WO2014037927A1 - Chlorate compositions and use of chlorate for treating radiation exposure - Google Patents

Description

Title: Chlorate Compositions and Use of Chlorate for Treating Radiation Exposure

Field of the Application

[0001] The present application relates to compositions comprising chlorate and uses of chlorate for treating subjects who have been exposed to radiation. More particularly, the application relates to the use of chlorate compositions for treating subjects with acute radiation syndrome.

Background of the Application

[0002] Ionizing radiation is present naturally in the environment. Normal background levels of radiation carry little risk to the general public. However, exposure to elevated levels of ionizing radiation can cause a large spectrum of health effects. The nature and severity of the health effects depends primarily on the dose of radiation and the exposure time.

[0003] For example, exposure to high levels of ionizing radiation can cause damage to DNA, protein and lipids in mammalian ceils, as well as increased mitochondria-dependent generation of reