsis, pancreatitis, gastritis, susceptibility to or infection by H. Pylori, bums, trauma, surgery, malignancy, and bone marrow transplantation. In some embodiments, the illness or injury is selected from thyroid surgery/surgical storm, nonthyroidal surgery, trauma, mountain sickness, manipulation of the thyroid gland, thyroiditis, preeclampsia, hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, parturition, burn, pulmonary embolism, cerebrovascular incidents, cytokine storm associated, hypoxia, extracorporeal membrane oxygenation (ECMO), diabetic ketoacidosis, hypoglycemia, ingestion of high doses of thyroid hormone, metastatic thyroid cancer, struma ovarii, molar pregnancy, emotional stress, and intense exercise. In some embodiments, the illness or injury is an infection, optionally a bacterial, viral or yeast infection. In some embodiments, the infection is an H1N1 infection. In some embodiments, the illness or injury is birth.

[0010] In particular embodiments of any of the methods disclosed herein, the NTIS is associated with or results from treatment with a medication or a medical treatment, or withdrawal of a medication or a medical treatment. In some embodiments, the medication is selected from the group consisting of anesthetic, salicylate, pseudoephedrine, amiodarone, interferon, radioactive iodine, a corticosteroid, epinephrine, a non-steroidal anti-inflammatory drug (NSAID), and an iodinated contrast agent. In some embodiments, the NTIS is associated with withdrawal of antithyroid treatment.

[0011] In a related embodiment, the disclosure provides a method for reducing serum levels of rT3 and/or TSH in a subject in need thereof, comprising providing to the subject an effective amount of a halogen compound, wherein the halogen compound is optionally an iodide, e.g., Nal or KI.

[0012] In a related embodiment, the disclosure provides a method for increasing serum levels of T3, T4 or FT4 in a subject in need thereof, comprising providing to the subject an effective amount of a halogen compound, wherein the halogen compound is optionally an iodide, e.g., Nal or KI.

[0013] In a related embodiment, the disclosure provides a method for inhibiting an increase in serum levels of rT3 and/or TSH in a subject in need thereof, comprising providing to the subject an effective amount of a halogen compound, wherein the halogen compound is optionally an iodide, e.g., Nal or KI.

[0014] In a related embodiment, the disclosure provides a method for maintaining or restoring normal thyroid hormone function is a subject in need thereof, comprising providing to the subject an effective amount of a halogen compound, wherein the halogen compound is optionally an iodide, e.g., Nal or KI.

[0015] In particular embodiments of any of the methods disclosed herein, the subject is diagnosed with or at risk of nonthyroidal illness syndrome (NTIS).

[0016] In particular embodiments of any of the methods disclosed herein, the halogen compound comprises iodine, bromine, chlorine, fluorine, or astatine. In particular embodiments of any of the methods disclosed herein, said halogen compound comprises iodine. In particular embodiments of any of the methods disclosed herein, said halogen compound is an iodide. In particular embodiments of any of the methods disclosed herein, said iodide is sodium iodide, potassium iodide, hydrogen iodide, calcium iodide, silver iodide, magnesium iodide, zinc iodide, or lithium iodide.

[0017] In particular embodiments of any of the methods disclosed herein, the halogen compound is provided to the subject in an amount sufficient to increase the blood concentration of the halogen compound, e.g., Nal or KI, at least five-fold, at least ten-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1,000-fold, at least 2,000-fold, at least 5,000-fold, at least 10,000-fold, at least 50,000 fold, or at least 100,000-fold for at least some time.

[0018] In particular embodiments of any of the methods disclosed herein, the halogen compound, e.g., Nal or KI, is present in a stable liquid pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient. In some methods disclosed herein, at least 90% of the halogen compound in the composition is present in a reduced form for at least one hour, at least one week, at least one month, or at least six months when stored at room temperature. In some methods disclosed herein, said composition comprising the halogen compound comprises one or more of a reducing agent, a tonicity agent, a stabilizer, a surfactant, a lycoprotectant, a polyol, an antioxidant, or a preservative.

[0019] In particular embodiments of any of the methods disclosed herein, the halogen compound, e.g., Nal or KI, is provided to the subject orally or parenterally.

[0020] In particular embodiments of any of the methods disclosed herein, the pharmaceutical composition is provided to the subject as a bolus dose prior to the illness or injury, optionally wherein the bolus dose comprises between 0.1 mg/kg - 10 mg/kg, optionally about 1.0 mg/kg or about 2.0 mg/kg of halogen compound, optionally iodide, e.g., Nal or KI.

[0021] In particular embodiments, any of the methods disclosed herein further comprise determining whether the subject has NTIS or is at risk of developing NTIS.

[0022] In particular embodiments, any of the methods disclosed herein further comprise determining a serum level of one or more of rT3, TSH, FT4, T4 and T3 in the subject. In particular embodiments, the serum level of T3 is determined or monitored during treatment with the halogen compound, and the treatment is continued until the serum level of T3 is stabilized. In particular embodiments, the serum level of TSH is determined or monitored during treatment with the halogen compound, and the treatment is continued until the serum level of TSH is elevated by at least 50% or is within a normal range.

[0023] In particular embodiments, any of the methods disclosed herein further comprise determining a serum level of cortisol in the subject. [0024] The method of claim 32, wherein the serum level of cortisol is determined or monitored during treatment with the halogen compound, and the treatment is continued until the serum level of cortisol falls within a normal range.

[0025] In particular embodiments of any of the methods disclosed herein, the halogen compound is sodium iodide.

[0026] In particular embodiments of any of the methods disclosed herein, the halogen compound is potassium iodide.

BRIEF DESCRIPTION OF THE DRAWINGiS)

[0027] FIG. 1 is a graph showing plasma iodide levels determined for 16 subjects at sea level, one day following ascent to 17,600 feet elevation (Al), and 16 days at 17,600 feet elevation (A2). Each dot represents one subject.

[0028] FIG. 2 is a graph showing creatine kinase levels in blood of various rodents subjected to hind limb occlusion following treatment with the indicated amounts of sodium iodide.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The present disclosure provides methods and compositions related to the use of a halogen compound to treat, reduce the severity of, or prevent NTIS, e.g., NTIS resulting from a primary injury or disease.

Definitions and Abbreviations

[0030] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[0031] As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0032] The term “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.

[0033] The words "a" and "an" denote one or more, unless specifically noted.

[0034] By “about” is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In any embodiment discussed in the context of a numerical value used in conjunction with the term "about," it is specifically contemplated that the term about can be omitted.

[0035] Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to”.

[0036] By “consisting of’ is meant including, and limited to, whatever follows the phrase “consisting of.” Thus, the phrase “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present.

[0037] By “consisting essentially of’ is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of’ indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0038] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0039] An “increased” or “enhanced” amount is typically a “statistically significant” amount, and may include an increase that is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 or more times ( e.g ., 100, 500, 1000 times) (including all integers and decimal points in between and above 1, e.g., 2.1, 2.2, 2.3, 2.4, etc.) greater than an amount or level described herein.

[0040] A “decreased” or “reduced” or “lesser” amount is typically a “statistically significant” amount, and may include a decrease that is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 or more times (e.g, 100, 500, 1000 times) (including all integers and decimal points in between and above 1, e.g, 1.5, 1.6, 1.7. 1.8, etc.) less than an amount or level described herein, for example an amount that is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of an amount or level described herein.

[0041] A “composition” can comprise an active agent, e.g. , a halogen compound, and a carrier, inert or active, e.g. , a pharmaceutically acceptable carrier, diluent or excipient. A composition may be a pharmaceutical composition. In particular embodiments, the compositions are sterile, substantially free of endotoxins or non-toxic to recipients at the dosage or concentration employed.

[0042] “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0043] The terms “mammal” and “subject” includes human and non-human mammals, such as, e.g. , a human, mouse, rat, rabbit, monkey, cow, hog, sheep, horse, dog, and cat.

[0044] “Pharmaceutically acceptable salts” include sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, lsomcotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate, chlorobenzoate, dimtrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2- benzoate, isobutyrate, phenylbutyrate, alpha -hydroxybutyrate, butyne-l,4-dicarboxylate, hexyne-l,4-dicarboxylate, caprate, caprylate, cinnamate, glycollate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, mesylate, mcotinate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethyl sulfonate, 2-hydroxy ethyl sulfonate, methyl sulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, naphthalene-1, 5-sulfonate, xylenesulfonate, and tartarate salts. The term "pharmaceutically acceptable salt" also refers to a salt of an antagonist of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium, hydroxides of alkaline earth metal such as calcium and magnesium, hydroxides of other metals, such as aluminum and zinc, ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri- alkylamines, dicyclohexylamine, tributylamine, pyridine, N-methyl, N-ethylamine, diethylamine, triethylamine, mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, N-methyl-D- glucamine, and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also includes a hydrate of a compound of the invention.

[0045] The terms “tissue” and “organ” are used according to their ordinary and plain meanings. Though tissue is composed of cells, it will be understood that the term “tissue” refers to an aggregate of similar cells forming a definite kind of structural material. Moreover, an “organ” pertains to a group of tissues that perform a specific function or group of functions. In certain embodiments, the tissue or organ is “isolated,” meaning that it is not located within an organism.

[0046] The term “buffer” as used herein denotes a pharmaceutically acceptable excipient, which stabilizes the pH of a pharmaceutical preparation. Suitable buffers are well known in the art. Suitable pharmaceutically acceptable buffers include but are not limited to acetate-buffers, histidine-buffers, citrate-buffers, succinate-buffers, tris-buffers and phosphate-buffers. In certain embodiments, the concentration of the buffer is from about O.OlmM to about 1000 mM, about 0 ImM to about 1000 mM, about 0 ImM to about 500 mM, about 0.1 to about 200 mM, about 0.1 to about 100 mM, about 1 mM to about 1000 mM, about 1 mM to about 500 mM, about 1 mM to about 200 mM, about 1 mM to about 100 mM, about 1 mM to about 50 mM, about 2 mM to about 60 mM, about 4 mM to about 60 mM, or about 4 mM to about 40 mM, about 5 mM to about 20 mM, or about 5 mM to about 25 mM.

[0047] The term “tonicity agent” or “tonicity modifier” as used herein denotes pharmaceutically acceptable agents used to modulate the tonicity of a composition. Suitable tonicity agents include, but are not limited to, sodium chloride, sorbitol, trehalose, potassium chloride, glycerin and any component from the group of amino acids, sugars, as defined herein as well as combinations thereof. In certain embodiments, tonicity agents may be used in an amount of about 1 mM to about 1000 mM, about 1 mM to about 500 mM, about 5 mM to about 500 mM, about 10 mM to about 450 mM, about 20 mM to about 400 mM, about 50 mM to about 300 mM, about 100 mM to about 200 mM, or about 125 mM to about 175 mM. In certain embodiments, a tonicity agent comprises an amino acid present in a composition at about 5 mM to about 500 mM. [0048] An “antioxidant” refers to a molecule capable of slowing or preventing the oxidation of other molecules. Antioxidants are often reducing agents, chelating agents and oxygen scavengers such as thiols, ascorbic acid or polyphenols. Non-limiting examples of antioxidants include ascorbic acid (AA, E300), thiosulfate, methionine, tocopherols (E306), propyl gallate (PG, E310), tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA, E320) and butylated hydroxytoluene (BHT, E321).

[0049] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:

[0050] “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

[0051] “Pharmaceutical composition” refers to a formulation of a compound and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g ., humans. Such a medium may include any pharmaceutically acceptable carriers, diluents or excipients therefore.

[0052] “Iodide” and “a reduced form of iodide” both refer to iodide, which has a -1 valence state (e.g, Nal). “A reduced form of iodine” includes iodide.

[0053] “Therapeutically effective amount” refers to that amount of a compound or composition of the invention that, when administered to a biological material, e.g, a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a disease, injury, or condition in the biological material, e.g, mammal, preferably a human. The amount of a compound or composition of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound or composition, the disease, injury or condition and its severity, the manner of administration, and the age of the biological material, e.g, mammal, to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

[0054] “Treating” or “treatment” as used herein covers the treatment of the disease, injury, or condition of interest, e.g, tissue injury, in a biological material, e.g, mammal, preferably a human, having the disease or condition of interest, and includes: (i) preventing or inhibiting the disease, injury, or condition from occurring in a biological material, e.g, mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it; (ii) reducing the severity or duration of the disease, injury or condition, e.g, when it occurs, e.g., in a mammal predisposed to the condition; (iii) inhibiting the disease, injury, or condition, i.e ., arresting its development; (iv) relieving the disease, injury, or condition, /. e. , causing regression of the disease or condition; or (v) relieving the symptoms resulting from the disease, injury, or condition. In certain embodiments, as used herein, the term “prevention” includes inhibiting or impeding the onset or progression of a disease or injury, or reducing the amount of injury or damage caused by a disease or injury. As used herein, the terms “disease,” “disorder,” and “condition” may be used interchangeably. As used herein, the term “injury” includes unintentional injuries and intentional injuries, including injuries that occur, “at the hand of man,” including injuries associated with medical procedures, such as surgeries and transplantations.

Halogen Compounds

[0055] Certain embodiments of the present invention relate to halogens, which include any element included in Group 17 of the periodic table. Halogen-containing compounds are also referred to as “halogen compounds.” In some embodiments, a halogen compound refers to any compound containing Fluorine, Chlorine, Bromine, Iodine, Astatine, or Ununseptium. In particular embodiments, the halogen-containing compounds are halides, i.e., salts of halogens in the -1 oxidation state. In particular embodiments, the present invention relates to halogen compounds in a reduced form, e.g ., iodide. In certain embodiments, other forms of halogen compounds may be used according to the present invention, including, e.g. , hydrogen halides, metal halides, interhalogen compounds, organohalogen compounds, and polyhalogenated compounds.

[0056] Fluorine (F), the lightest halogen, is the non-metal element with atomic number 9. Under standard pressure and temperature it exists as a diatomic gas F2. Fluorine is the most chemically reactive element, reacting with all other elements except oxygen, helium, neon, and krypton. It is also the most electronegative element, thus attracting electrons more strongly than all other elements. There are 11 fluorine isotopes with known half-lives, said isotopes having mass numbers ranging from 15 to 25. Natural Fluorine, however, consists of one stable isotope, ¹⁹ F.

[0057] Chlorine (Cl), the second lightest halogen, is the non-metal element with atomic number 17. Under standard pressure and temperature it exists as a diatomic gas F2. Chlorine is the element with the highest electron affinity, and the third highest electronegativity. There are 16 chlorine isotopes with known half-lives, said isotopes having mass numbers ranging from 31 to 46. Naturally occurring chlorine is a mixture of two stable isotope ³⁵ C1 and ³⁷ C1, existing in natural abundance ratios of approximately 3:1. [0058] Bromine (Br), the third lightest halogen, is the non-metal element with atomic number 35. Under standard pressure and temperature it exists as a diatomic liquid Bn. There are 26 bromine isotopes with known half-lives, said isotopes having mass numbers ranging from 68 to 94. Naturally occurring bromine is a mixture of two stable isotope ⁷⁹ C1 and ⁸¹ C1, existing in natural abundance ratios of approximately 1:1.

[0059] Iodine (I), the second heaviest natural halogen, is the non-metal element with atomic number 53. Under standard pressure and temperature it exists as a solid diatomic h molecule. There are 34 iodine isotopes with known half-lives, said isotopes having mass numbers ranging from 108 to 144. Natural iodine, however, consists of one stable isotope, ¹²⁷ I.

[0060] Astatine, the heaviest natural halogen, is a highly radioactive the non-metal element with atomic number 85. It decays so rapidly (longest half-life less than 12 hours) that its properties are not known with great certainty. It is debated if astatine exists as a diatomic At2 molecule, as this form has never actually been observed. Astatine can react with hydrogen to form hydrogen astatide, and it is predicted to react with metals such as sodium to form salts. There are 37 known astatine isotopes, all of which are radioactive, with very short half-lives. Said isotopes have mass numbers ranging from 207 to 221. No stable isotopes of astatine exist. [0061] In various embodiments, compositions and methods of the present invention comprise one or more halogen compounds, such as various forms of iodine or bromine.

[0062] In one embodiment, the present invention relates to a halogen compound containing iodine. In particular embodiments, the halogen compound contains a reduced form of iodine, such as iodide. Certain embodiments may comprise an iodine-containing halogen compound that is an iodide, iodate, organoiodide, periodate, or periodinane.

[0063] In some embodiments, said halogen compound is an iodide comprising one or more compounds from the non-limiting list of Aluminium iodide, Aluminium monoiodide, Ammonium iodide, Antimony triiodide, Arsenic diiodide, Arsenic triiodide, Barium iodide, Beryllium iodide, Bismuth(III) iodide, Boron triiodide, Cadmium iodide, Caesium iodide, Calcium iodide, Candocuronium iodide, Carbon tetraiodide, Cobalt(II) iodide, Coccinite, Copper(I) iodide, DiOC6, Diphosphorus tetraiodide, Dithiazanine iodide, Echothiophate, Einsteinium(III) iodide, Eschenmoser's salt, Ethylenediamine dihydroiodide, Gallium(III) iodide, GelGreen, GelRed, Germanium iodide, Gold monoiodide, Gold triiodide, Hydrogen iodide, Iodine oxide, Iodomethylzinc iodide, Iodosilane, Iron(II) iodide, Lead(II) iodide, Lithium iodide, Magnesium iodide, Manganese(II) iodide, Mercury(I) iodide, Mercury(II) iodide, Nickel(II) iodide, Nitrogen triiodide, Palladium(II) iodide, Phosphorus triiodide, Polyiodide, Potassium iodide, Potassium tetraiodomercurate(II), Propidium iodide, Rubidium iodide, Rubidium silver iodide, Samarium(II) iodide, Silicon tetraiodide, Silver iodide, Sodium iodide, Strontium iodide, Tellurium iodide, Tellurium tetraiodide, Terbium(III) iodide, Tetraethylammonium iodide, Thallium triiodide, Thallium(I) iodide, Thorium(IV) iodide, Tibezonium iodide, Tiemonium iodide, Tin(II) iodide, Tin(IV) iodide, Titanium tetraiodide, Triiodide, Trimethyl silyl iodide, Trimethyl sulfoxonium iodide, Uranium pentaiodide, Uranium tetraiodide, Uranium triiodide, Vanadium(III) iodide, Zinc iodide, and Zirconium(IV) iodide. [0064] In particular embodiments, said halogen compound is an iodide comprising sodium iodide, potassium iodide, hydrogen iodide, calcium iodide, or silver iodide.

[0065] In some embodiments, said halogen compound is an iodate comprising one or more compounds from the non-limiting list of Calcium iodate, Iodic acid, Potassium iodate, Seeligerite, Silver iodate, and Sodium iodate.

[0066] In particular embodiments, said halogen compound is an iodate comprising sodium iodate, potassium iodate, calcium iodate, or silver iodate.

[0067] In some embodiments, said halogen compound is an organoiodide comprising one or more compounds from the non-limiting list of ²⁵ I-NBF, ²⁵ I-NBMD, ²⁵ I-NBOH, ²⁵ I-NBOMe, 2C-I, 5, 5-I-R91150, Acetrizoic acid, Adipiodone, Adosterol, Altropane, AM-1241, AM-2233, AM-630, AM-679 (cannabinoid), AM-694, AM251, Amiodarone, Benziodarone,

Bromoiodomethane, Budiodarone, Butyl iodide, Carbon tetraiodide, Chiniofon, Chloroiodomethane, Clioquinol, Diatrizoic acid, Diiodohydroxypropane, Diiodohydroxyquinoline, Diiodomethane, 2,5-Dimethoxy-4-iodoamphetamine, Domiodol, Erythrosine, Ethyl iodide, Ethyl iodoacetate, Fialuridine, Fluoroiodomethane, Haloprogin, Herapathite, IAEDANS, Ibacitabine, IDNNA, Idoxifene, Idoxuridine, Iniparib, Iobenguane, Iobenzamic acid, Iobitridol, Iocarmic acid, Iocetamic acid, Iodamide, Iodixanol, Iodoacetamide, Iodoacetic acid, Para-Iodoamphetamine, Iodobenzamide, Iodobenzene, 2- Iodobenzoic acid, 19-Iodocholesterol, Iodocyanopindolol, Iodoform, 1-Iodomorphine, Iodophenol, Iodophenpropit, 4-Iodopropofol, Iodopropynyl butylcarbamate, Iodotrifluoroethylene, Iodoxamic acid, 2-Iodoxybenzoic acid, Iofetamine (1231), Ioflupane (1231), Ioglicic acid, Ioglycamic acid, Iomazenil, Iomeprol, Iopamidol, Iopanoic acid, Iopentol, Iopromide, Iopydol, Iotrolan, Iotroxic acid, Ioversol, Ioxaglic acid, Ioxilan, Ipodate sodium, Isopropyl iodide, Methiodal, Methyl iodide, Metrizamide, Metrizoic acid, Pentafluoroethyl iodide, Plakohypaphorine, N-Propyl iodide, Propyliodone, Rafoxanide, Rose bengal, RTI-121, RTI-229, RTI-353, RTI-55, SB-258,585, Sodium acetrizoate, Tiratricol,

Trifluoroiodomethane, and Tyropanoic acid.

[0068] In particular embodiments, said halogen compound is an organoiodide. Organoiodine compounds are organic compounds that contain one or more carbon-iodine bonds. Almost all organoiodine compounds feature iodide connected to one carbon center. These are usually classified as derivatives of G. Some organoiodine compounds feature iodine in higher oxidation states. Organoiodine compounds, often used as disinfectants or pesticides, include, e.g ., iodoform (CHL·), methylene iodide (CH2I2), and methyl iodide (CH3I). In particular embodiment, the organoiodide is a polyiodoorganic compound. Polyiodoorganic compounds are sometimes employed as X-ray contrast agents, in fluoroscopy, a type of medical imaging. A variety of such polyiodoorganic compounds are available commercially; many are derivatives of 1,3,5-triiodobenzene and contain about 50% by weight iodine. In certain embodiments, the agent is soluble in water, non-toxic and/or readily excreted. A representative reagent is Ioversol, which has water-solubilizing diol substituents. Other organoiodine compounds include but are not limited to the two thyroid hormones thyroxine ("T4") and triiodothyronine ("T3"). Marine natural products are rich sources of organoiodine compounds, including the recently discovered plakohypaphorines from the sponge Plakortis simplex.

[0069] The present invention also includes the use of compounds, e.g. , drug compounds, into which an iodine is incorporated. For example, an iodine may be incorporated into existing drugs such as N-acetyl cysteine, standard pain relievers, and non-steroidal anti-inflammatory drugs, such as, e.g. , aspirin, ibuprofen and naproxen. Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase- 1 (COX- 1) and cyclooxygenase-2 (COX-2) isoenzymes.

[0070] In certain embodiments, said halogen compound is a polyiodide. The polyiodides are a class of polyhalogen anions composed of entirely iodine atoms. The most common and simplest member is the triiodide ion, L·-. Other known, larger polyiodides include [I4] ² , [Is] , [l7]\ M ² -, [l9]\ [I10] ² , [I10] ⁴ , [Ill]·, [I12] ² -, [I13] ³ -, [lie] ² -, [I22] ⁴ -, [I26] ³ -, [I26] ⁴ -, [Ls] ⁴ and [I29] ³ -. One example of a polyiodide is LugoTs iodine, also called LugoTs solution. Lugol's solution is commercially available in different potencies of 1%, 2%, or 5% Iodine. The 5% solution consists of 5% (wt/v) iodine (I2) and 10% (wt/v) potassium iodide (KI) mixed in distilled water and has a total iodine content of 130 mg/mL. Potassium iodide renders the elementary iodine soluble in water through the formation of the triiodide (G ³ ) ion. Other names for Lugol's solution are I2KI (iodine-potassium iodide); Markodine, Strong solution (Systemic); and Aqueous Iodine Solution BCP. Examples of polyiodides, including their ions and counter cations are shown in Table 1.

Table 1. Polyiodides

[0071] In one embodiment, is a tincture of iodine solutions, which comprises or consists of elemental iodine, and iodide salts dissolved in water and alcohol. [0072] In some embodiments, said halogen compound is a periodate comprising one or more compounds from the non-limiting list of Dess-Martin periodinane, I, 2-Iodoxybenzoic acid, Periodic acid, Potassium periodate, and Sodium periodate.

[0073] In particular embodiments, said halogen compound is a periodate comprising sodium periodate, potassium periodate, calcium periodate, or silver periodate.

[0074] In particular embodiments, said halogen compound is a periodinane. Periodinanes are chemical compounds containing hypervalent iodine. In some embodiments, said halogen compound is a periodinane comprising one or more compounds from the non-limiting list of (Bis(trifluoroacetoxy)iodo)benzene, Dess-Martin periodinane, Iodobenzene dichloride, Iodosobenzene, and 2-Iodoxybenzoic acid.

[0075] In one embodiment, the halogen compound is an oil-infused iodide or iodine oil infusion.

[0076] In one embodiment, the present invention relates to a halogen compound containing bromine. Certain embodiments may comprise a bromine-containing halogen compound that is a bromide, bromate, organobromide, or a perbromate.

[0077] Particular embodiments of the present invention relate to a reduced form of a halogen compound. Many acceptable means of reduction of halogen compounds are possible and known to one skilled in the art. Examples of reduced forms of halogen compounds include halides, e.g ., iodide and bromide, wherein the halogen has a valency of -1, including salt forms, such as Nal. Non-limiting examples of reduction methods include chemical reduction with electropositive elemental metals (such as lithium, sodium, magnesium, iron, zinc, and aluminum, e.g.), hydride transfer reagents (such as NaBEE and LiAIEE e/g), or the use of hydrogen gas with a palladium, platinum, or nickel catalyst.

[0078] A particular embodiment of the present invention relates to the administration of a halogen compound of the type described herein, e.g., a halide such as an iodide (e.g., Nal), to a mammalian subject, in a composition, concentration or formulation that is not significantly toxic to said mammals, e.g, a pharmaceutical composition. In particular embodiments, a halogen compound known to be toxic to a mammalian subject is excluded from the present invention. Thus, in particular embodiments, potassium iodide is excluded from the present invention. It is further contemplated that some embodiments may comprise the administration of more than one of said halogen compounds to said mammal, either simultaneously or separately, such that the combination of said compounds that are not individually significantly toxic are also not significantly toxic when combined. [0079] Other compounds comprising a halogen compound or halogen element may also be used according to methods of and/or included in compositions of the present invention. In some embodiments, said halogen compound is a commercially available substance. In certain embodiments, said commercially available substances may include radiological contrast agents, topical iodine preparations, solutions, or drugs. In certain embodiments, said commercially available substance comprises iodine, and may be selected from the non-limiting list of Diatrizoate, Ipanoic acid, Ipodate, Iothalamate, Metrizamide, Diatrozide, Diiodohydroxyquinolone, Iodine tincture, Povidone iodine, Iodochlorohydroxyquinolone, Iodoform gauze, Saturated potassium iodide (SSKI), Lugol solution, Iodinated glycerol, Echothiopate iodide, Hydriodic acid syrup, Calcium iodide, Amiodarone, Expectorants, Vitamins containing iodine, Iodochlorohydroxyquinolone, Diiodohydroxyquinolone, Potassium iodide, Benziodarone, Isopropamide iodide, levothyroxine, and Erythrosine. In certain embodiments, said commercially available substance comprises bromine, and may be selected from the non-limiting list of Alphagen (brimonidine), Atrovent (Ipratropium), Celexa (citalopram), Combivent (ipratropium bromide), Enablex (darifenacin), Guaifenex DM (dextromethorphan), Razadyne (galantamine), and Spiriva (tiotropium).

Compositions and Unit Dosage Forms

[0080] The present invention also includes compositions comprising a halogen compound ( e.g ., an iodide or bromide). In particular embodiments, the compositions are pharmaceutical compositions comprising a halogen compound and one or more pharmaceutically acceptable carriers, diluents or excipients, e.g., a buffer. In particular embodiments, the composition further comprises one or more additional active agents. In certain embodiments, compositions of the present invention are pharmaceutical compositions comprising a halogen compound, optionally a halide, e.g., an iodide, such as Nal. In certain embodiments, the compositions comprise a reduced form of a halogen compound, i.e., a halogen in a -1 valence state. In particular embodiments, the reduced form of a halogen is a reduced form of iodine, such as iodide. In particular embodiments, the compound containing a reduced form of iodine is Nal, KI, HI, Cal or Agl. In particular embodiments, the compound is Nal or KI.

[0081] In certain embodiments, the present invention includes compositions comprising a halogen compound, e.g, a reduced form of a halogen compound. In certain embodiments of any of the compositions of the invention, the halogen compound is a reduced form of a halogen compound, which comprises a halogen in a -1 valence state, e.g, an iodide or bromide, such as sodium iodide. The reduced form of halogen compound may be any of those described herein. In certain embodiments of any of the compositions described herein, the composition further comprises glutathione or another reducing agent. In particular embodiments, a composition comprises glutathione and iodide. In particular embodiments, at least a portion of the iodide or iodate is in reduced form, and the glutathione inhibits the oxidation of the halogen compound in the composition.

[0082] In particular embodiments, the compositions are formulated to maintain the halogen in a reduced form when stored over a period of time. Thus, the compositions may be stable compositions of reduced forms of halogen compounds or salts or precursors thereof, whose effectiveness as a therapeutic may normally be compromised during manufacture and storage, as a result of oxidation reactions that produce oxidation products. Compositions of the present invention have increased shelf-life, are easily and reproducibly manufactured, are designed for standard routes of administration, and are, therefore, advantageous in the treatment and prevention of a number of diseases, conditions and injuries. In certain embodiments, a stable composition comprising a halogen compound comprises glutathione or another reducing agent. [0083] In certain embodiments of the compositions, a composition is considered stable, i.e., a stable composition, if at least 90% of the halogen compound in the composition is present in reduced form for at least one hour either when stored at room temperature, 4°C, 25°C, 40°C or 50°C. In related embodiments, a composition is considered stable if at least 70%, at least 80%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the halogen compound in the composition is present in reduced form for at least one hour either when stored at room temperature or when stored at 4°C. In certain embodiments of the stable compositions, at least 90% of the halogen compound in said composition is present in said reduced form for at least one day, at least one week, at least one month, at least two months, at least four months, at least six months, or at least one year, either when stored at room temperature or when stored at 4°C, 25°C, 40°C or 50°C. In related embodiments, at least 70%, at least 80%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the halogen compound in the stable composition is present in said reduced form for at least one day, at least one week, at least one month, at least two months, at least four months, at least six months, or at least one year, either when stored at room temperature or when stored at 4°C. In particular embodiments, at least 98% of the halogen compound in the stable composition is present in said reduced form for at least one month or at least six months when stored at 4°C. In related embodiments, at least 70%, at least 80%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the halogen compound in the stable composition is present in said reduced form for at least one day, at least one week, at least one month, at least two months, at least four months, at least six months, or at least one year, either when stored at room temperature or when stored at room temperature or 25 °C. In particular embodiments, at least 98% of the halogen compound in the stable composition is present in said reduced form for at least one month or at least six months when stored at room temperature or 25°C. In related embodiments, at least 70%, at least 80%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the halogen compound in the stable composition is present in said reduced form for at least one day, at least one week, at least one month, at least two months, at least four months, at least six months, or at least one year, either when stored at room temperature or when stored at 40°C or 50°C. In particular embodiments, at least 98% of the halogen compound in the stable composition is present in said reduced form for at least one month or at least six months when stored at 40°C or 50°C. In various embodiments, the composition is a liquid pharmaceutical composition, while in other embodiments, the composition is a solid or powder, or is dried, lyophilized, or freeze-dried.

[0084] In particular embodiments, the present invention relates to a stable liquid composition comprising iodide, e.g., Nal, wherein the stable liquid composition comprises less than 1% of any of the following oxidation products of iodide (-1 oxidation state): hypoiodite (+1 oxidation state), iodite (+3 oxidation state), iodate (+5 oxidation state), or periodate (+7 oxidation state). In particular embodiments, the stable liquid composition comprising iodide comprises less than 1% iodine (I2).

[0085] In particular embodiments, any of the compositions described herein comprise a pharmaceutically acceptable carrier, diluent or excipient. Further, any of the compositions may comprise one or more of a buffer, a reducing agent, a tonicity agent, a stabilizer, a surfactant, a lycoprotectant, a polyol, an antioxidant, or a preservative. In particular embodiments, any of the compositions described herein comprise glutathione.

[0086] In particular embodiments, compositions may comprise one or more solvents. In particular embodiments, the solvent is water. In particular embodiments, the solvent is a phosphate-buffered saline.

[0087] Compositions of the present invention and methods of the present invention may include a halogen compound, or salt or precursor thereof, in any desired concentration. The concentration may be readily optimized, e.g., depending upon the type of injury or disease being treated and the route of administration, so as to deliver an effective amount in a convenient manner and over an appropriate time-frame.

[0088] In some embodiments, the concentration of halogen compound or salt or precursor thereof (e.g., iodide, such as Nal or KI) present in a composition of the present invention is about 0.0001 mM to about 100 M, about 0.0005 mM to about 50 M, about 0.001 mM to about 10 M, about 0.001 mM to about 5 M, about 0.001 mM to about 1 M, about 0.005 mM to about 10 M, about 0.005 mM to about 5 M, about 0.005 mM to about 1 M, about 0.005 mM to about 0.5 M, about 0.01 mM to about 10 M, about 0.01 mM to about 5 M, about 0.01 mM to about 2 M, about 0.1 mM to about 1 M, about 0.1 mM to about 0.5 M, about 0.5 mM to about 5 M, about 0.5 mM to about 2 M, about 0.5 mM to about 1 M, about 0.5 mM to about 0.5 M, about 1 mM to about 5 M, about 1 mM to about 2 M, about 1 mM to about 1 M, about 1 mM to about 0.5 M, about 5 mM to about 5 M, about 5 mM to about 2 M, about 5 mM to about 1 M, about 5 mM to about 0.5 M, about 5 mM to about 0.25 M, about 10 mM to about 1 M, about 10 mM to about 0.5 M, about 10 mM to about 0.25 M, or about 10 mM, about 50 mM about 100 mM, or about 200 mM.

[0089] As used herein, the term “%” when used without qualification (as with w/v, v/v, or w/w) means % weight-in-volume for solutions of solids in s (w/v), % weight-in-volume for solutions of gases in s (w/v), % volume-in-volume for solutions of s in s (v/v) and weight-in- weight for mixtures of solids and semisolids (w/w) (Remington's Pharmaceutical Sciences (2005); 21st Edition, Troy, David B. Ed. Lippincott, Williams and Wilkins).

[0090] In certain embodiments, a composition comprises glutathione at a concentration of about 1.5 mM to about 10 M, about 15 mM to about 1 M, about 150 mM to about 1 M, about 1.5 mM to about 1 M, about 10 mM to about 500 mM, about 10 mM to about 250 mM, or about 100 mM, about 120 mM, about 150 mM, about 170 mM, or about 200 mM.

[0091] In certain embodiments, a composition of the invention comprises a halogen compound (e.g., iodide, such as Nal or KI), and optionally glutathione, wherein the concentration of glutathione is about 100 mM to about 1 M, about 1 mM to about 1 M, or about 10 mM to about 500 mM, and, the concentration of halogen compound is about 0.01 mM to about 5 M, about 1 mM to about 0.5 M, or about 10 mM to about 250 mM. In particular embodiments, the halogen compound is an iodide. In particular embodiments of any of these compositions, the composition is formulated for oral delivery, or is an oral dosage form, the halogen compound (when present) comprises iodine (e.g., iodide). In particular embodiments, the composition is formulated for intravenous administration, and the halogen compound (if present) is iodide. In one embodiment, the composition comprises iodide and glutathione, each within any of the concentration ranges or at a concentration described herein.

[0092] In particular embodiments, the pH of a composition of the present invention is in the range of (3.0-12.0), while in other embodiments, the pH is in the range of (5.0-9.0). The pH of the pharmaceutical composition may be adjusted to a physiologically compatible range. For example, in one embodiment, the pH of the stable composition is in the range of 6.5-8.5. In other embodiments, the compositions of the present invention have a pH in the range of 7.5- 8.5 or 7.4-9.0.

[0093] In particular embodiments, oxygen is present in a composition of the present invention at a concentration in the range of 0 pM-5 mM or 0 pM-l mM or 0 pM-0.1 pM or 0 pM-0.01 pM. In particular embodiments, oxygen is present in the composition at a concentration of less than 3 pM, less than 1 pM, less than 0.1 pM, less than 0.01 pM, or less than 0.001 pM.

[0094] In certain embodiments, the compositions of the present invention may further comprise a limited amount of oxidation products. Oxidation products that may be present in various embodiments of the present invention include, but are not limited to, iodine, iodate, bromine, and bromate. In various embodiments, one or more of these oxidation products is present in a composition in an amount less than 10%, less than 5.0%, less than 2.0%, less than 1.0%, less than 0.5%, less than 0.2%, less than 0.1%, less than 0.05%, or less than 0.01% (w/v) of the total halogen compound in the composition.

[0095] In one embodiment, a composition has an osmolarity in the range of 200-400 mOsmol/L. NaCl may be used as an excipient to adjust osmolality.

[0096] In certain embodiments, isotonicity of the compositions is desirable as it results in reduced pain upon administration and minimizes potential hemolytic effects associated with hypertonic or hypotonic compositions. Thus, the compositions of the invention not only have increased storage stability, but also have the added benefit of substantially reduced pain upon administration when compared with formulations using other more traditional buffer systems consisting of an acid and a salt form of the acid.

[0097] In certain embodiments, the composition has a pH in the range of 6.5 to 8.5 and has an oxygen content of less than or equal to 5 mM for 3 months when stored within a temperature range of 23°-27° or 6 months when stored at a temperature range of (23°-27°). In one embodiment, the composition has an osmolarity in the range of 250-330 mOsmol/L. It may be isotonic or near isotonic. [0098] The present invention further includes kits comprising composition(s) of the present invention. In certain embodiments, such kits comprise one or more containers to store the composition(s) of the present invention. In one embodiment, a composition is stored in the container under an inert or noble gas, and the container is a sealed and has an oxygen impermeable light-protective container ( e.g ., an amber vial). In certain embodiments, a kit comprises a first pharmaceutical composition comprising a halogen compound, e.g., a reduced form of iodine, such as iodide. In certain embodiments, a composition is packaged in an impermeable container. “Impermeable container” refers to containers that provide a barrier to the passage of gas molecules. Impermeable containers are known to those skilled in the art and include, but are not limited to, “i.v. bags” or syringes comprising a gas impermeable construction material, or a sealed glass vial. In particular embodiments, the composition may be packaged into an impermeable container containing an inert atmosphere, an inert gas, or a noble gas. Noble gas refers to helium (He), neon (Ne), argon (Ar), krypton (Kr), xenon (Xe), and radon (Rn). Inert gas refers to nitrogen (N2). The term “inert atmosphere” refers to a nitrogen or argon atmosphere in a container. In particular embodiments, the container comprises a reduced oxygen or oxygen-free environment. A “reduced oxygen environment” is an environment having an oxygen concentration of less than 100 parts per million. The composition may be packaged in a light-protective vial or container, e.g, amber vials. In one embodiment, the composition is sealed and stored in a glass ampoule.

[0099] In some embodiments, compositions of the present invention comprise one or more excipients included to prevent oxidation of the halogen compound during storage, where storage is in the range of one to twelve months or longer. In some embodiments, storage is in the range of one to six months. In some embodiments, storage is in the range of three to six months. In some embodiments, storage is in the range of four to five months. Embodiments of the present invention may use a single excipient or a combination of excipients. There are many suitable excipients. Examples include chelators, pH modifying agents, reducing agents, antioxidants, spin-trap agents and preservatives.

[00100] Compositions of the present invention may further comprise one or more pH modifying agents. pH modifying agents, include, but are not limited to, inorganic salts, such as zinc carbonate, magnesium carbonate, calcium carbonate, magnesium hydroxide, calcium hydrogen phosphate, calcium acetate, calcium hydroxide, calcium lactate, calcium maleate, calcium oleate, calcium oxalate, calcium phosphate, magnesium acetate, magnesium hydrogen phosphate, magnesium phosphate, magnesium lactate, magnesium maleate, magnesium oleate, magnesium oxalate, sodium chloride, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium phosphate, sodium bicarbonate, thioglycolic acid, zinc acetate, zinc hydrogen phosphate, zinc phosphate, zinc lactate, zinc maleate, zinc oleate, zinc oxalate, and combinations thereof. Other pH modifying agents include, e.g ., acetic acid, fumaric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, carbon dioxide, carbonic acid, N-methyl-D-glucamine, 4-(2-hydroxyethyl)-morpholine, Tromethamine, Orotic acid, and hydrochloric acid. In one embodiment, the pH modifying agent is sodium hydroxide. [00101] A pH modifying agent may serve as a buffering agent when it is added to an already acidic or basic solution, which it then modifies and maintains at a new pH (see: The United States Pharmacopeia-National Formulary 29th Edition, (2006) Rockville, Md.; Stahl, P. Wermuth, C. ed. Handbook of Pharmaceutical Salts Properties, Selection and Use. Wiley (2002)).

[00102] In certain embodiments, compositions of the present invention include one more excipients that are reducing agents, such as, e.g. , glutathione (see: U.S. Pat. No. 6,586,404), tris(2-carboxyethyl) phosphine hydrochloride (TSEP), thiosulfate, I-cysteine, cysteine or methionine. In one embodiment, the reducing agent is glutathione (see: Vincent et ah, Endocrine Reviews (2004) 25:612-628), dithiothreitol (DTT) (Weir et ah, Respir and Physiol Biol; (2002) 132:121-30) or dithioerythritol (DTE). In certain embodiments, the concentration of glutathione is about, at least about, or at most about 0, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 mM or M or more or any range derivable therein. In certain embodiments, the concentration of dithiothreitol (DTT), which present at about, at least about, or at most about 0, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 mM or 1 M, or any range derivable therein. In certain embodiments, the reducing agent is dithioerythritol (DTE), is about, at least about, or at most about 0, 0.001, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 mM or M, or any range derivable therein. [00103] Compositions of the present invention may optionally comprise a free radical scavenger or antioxidant. Examples of free radical scavengers or antioxidants include, but are not limited to, ascorbic acid (vitamin C), D-alpha tocopherol acetate, DL-alpha-tocopherol (vitamin E), melatonin, sodium bisulfite, sodium sulfite, sodium metabi sulfite, Trolox (6-hydroxy-2, 5,7,8- tetramethyl chroman-2-carboxylic acid), Tris(2-Carboxyethyl) phosphine Hydrochloride (TCEP), melatonin, dithionite, pyrosulfite, cysteine, potassium disulfite, sodium thioglycolate, thioethylene glycol, L-threoascobic acid, acetylsalicylic acid, salicylic acid, lecithin, ascorbyl palmitate, butylated hydroxyanidole, ascorbic acid, butylated hydroxyanisole, butylated hydroxyquinone, butylhydroxyanisol, hydroxycomarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propylhydroxybenzoate, trihydroxybutylrophenone, dimethylphenol, lecithin, ethanolamine, meglumine and combinations thereof (see US 2005/0106214). In one embodiment, the anti-oxidant agent is a spin-trap agent. Examples of spin-trap agents include, but are not limited to, N-t-butyl- phenylnitrone (PBN) (see: Kotake, Y., Antioxid Redox Signal (1999) 481), 4-Hydroxy-2,2,6,6- tetramethylpiperidine-l-oxyl (TEMPOL) (Gariboldi, M. B., et al. (2000), Free Radic. Biol. Med. 29:633; Miura, Y., et al. J. Radiat. Res. (Tokyo) (2000) 41:103; Mota-Filipe, FL, et al. (1999), Shock 12:255R: 22-41; S: 39-262,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) (see: Lapchak, et al., Stroke (2001) 32:147-53); (di sodium- [(tert-butylimino) methyl]benzene-l,3- disulfonateN-oxide (NXY-059) (see: Lapchak etak, CNS Drug Rev (2003) 9:253-62). In some embodiments, the spin-trap agent is TEMPO, which is present in the range of 0 mg/kg-1,000 mg/kg. In some embodiments, the spin-trap agent is TEMPO and is present in the range of 100 mg/kg-1,000 mg/kg. In another embodiment, the spin-trap agent is TEMPO and is present in the range of 0 mg/kg- 100 mg/kg.

[00104] Compositions of the present invention may optionally comprise a preservative. As used herein, the term “preservative” is intended to mean a compound used to prevent the growth of microorganisms.

[00105] The present invention also includes unit dosage forms of compositions of the present invention. In certain embodiments, the unit dosage form comprises or consists of an effective amount of a halogen compound, e.g., iodide, for treating, reducing the severity or duration of, or preventing PICS. In certain embodiments, a unit dosage form further comprises glutathione in an amount effective to maintain the halogen compound in a reduced form under any of the conditions described herein. In particular embodiments, the unit dosage form is formulated for intravenous administration, administration by infusion, or oral administration.

[00106] In particular embodiments, a unit dosage form comprising a halogen compound, such as an iodide, e.g., Nal or KI, comprises or consists of about 0.005 mg to about 5000 mg, about 0.05 to about 1000 mg, about 0.5 mg to about 100 mg, about 1 mg to about 100 mg, about 2.5 mg to about 100 mg, about 0.5 mg to about 50 mg, about 1 mg to about 50 mg, about 2.5 mg to about 50 mg, about 5 mg to about 50 mg, about 10 mg to about 50 mg, or about 1 mg, about 2 mg, about 5 mg, about 10 mg, or about 15 mg of the halogen compound, e.g., Nal. In certain embodiments, the unit dosage form comprises between about 1 mg and about 150 mg (including any interval in this range), between about 1 mg and about 125 mg, between about 1 mg and about 100 mg, between about 1 mg and about 75 mg, between about 1 mg and about 50 mg, between about 1 mg and about 25 mg or between about 1 mg and about 10 mg of the halogen compound. In certain embodiments, the unit dosage form comprises about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg, about 25 mg or about 10 mg of the halogen compound. In certain embodiments, the unit dosage form comprises or a subject between about 50 mg and 500 mg, about 50 mg and 100 mg, about 100 mg and about 1000 mg (including any interval in this range), between about 150 mg and about 800 mg, between about 200 mg and about 700 mg, between about 250 mg and about 600 mg, between about 300 mg and about 500 mg, between about 350 mg and about 450 mg or between about 300 mg and about 700 mg of the halogen compound. In certain embodiments, the unit dosage form comprises about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg of the halogen compound. In certain embodiments, the unit dosage form comprises less than or equal to 1000 mg, less than or equal to 800 mg, less than or equal to 700 mg, less than or equal to 500 mg, less than or equal to 250 mg, less than or equal to 200 mg, or less than or equal to 150 mg of the halogen compound. In related embodiments, the unit dosage form comprises less than or equal to 150 mg, less than or equal to 125 mg, less than or equal to 100 mg, less than or equal to 75 mg, less than or equal to 50 mg, less than or equal to 25 mg, or less than or equal to 10 mg of the halogen compound. In related embodiments of methods disclosed herein, the subject in need thereof is administered an amount of halogen compounds, e.g., iodide, such as Nal, that falls within any of these ranges or values.

[00107] In some embodiments, including, e.g., embodiments where the unit dosage form is formulated as a liquid, e.g, for intravenous administration or administration by infusion, the concentration of halogen compound or salt or precursor thereof present in a unit dosage form of the present invention is about 0.0001 mM to about 100 M, about 0.0005 mM to about 50 M, about 0.001 mM to about 10 M, about 0.001 mM to about 5 M, about 0.001 mM to about 1 M, about 0.005 mM to about 10 M, about 0.005 mM to about 5 M, about 0.005 mM to about 1 M about 0.005 mM to about 0.5 M, about 0.01 mM to about 10 M, about 0.01 mM to about 5 M, about 0.01 mM to about 2 M, about 0.1 mM to about 1 M, about 0.1 mM to about 0.5 M, about 0.5 mM to about 5 M, about 0.5 mM to about 2 M, about 0.5 mM to about 1 M, about 0.5 mM to about 0.5 M, about 1 mM to about 5 M, about 1 mM to about 2 M, about 1 mM to about 1 M, about 1 mM to about 0.5 M, about 5 mM to about 5 M, about 5 mM to about 2 M about 5 mM to about 1 M, about 5 mM to about 0.5 M, about 5 mM to about 0.25 M, about 10 mM to about 1 M, about 10 mM to about 0.5 M, about 10 mM to about 0.25 M, or about 10 mM, about 50 mM about 100 mM, or about 200 mM. The unit dosage form may further comprise one or more pharmaceutically acceptable diluents, excipients or carriers.

[00108] In certain embodiment, the unit dosage form comprises iodide, e.g ., Nal or KI, and the effective amount is greater than or equal to about 150 pg, greater than or equal to about 300 pg, greater than or equal to about 500 pg, greater than or equal to about 1 mg, greater than or equal to about 2 mg, greater than or equal to about 5 mg, greater than or equal to about 10 mg, greater than or equal to about 15 mg, or greater than or equal to about 20 mg. In certain embodiments, the effective amount is 150 pg to 1000 mg, 300 pg to 1000 mg, 500 pg to 1000 mg, 1 mg to 1000 mg, 2 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 1000 mg, 150 pg to 100 mg, 300 pg to 100 mg, 500 pg to 100 mg, 1 mg to 100 mg, 2 mg to 100 mg, 5 mg to 100 mg, or 10 mg to 100 mg.

[00109] In certain embodiments, a subject is administered an effective amount of halide, e.g., Nal or KI, where the effective amount is between about 0.1 mg/kg to about 100 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.5 mg/kg to about 5 mg/kg, about 0.2 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, about 3.0 mg/kg, about 4.0 mg/kg, about 5.0 mg/kg, about 6.0 mg/kg, about 7.0 mg/kg, about 8.0 mg/kg, about 9.0 mg/kg or about 10 mg/kg. In certain embodiments, the effective amount is 150 pg to 50 mg, 300 pg to 20 mg, 500 pg to 10 mg, 1 mg to 20 mg, 1 mg to 10 mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg. In other embodiments, the effective amount is between about 1 mg and about 150 mg (including any interval in this range), between about 1 mg and about 125 mg, between about 1 mg and about 100 mg, between about 1 mg and about 75 mg, between about 1 mg and about 50 mg, between about 1 mg and about 25 mg or between about 1 mg and about 10 mg of the halogen compound. In certain embodiments, the effective amount is about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg, about 25 mg or about 10 mg of the halogen compound. In certain embodiments, the effective amount comprises less than or equal to 1000 mg, less than or equal to 800 mg, less than or equal to 700 mg, less than or equal to 500 mg, less than or equal to 250 mg, less than or equal to 200 mg, or less than or equal to 150 mg of the halogen compound. In certain embodiments, the effective amount is between about 100 mg and about 1000 mg (including any interval in this range), between about 150 mg and about 800 mg, between about 200 mg and about 700 mg, between about 250 mg and about 600 mg, between about 300 mg and about 500 mg, between about 350 mg and about 450 mg or between about 300 mg and about 700 mg of the halogen compound. In certain embodiments, the effective amount is about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg of the halogen compound. In particular embodiments, the effective amount is the amount per day.

[00110] In certain embodiments, a composition of the invention may be formulated in a dosage form suitable for oral or parenteral administration. In addition, in particular embodiments, a composition of the invention may be in the form of an immediate or modified release formulation. For example, formulations of the halogen compound can be used to provide controlled release, in which the release of the compound(s) is controlled and regulated to allow less frequency of dosing or to improve the pharmacokinetic or toxicity profile of a given active agent.

[00111] In general the amount of the active compound present in a composition or unit dosage form depends inter alia on the specific compound and formulation, the age and condition of the subject, and the specific features of the injury, condition, or disease being treated or prevented, the route of administration and the dosage frequency.

[00112] The dosage frequency also depends on the injury, condition or disease being treated or prevented, the amount or concentration of the compound, the specific composition used, the route of administration and may incorporate subject-specific variation including, but not limited to age, weight, gender, or overall health.

[00113] In certain embodiments, a unit dosage form suitable for oral administration is in the form of a pill, drenches (aqueous or non-aqueous solutions or suspensions), boluses, powders, granules, polymer release formulations, pastes for application to the tongue tablet, caplet or a capsule. A pill is a small, round, solid pharmaceutical oral dosage form that was in use before the advent of tablets and capsules. In colloquial usage, tablets, capsules, and caplets are still often referred to as "pills" collectively. In certain embodiments, pills are made by mixing the active ingredients with an excipient such as glucose syrup in a mortar and pestle to form a paste, then divided into suitable sizes, and often coated with sugar to make them more palatable. [00114] Dosage levels of a halogen compound present in a composition described herein may be varied as so to obtain an amount of the halogen compound that is effective to achieved the desired therapeutic effect for a particular subject, halogen compound and mode of administration, without being toxic to the subject. [00115] In various embodiments, compositions and unit dosage forms of the invention may be formulated in any different manner suitable for a desired delivery route. Typically, formulations include all physiologically acceptable compositions. Such formulations may include a halogen compound, optionally in combination with one or more additional active agents, in combination with any physiologically acceptable carrier, diluent or excipient. Halogen compounds may be formulated for administration with any biologically acceptable medium, including but not limited to water, buffered saline, polyol, or mixtures thereof. “Biologically acceptable medium” includes any and all solvents, dispersion media, and the like that may be appropriate for the desired route of administration of the pharmaceutical composition. Suitable biologically acceptable media and their formulations are described, for example, in the most recent Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, Pa., USA 1985).

[00116] Formulations, and unit dosages forms thereof, may contain suitable physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the halogen compound and/or other active agent into preparations that can be used pharmaceutically. Formulations, and unit dosage forms thereof, may also include agents that increase or otherwise affect the bioavailability of the halogen compound and/or other active agent. As used herein, “bioavailability” refers to the effect, availability and persistence of the active agent(s) after being administered to a subject.

[00117] Pharmaceutically acceptable carriers can be any pharmaceutically acceptable material, composition, or vehicle, including but not limited to a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agonists to an organ, or portion of the body.

[00118] The present invention further includes stable liquid pharmaceutical compositions formulated for parenteral administration, e.g ., intravenous administration or administration by infusion. In certain embodiments, the stable liquid pharmaceutical compositions comprise a reduced form of a reduced form of a halogen compound. In particular embodiments, the composition further comprises glutathione. In particular embodiments, a stable liquid pharmaceutical compositions formulated for parenteral administration comprises a halogen compound, e.g. , iodide, and glutathione. In particular embodiments, a stable liquid pharmaceutical compositions formulated for parenteral administration comprises iodide, and glutathione. The iodide and glutathione may be present at a concentration described herein, or in amount sufficient or appropriate to deliver an amount described herein to a subject. The concentration of each active agent in the composition may be readily determined based on the desired amount of each active agent to be delivered to a subject in need thereof. In particular embodiments, the composition comprises iodide, e.g., Nal or KI, at a concentration of about 1 mM to about 1M or about 10 mM to about 500 mM, and optionally glutathione at a concentration of about 1 mM to about 500 mM or about 10 mM to about 500 mM. In particular embodiments, the composition is contained within an oxygen-impermeable container, and may be under nitrogen or argon gas. In particular embodiments, the amount of composition present in the container is a unit dosage amount comprising or consisting of a suitable dosage amount for administration to a subject in need thereof.

[00119] Formulations of halogen compound for parenteral administration may comprise a halogen compound in combination with one or more pharmaceutically acceptable isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use. Parenteral formulations may contain antioxidants; buffers or solutes which render the formulation isotonic with the blood of the intended subject; bacteriostats; suspending; or thickening agents.

[00120] The present invention further includes kits comprising compositions or unit dosage forms of the present invention. In certain embodiments, such kits comprise one or more containers to store the compositions of the present invention. In one embodiment, the composition is stored in the container under an inert or noble gas, and the container is a sealed and has an oxygen impermeable light-protective container (e.g., an amber vial).

[00121] Compositions comprising halogen compounds, including reduced forms of halogen compounds, such as iodide and bromide, may be prepared by any means known and available. In certain embodiments, a halogen compound is dissolved in water or a suitable buffer, such as a NaCl buffer.

[00122] In certain embodiments, once produced, in various embodiments, a composition is stored in an impermeable container, e.g, an oxygen impermeable container. This is particularly desirable to prevent oxidation of the reduced form of halogen compound. Impermeable containers are known to those skilled in the art and include, but are not limited to, “i.v. bags” comprising a gas impermeable construction material, or a sealed glass vial. In particular embodiments, the impermeable container comprises an oxygen impermeable material having an oxygen transmission coefficient less than 10 ¹⁰ [cm ³ (STP)/cm/(cm ² +s+Pa)], wherein STP = standard temperature and pressure (25 degrees centigrade and pressure 1 atmosphere); PA = pascals, and s = second. For example, the walls of the container may comprise a layer of an oxygen impermeable polymer. Exemplary oxygen impermeable polymers include but are not limited to: silicon rubber, natural rubber, low density poly ethylene (LDPE), polystyrene (PS), polyethylene (PE), polycarbonate (PC), polyvinyl acetate (PVAc), amorphous polyethylene terephthalate (APET), polyvinly chloride (PVC), nylon 6 (Ny6), polyvinyl fluoride (PVF), polyvinylidene chloride (PVdC), polyacetonitrile (PAN), ethylene vinyl alcohol (EVOH), and polyvinyl alcohol (PVA). In certain embodiments, the oxygen transmission coefficient of said polymer is less than 10 ¹⁰ [cm ³ (STP)/cm/(cm ² +s+Pa)]. In particular embodiments, the walls of the container comprise multiple layers of one or more oxygen impermeable polymers.

[00123] To prevent exposure to air in the gas-tight storage container, an inert or noble gas, such as nitrogen or argon, may be introduced into a container containing a composition of the present invention prior to closure.

[00124] In other related embodiments, compositions are stored in a light-resistant or a light- protective container or vial, such as an amber vial. The composition may be packaged in a glass vial. It may be filled to a slight over-pressure in an inert atmosphere, e.g ., nitrogen, to prevent/slow oxidative breakdown of the composition, and may be contained in a form such that ingress of light is prevented, thereby preventing photochemical degradation of the composition. This may be achieved using an amber vial. Additional container systems that permit a solution to be stored in an oxygen-free environment are known, as many intravenous solutions are sensitive to oxygen. For example, a glass container that is purged of oxygen during the filling and sealing process may be used. In another embodiment, flexible plastic containers are available that may be enclosed in an overwrap to seal against oxygen. Basically, any container that prevents oxygen from interacting with the stable composition may be used (see, e.g. , U.S. Pat. No. 6,458,758). In one embodiment, the container includes one or more oxygen scavenger. For example, the oxygen scavenging composition can be applied as a coating or lining upon the inside surface of the product supporting or retaining means to function as a barrier to oxygen permeation (see, e.g., U.S. Pat. No. 5,492,742).

[00125] In particular embodiments, a container or vial may comprise a unit dosage of a composition of the present invention. In certain embodiments, the unit dosage form comprises or consists of an effective amount of the composition to treat or prevent a disease, condition, or injury, including any of those described herein, in a subject.

[00126] In particular embodiments, the present invention includes a container, such as a saline bag, that includes a premixed liquid composition of a halogen e.g, an iodide or bromide, wherein the amount of premixed liquid composition constitutes a dosage useful in treating or preventing a disease, condition, or injury, including any of those described herein, in a subject in need thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipient. In particular embodiments, the liquid composition is sterile.

[00127] In particular embodiments, the present invention includes a container, such as a vial, that includes a dry composition of a halogen compound, e.g ., an iodide or bromide, wherein the amount of dry composition constitutes a dosage useful in treating or preventing a disease, condition, or injury, including any of those described herein, in a subject in need thereof. The dry composition may be reconstituted, e.g. , with a pharmaceutically acceptable carrier, diluent, or excipient, e.g. , sterile water, prior to delivery to a subject in need thereof.

Methods of Using Halogen Compounds

[00128] In some embodiments, the present disclosure provides methods for treating, reducing the severity of, inhibiting, or preventing nonthyroidal illness syndrome (NTIS) in a subject in need thereof, comprising providing to said subject a halogen compound and a pharmaceutically acceptable carrier, diluent, or excipient. In particular embodiments, the halogen compound is an iodide, e.g., Nal or KI. In particular embodiments, the halogen compound is present in a pharmaceutical composition.

[00129] In certain embodiments, a composition disclosed herein is used to treat, reduce the severity of, inhibit, or prevent NTIS in a subject, wherein the subject has been diagnosed with or is considered at risk of a nonthyroidal illness. In particular embodiments, the subject has not been diagnosed with a preexisting hypothalamic-pituitary and thyroid gland dysfunction, or it has been determined that the subject does not have a preexisting hypothalamic-pituitary and thyroid gland dysfunction.

[00130] The subject may be diagnosed with NTIS based on one or more alterations in the serum level of a marker of thyroid function. In particular embodiments, the subject displays one or more alterations in serum thyroid function test findings.

[00131] In certain embodiments, a subject is diagnosed based on measurement of the subject’s TSH level, which in NTIS is low, normal, or slightly elevated but not as high as it would be in hypothyroidism. In certain embodiments, the subject’s serum TSH level is above 0.05 m IU/mL. Examples of normal ranges of serum marker of thyroid function are provided in Table 2

Table 2. Normal Laboratory Values for Thyroid Function Tests

Test Abbreviation Typical Ranges

Serum thyroxine T4 4.6-12 ug/dl

Free thyroxine fraction FT4F 0.03-0.005% Free Thyroxine FT4 0.7- 1.9 ng/dl Thyroid hormone binding ratio THBR 0.9-1.1 Free Thyroxine index FT4I 4-11 Serum Triiodothyronine T3 80-180 ng/dl Free Triiodothyronine 1 FT3 230-619 pg/d Free T3 Index FT3I 80-180 Radioactive iodine uptake RAIU 10-30% Serum thyrotropin TSH 0.5-6 uU/ml Thyroxine-binding globulin TBG 12-20 ug/dl T4 +1.8 ugm TRH stimulation test Peak TSH 9-30 ulU/ml at 20-30 min Serum thyroglobulin 1 Tg 0-30 ng/m

[00132] In certain embodiments, the subject has low serum triiodothyronine (T3) and/or elevated reverse T3 (rT3), which is referred to as "low T3 syndrome." In certain embodiments, thyroid-stimulating hormone (TSH), thyroxine (T4), free T4 (FT4), and free T4 index (FTI) serum levels are altered. Generally, as the severity of the NTI increases, both serum T3 and T4 levels fall, but they gradually normalize as the patient recovers. In certain embodiments, the subject’s T3 serum level is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, as compared to the subject’s normal baseline level, or as compared to a normal range in the same species, e.g., human. In certain embodiments, rT3 is elevated by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least two fold, at least three-fold, at least four-fold, or at least five-fold as compared to the subject’s normal baseline level, or as compared to a normal range in the same species. In certain embodiments, the subj ect’ s T4 and/or FT4 serum level is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, as compared to the subject’s normal baseline level, or as compared to a normal range in the same species.

[00133] In certain embodiments, the subject’s T3 or serum T3 level is less than or equal to 100 ng/dL, less than or equal to 80 ng/dL, less than or equal to 60 ng/dL, less than or equal to 50 ng/dL, less than or equal to 40 ng/dL, less than or equal to 30 ng/dL, or less than or equal to 20 ng/dL.

[00134] In certain embodiments, the subject’s T4 or serum T4 level is less than or equal to 10 g/dL, less than or equal to 8 g/dL, less than or equal to 6 g/dL, less than or equal to 5 g/dL, less than or equal to 4 g/dL, less than or equal to 3 g/dL, or less than or equal to 2 g/dL. In certain embodiments, the subject’s T4 or serum T4 level is less than or equal to 8 ug/dL, less than or equal to 6 ug/dL, less than or equal to 5 ug/dL, less than or equal to 4 ug/dL, less than or equal to 3 ug/dL, less than or equal to 2 ug/dL or less than or equal to 1 ug/dL.

[00135] In certain embodiments, the subject’s serum TSH level is above 0.05 m IU/mL. In certain embodiments, it is at or between between 0.05 and 2.0 m IU/mL, or at or between 0.05 and 1.0 m IU/mL, or at or between 0.05 and 0.5 m IU/mL, or at or between 0.05 and 0.1 m IU/mL. In certain embodiments, the subject’s TSH level is above 4.0 uU/mL, above 5.0 uU/mL, above 6.0 uU/mL, above 7.0 uU/mL, above 8.0 uU/mL, or above 10 uU/mL.

[00136] Serum levels of T3, rT3, TSH, T4, FT4 and FTI may be measured using standard laboratory techniques. For example, a blood or serum sample may be obtained from a subject and tested, e.g., using an immunological assay, such as an ELISA assay. Equilibrium dialysis or ultrafiltration methods may be used for the measurement of free thyroid hormones in serum. [00137] Several methods can be used to measure free T4 directly, including, e.g., equilibrium dialysis, a 2-step immunoextracti on technique, a 1-step (analog) method, FTI (T3 resin-binding ratio), and ultrafiltration. Equilibrium dialysis usually is the reference method but any may be employed. In equilibrium dialysis, a small amount of radioactive tracer T4 and the unknown sample are placed in a dialysis membrane, which limits the diffusion of bound T4. The proportion of the hormone that is dialyzable (ie, free) is determined. The dialyzable hormone- to-total hormone ratio is used, with the concentration of T4 determined in a standard assay and used to calculate the concentration of free T4. Another assay is the 2-step radioimmunoassay (RIA). The subject's serum is equilibrated with a solid phase antibody to T4. The unoccupied antibody binding sites are quantified in a second step in which labeled hormone is added to the solid phase system. An FTI is calculated by multiplying the total T4 concentration by the T3 uptake (T3U). The T3U is an indirect estimate free T4 fraction, which is obtained by adding labeled T3 to serum and estimating how much of it remains free for binding to a secondary binder (e.g., charcoal, talc, ion-exchange resin, anti-T3 antibody, immobilized albumin) added to the serum. In this way, the FTI reflects the actual free T4 concentration, although this appears to be less accurate in cases of very low or high TBG concentrations. The ultrafiltration method is a research assay in which ultrafiltrates of undiluted serum are used to measure free T4. In a study of 504 patients by Docter et al, free T4 was elevated in 54% of the patients with mild-to- severe NTI, according to measurements using equilibrium dialysis, and free T4 was elevated in about 24% of patients in the most severely ill group (Docter R, Krenning EP, de Jong M, Hennemann G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf). 1993 Nov. 39(5):499-518. [Medline]). Another study by Melmed et al demonstrated that free T4 was reduced in ICU patients as measured by 6 different methods, including equilibrium dialysis (Melmed S, Geola FL, Reed AW, et al. A comparison of methods for assessing thyroid function in nonthyroidal illness. J Clin Endocrinol Metab. 1982 Feb. 54(2):300-6. [Medline]). Free T4 was found to be uniformly reduced as measured by all methods, but patients with liver disease and chronic renal failure exhibited more variable results. This study demonstrated that, overall, patients with NTI who have serum total T4 levels within the reference range typically do not have reduced free T4 by most assay methods.

[00138] Serum TSH may be measured with immunometric assays, such as, e.g., a sandwiched ELISA assay.

[00139] In particular embodiments, the NTIS is associated with, concurrent with, or resulted from an illness, disease, or injury, e.g., a primary or acute illness or injury, in the subject. In particular embodiments, the subject is considered to be at risk of NTIS due to an illness, disease, or injury, e.g., a primary or acute illness or injury, in the subject. In various embodiments, the illness or injury is selected from gastrointestinal diseases, pulmonary diseases, cardiovascular diseases, renal diseases, infiltrative and metabolic disorders, inflammatory conditions, myocardial infarction, starvation or diminished food intake, septicemia, e.g., meningococcal septicemia, pancreatitis, gastritis, susceptibility to or infection by H. Pylorisepsis, burns, trauma, surgery, malignancy, or bone marrow transplantation. In other related embodiments, the illness or injury is selected from thyroid surgery/surgical storm, nonthyroidal surgery (i.e., all other surgeries), trauma, mountain sickness (e.g., acute mountain sickness), manipulation of the thyroid gland, thyroiditis, preeclampsia, HELLP syndrome, parturition, bum, pulmonary embolism, cerebrovascular incidents, cytokine storm associated (e.g., associated with immune therapy), hypoxia, extracorporeal membrane oxygenation (ECMO), diabetic ketoacidosis, hypoglycemia, ingestion of high doses of thyroid hormone, metastatic thyroid cancer, struma ovarii, molar pregnancy, emotional stress, or intense exercise. In certain embodiments, the injury or illness is an acute or chronic illness, particularly fasting, starvation, protein-energy undemutrition, severe trauma, myocardial infarction, chronic kidney disease, diabetic ketoacidosis, anorexia nervosa, cirrhosis, thermal injury, or sepsis, e.g., septicemia.

[00140] In particular embodiments, the NTIS is associated with, concurrent with, or resulted from an infection, e.g., a bacterial, viral or yeast infection. In particular embodiments, the subject is considered to be at risk of NTIS due to an infection, e.g., a bacterial, viral or fungal (e.g., yeast) infection. In one embodiment, the infection is an H1N1 infection.

[00141] In certain embodiments, the NTIS is associated with, concurrent with, or results from treatment with a medication or withdrawal of a medication or medical treatment. In certain embodiments, the subject is considered to be at risk of NTIS due to treatment with a medication or withdrawal of a medication or medical treatment. In certain embodiments, the NTIS is associated with, concurrent with, or resulted from withdrawal of antithyroid treatment. In some embodiments, the NTIS is associated with concurrent with, or resulted from treatment with one or more anesthetic, salicylate, pseudoephedrine, amiodarone, interferon, radioactive iodine, or exposure to iodinated contrast agent. In particular embodiments, the medication is a steroid (e.g., epinephrine), or a non-steroidal anti-inflammatory drug (NS AID, e.g., aspirin). In certain embodiments, the NTIS is associated with treatment with any of the following: steroids including, but not limited to, corticosteroids, such as a glucocorticoid selected from cortisol, hydrocortisone, cortisone, triamcinolone, methyprednisone, fludrocortisone, prednisolone, prednisone, demamethasone, betamethasone, beclomethasone, budesonide, clobetasol, and fluticasone; epinephrine; or a nonsteroidal anti-inflammatory drug (NS AID) including, but are not limited to, aspirin, celecoxib, diclofenac, diflunisol, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac and tolmetin. Accordingly, the subject may be provided with a halogen compound (e.g., iodide, such as Nal) in combination with any of these medications, or after treatment with any of these medications, to treat, inhibit, or prevent NTIS.

[00142] In some embodiments, the NTIS is associated with exposure of a subject to low oxygen, high altitude, fever, or anorexia. In particular embodiments, the subject is exposed to oxygen levels lower than 3%, lower than 4%, lower than 5%, lower than 6%, or lower than 7% for a period of time, e.g., at least 15 minutes, at least 30 minutes, at least 1 hour, or at least 2 hours. In particular embodiments, the subject is exposed to high altitude, e.g., at least 10,000 feet above sea level, at least 12,000 feet above sea level, or at least 14,000 feet above sea level for a period of time, e.g., at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, or at least 48 hours. In particular embodiments, the subject has acute mountain sickness or high altitude edema. In particular embodiments, the subject has a fever, e.g., a temperature greater than 100 degrees fahrenheit, geater than 102 degrees fahrenheit, greater than 104 degrees fahrenheit, or greater than 106 degrees Fahrenheit for a period of time, e.g., at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, or at least 48 hours. In some embodiments, the subject is diagnosed with anorexia or another eating disorder, or the subject is at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% below average weight.

[00143] In some embodiments, newborn babies suffer from NTIS. Accordingly, in some embodiments, the disclosure provides methods to treat, reduce the severity of, or prevent NTIS in a newborn baby, wherein the newborn baby is provided with an effective amount of a halogen compound, e.g., iodide, before birth, during birth, or within one hour, two hours, four hours, 12 hours, 24 hours, 48 hours, or one week post-birth. In certain embodiments, a pregnant mammal, e.g., a human, is provided with an amount of halogen compound, e.g., iodide, sufficient to achieve an effective amount in the fetus being carried by the subject prior to the fetus’s birth. In certain embodiments, the mother is provided with the halogen compound over a time period that includes a time within one day, two days, three days or one week prior to the anticipated birth date. In certain embodiments, the mother is provided with the halogen compound during labor. In particular embodiments, these methods are performed on premature babies or babies weighing less than 2,500 grams, less than 2,000 grams or less than 1,500 grams, either before, during or after birth. In particular embodiments, these methods are performed on premature babies or babies considered to be at risk of or diagnosed with necrotizing enterocolitis, either before, during or after birth.

[00144] The present disclosure further provides methods of reducing serum levels of rT3 or TSH in a subject in need thereof, e.g., a subject with NTIS, comprising providing to the subject an effective amount of a halogen compound, e.g., an iodide, such as Nal or KI. In a related embodiment, methods of preventing or diminishing an increase in serum levels of rT3 or TSH in a subject in need thereof, e.g., a subject at risk of NTIS, are provided, comprising providing to the subject an effective amount of a halogen compound, e.g., an iodide, such as Nal, are provided. In particular embodiments, the subject at risk of NTIS has one or more of the illnesses or injuries disclosed herein to be associated with or result in NTIS. In particular embodiments, the method results in reducing one or more of rT3 or TSH. In certain embodiments, rT3 and/or TSH is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In a related embodiment, the disclosure provides a method for inhibiting an increase in serum levels of rT3 and/or TSH in a subject in need thereof, comprising providing to the subject an effective amount of a halogen compound, wherein the halogen compound is optionally an iodide. [00145] The present disclosure further provides methods of increasing serum levels of T3, T4 or FT4 in a subject in need thereof, e.g., a subject with NTIS, comprising providing to the subject an effective amount of a halogen compound, e.g., an iodide, such as Nal or KI. In a related embodiment, methods of preventing or diminishing a reduction in serum levels of T3, T4 or FT4 in a subject in need thereof, e.g., a subject at risk of NTIS, comprising providing to the subject an effective amount of a halogen compound, e.g., an iodide, such as Nal, are provided. In particular embodiments, the subject at risk of NTIS has one or more of the illnesses or injuries disclosed herein to be associated with or result in NTIS. In particular embodiments, the method results in increasing one or more of T3, T4, or FT4. In certain embodiments, T3, T4 and/or FT4 is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least two-fold, at least three-fold, at least five-fold, or at least 10-fold.

[00146] The disclosure also provides a method for maintaining or restoring normal thyroid hormone function is a subject in need thereof, comprising providing to the subject an effective amount of a halogen compound, wherein the halogen compound is optionally an iodide. [00147] In certain embodiments, the composition is provided to the subject in an amount sufficient to increase the blood concentration of the halogen compound, e.g., Nal or KI, at least five-fold, at least ten-fold, at least 50-fold, at least 100-fold, at least 500-fold, or at least 1000- fold for at least some time.

[00148] In certain embodiments, a subject is treated for NTIS with an iodide, e.g., Nal or KI. In particular embodiments, the subject being treated has higher cortisol serum levels than normal or above a normal range for the species, e.g., human.

[00149] In particular embodiments, any of the methods disclosed herein further comprise determining a serum level of cortisol in the subject. In certain embodiments, the serum level of cortisol is monitored over a time period of treatment with the halogen compound, and the treatment is continued until the serum level of cortisol falls within a normal range. In some embodiments, serum cortisol range is considered normal if it falls within a range of 2-28 pg/dL. [00150] Cortisol is secreted in short bursts and blood levels are usually highest early in the morning, decreasing gradually throughout the day and reaching a low point in the late evening. Consequently, normal levels of plasma cortisol constitute a broad range. When assessed with a typical radioimmunoassay, cortisol levels range from about 10 to 20 micrograms per deciliter (ug/dl) in the early morning (within one hour of the usual time of awakening), from 3 to 10 ug/dl at 4 PM, and are usually less than 5 ug/dl after the usual bedtime, but there is considerable variation. These assays measure ‘total’ cortisol, most of which is bound to proteins in the bloodstream, and only unbound is biologically active.

[00151] In certain embodiment, the serum level of one or more of rT3, TSH, FT4, T4 and T3 is determined in a subject being treated for NTIS with an iodide, e.g., Nal, and the subject is treated until the serum level of the one or more is stabilized or falls within a normal range. In certain embodiments, the serum level of one or more of rT3, TSH, FT4, T4 and T3 is monitored over a time period of treatment with the halogen compound. In particular embodiments, the serum level of T3 is monitored during treatment with the halogen compound, and the treatment is continued until the serum level of T3 is stabilized. In particular embodiments, the serum level of T4 is monitored during treatment with the halogen compound, and the treatment is continued until the serum level of T4 is stabilized or greater than 5 g/dL or 10 g/ dL. In particular embodiments, the serum level of TSH is monitored during treatment with the halogen compound, and the treatment is continued until the serum level of TSH is elevated by at least 50% or falls within a normal range.

[00152] In some situations, an injury or disease that causes NTIS may result in increased plasma iodide levels in a subject, whereas in some situations, an injury or disease that causes NTIS may results in no change or descreased plasma iodide levels. In any of these siutations, the subject may be treated with iodide, e.g., Nal or KI, in order to treat, prevent, inhibit or reduce NTIS. Without wishing to be bound by theory, it is understood that in any of these cases, the plasma iodide level may still be below the threshold level for a therapeutic effect in treating or preventing NTIS in the subject.

[00153] In certain embodiments, the halogen compound (e.g., Nal or KI) is provided to the subject in a liquid pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, at least 90% of the halogen compound in the composition is present in a reduced form for at least one hour, at least one week, at least one month, or at least six months when stored at room temperature. In particular embodiments, a composition comprising the halogen compound comprises one or more of a reducing agent, a tonicity agent, a stabilizer, a surfactant, a lycoprotectant, a polyol, an antioxidant, or a preservative.

[00154] In particular embodiments, the pharmaceutical composition is provided to the subject prior to, during, or following the primary injury or disease.

[00155] In certain embodiments, the pharmaceutical composition is provided to the subject orally or parenterally. For example the pharmaceutical composition may be provided to the subject as a bolus dose prior to the primary injury or disease, optionally wherein the bolus dose comprises less than or equal to about 10 mg/kg, optionally about 1.0 mg/kg of iodide, e.g., Nal or KI. In other examples, the pharmaceutical composition is provided to the subject following the primary injury or disease.

[00156] In some embodiments the chalcogenide, e.g., Nal or KI is provided to the subject at a dosage sufficient to achieve a blood concentration in the subject of about 300 ng/ml to about 6 ug/ml, about 1 ug/ml to about 5 ug/ml, e.g., about 2 ug/ml, about 3 ug/ml, about 4 ug/ml, or about 5 ug/ml. In some embodiments, the dosage is sufficient to achieve a blood concentration of at least or about 1 ug/ml or 1 ppm, at least or about 2 ug/ml or 2 ppm, at least or about 3 ug/ml or 3 ppm, at least or about 4 ug/ml or 4 ppm, or at least or about 5 ug/ml or 5 ppm. In some embodiments, the dosage is sufficient to achieve a blood concentration of at least or about 3 ug/ml or 3 ppm.

[00157] In particular embodiments of any of the methods disclosed herein, the halogen compound is sodium iodide.

[00158] In particular embodiments of any of the methods disclosed herein, the subject is a mammal, e.g., a human.

[00159] In particular embodiments, the composition is a stable formulation formulated to maintain the halogen compound, e.g., a halide, such as iodide or Nal or KI, in a reduced state. [00160] In particular embodiments of any of the methods described herein, the subject is treated prior to, during, and/or following a medical treatment. In certain embodiments, the subject is treated prior to, during, and/or after a scheduled medical treatment.

[00161] In various embodiments of any of the methods disclosed herein, the severity of one or more symptoms or the duration of one or more symptoms is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[00162] In certain embodiments, the present invention includes methods comprising providing to the subject an effective amount of a halide or a composition of the present invention. In particular embodiments, the composition comprises an effective amount of one or more halides and optionally one or more additional active agents. In particular embodiments, the halide or halogen compound comprises iodine, e.g, iodide or iodate, such as Nal or KI. In particular embodiments, the composition also comprises glutathione or another reducing agent.

[00163] In certain embodiments of methods of the invention, the halogen compound comprises iodine or iodide, e.g, Nal or KI, and the effective amount is greater than or equal to about 150 qg, greater than or equal to about 300 qg, greater than or equal to about 500 qg, greater than or equal to about 1 mg, greater than or equal to about 2 mg, greater than or equal to about 5 mg, greater than or equal to about 10 mg, greater than or equal to about 15 mg, or greater than or equal to about 20 mg. In certain embodiments, the effective amount is 150 qg to 1000 mg, 300 qg to 1000 mg, 500 qg to 1000 mg, 1 mg to 1000 mg, 2 mg to 1000 mg, 5 mg to 1000 mg,

10 mg to 1000 mg, 150 qg to 100 mg, 300 qg to 100 mg, 500 qg to 100 mg, 1 mg to 100 mg, 2 mg to 100 mg, 5 mg to 100 mg, or 10 mg to 100 mg. In certain embodiments, the effective amount is 150 qg to 50 mg, 300 qg to 20 mg, 500 qg to 10 mg, 1 mg to 20 mg, 1 mg to 10 mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg. [00164] In particular embodiments of any of the methods of the present invention, a subject is treated with or contacted with an effective amount of a composition or compound of the present invention, wherein said effective amount of about 0.01 mg/kg to about 20 mg/kg, about 0.05 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 0.5 mg/kg to about 2 mg/kg, about 0.5 mg/kg to about 1 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg or about 1.2 mg/kg. In certain embodiments, the composition comprises a halogen compound, e.g., Nal or KI.

[00165] In particular embodiments, an effective amount of iodine or iodide is an amount at least or about two-fold, three-fold, four-fold, five-fold, six-fold, seven-fold, eight-fold, nine-fold, ten-fold, twelve-fold, fifteen-fold, 100-fold, 1,000-fold, 10,000-fold or 100,000-fold of the average daily recommended amounts as listed below. In particular embodiments, the effective amount of iodine or iodide is an amount between two-fold and twenty-fold, between five-fold and fifteen-fold, or between five-fold and ten-fold of the average daily recommended amounts of iodine as listed below.

'NIH Office of Dietary Supplements Iodine Fact Sheet for Consumers, reviewed June 24, 2011, obtained 2013.

[00166] In certain embodiments of methods of the invention, the halogen compound comprises iodine, e.g ., Nal, and the effective amount is about 0.01 mg/kg to about 20 mg/kg, about 0.05 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 0.5 mg/kg to about 2 mg/kg, about 0.5 mg/kg to about 1 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg or about 100 mg/kg. In certain embodiments, the halogen compound comprises iodine, and the effective amount is an amount that achieves about the same concentration or amount that is achieved by an effective amount of iodine that is at least or about two-fold, three-fold, four-fold, five-fold, six-fold, seven-fold, eight-fold, nine-fold, ten-fold, twelve-fold, fifteen-fold, or twenty-fold of the average daily recommended amounts as listed below.

[00167] In certain embodiments of methods disclosed herein, a subject in need thereof is provided with an effective amount of a halogen compound, e.g., a halogen compound comprising iodine, bromine, or fluorine, an iodide, such as e.g., sodium iodide, potassium iodide, magnesium iodide, hydrogen iodide, calcium iodide, or silver iodide. In particular embodiments, the halogen compound is provided parenterally, orally or systemically in an amount sufficient to achieve a blood concentration of 20 parts per billion (ppb) to 20 parts per million (ppm). In particular embodiments, the effective amount achieves a blood concentration in the subject in the range of: 100 ng/mL to 100 ug/mL, 100 ng/mL to 50 ug/mL, 100 ng/mL to 10 uh/mL, or 300 ng/ml to 6 ug/ml In particular embodiments, the subject is a human. [00168] A composition comprising the halogen compound, and a composition comprising an additional active agent may be provided to the subject at the same time, at different times, or during overlapping time periods. In particular embodiments when both are present, the halogen compound and the additional active agent are present in the same or different compositions. [00169] In particular embodiments where the composition comprises glutathione and a halogen compound, glutathione is present in an amount sufficient to inhibit oxidation of the halogen compound, including any of the ranges described herein. In particular embodiments, the halogen compound is iodide, e.g. , Nal.

[00170] In various embodiments of methods of the present invention, a subject is exposed to a composition of the current invention for about, at least, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 hours, 1, 2, 3, 4, 5, 6, 7 days, 1, 2, 3, 4 weeks, 1, 2, 3, 4, 5, 6, 7, 8 or 9 months or more, and any range or combination therein.

[00171] Furthermore, when administration of a composition according to the present invention is intravenous or by infusion, it is contemplated that the following parameters may be applied. A flow rate of about, at least about, or at most about 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, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,

40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,

65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,

90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 gtts/min or pgtts/min, or any range derivable therein. In some embodiments, the amount of the composition is specified by volume, depending on the concentration of the halogen compound in the composition. An amount of time may be about, at least about, or at most about 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, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,

44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 minutes, 1, 2, 3, 4, 5, 6, 7, 8, 9,

10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 hours, 1, 2, 3, 4, 5, 6, 7 days, 1, 2, 3, 4,

5 weeks, and/or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or any range derivable therein. [00172] Volumes of 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, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,

49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,

74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,

99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270,

280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 441, 450,

460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640,

650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830,

840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 mis or liters, or any range therein, may be administered overall or in a single session.

[00173] According to various embodiments of the methods of the present invention, a subject is provided with a composition of the invention, e.g ., intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intraperitoneally, intraocularly, subcutaneously, subconjunctival, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, topically, locally, by injection, by infusion, by continuous infusion, by absorption, by adsorption, by immersion, by localized perfusion, via a catheter, or via a lavage. In particular embodiments, it is provided parenterally, e.g, intravenously, or by inhalation. “Parenteral” refers to any route of administration of a substance other than via the digestive tract. In specific embodiments, a halogen compound is provided to the subject by intravenous administration or infusion.

EXAMPLES Example 1

NTIS is ASSOCIATED WITH INCREASED IODIDE LEVELS [00174] A variety of different conditions or agents known to cause NTIS were tested to determine if they affected iodide levels in subjects.

Epinephrine

[00175] Rats were treated by injection of epinephrine or left untreated. Blood was obtained from the rats at a later time and tested for iodide levels. The blood iodide level was increased by about 30% in the rats treated with epinephrine as compared to the untreated rats.

Physical Restraint

[00176] Rats were placed in a physical restraint device for two hours or left unrestrained. Blood was obtained from the rats at a later time and tested for iodide levels. The blood iodide level was increased by about 30% in the rats subjected to the restraint device as compared to the unrestrained rats.

Low Oxygen

[00177] Unrestrained rats were exposed to 5.5% or 8% oxygen for 15 minutes. Blood was then obtained from the rats and tested for iodide levels. The blood iodide level was increased 8-fold in the rats exposed to 5.5% oxygen as compared to the rats exposed to 8% oxygen.

Trauma

[00178] An observational study of 60 human trauma patients in intensive care in a hospital was conducted, in which blood iodide levels were measured within 2 hours of the patient’s trauma event. Blood iodide levels were also measured in 50 control healthy subjects. The results showed that the trauma patients had a 30-fold increase in blood iodide levels as compared to the control healthy subjects, within two hours of the trauma event. Given the magnitude of the increase in blood ioide, it is believed that the iodide came from the thyroid, and was not simply the result of deiodinating thyroid hormones already present in the blood or non-thyroidal tissues. Example 2

HIGH ALTITUDE RESULTS IN REDUCED IODIDE

[00179] Blood Iodide levels were determined in sixteen people in three different conditions as they went from sea level (Baseline) to 17,600 feet for 16 days. Acute mountain sickness was diagnosed in 86% of the patients on the first day at high elevation (A1 in FIG. 1) and not at all prior to ascent or after 16 days at 17.600 feet elevation. The three groups in FIG. 1 are B, Baseline; Al, 1 day at 17,600 feet elevation; and A16, 16 days at 17,600 feet elevation. As shown in FIG. 1, blood iodide levels decreased following ascent. These data support the administration of iodide prior to or early during or after ascent to prevent, inhibit, or improve outcome, for Acute Mountain Sickness.

Example 3

IODIDE REDUCES NTIS

[00180] Effective amounts of iodide for minimizing NTIS were determining in an animal model of NTIS in which the amount of NTIS is correlated with the amount of damage or creatine kinase in the blood.

[00181] Increasing amounts of sodium iodide was provided to rodents in their drinking water for 5 days prior to conducting hind limb occlusion for two hours of ischemia followed by three hours of reperfusion, sfter which levels of creatine kinase in the blood was measured. The amount of NTIS is known to correlate with the amount of damage or creatine kinase in the blood, and the degree of protection from injury and NTIS is indicated by the amount of creatine kinase in the blood following injury.

[00182] As shown in FIG. 2, The optimal dose of iodide in the drinking water was 100 ug/ml, which resulted in a blood concentration of 3 ug/ml. The evidence indicates that a concentration of iodide in the blood to minimize NTIS can range from at least as low as 300 ng/ml to at least as high as 6 ug/ml.

[00183] All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety.

[00184] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.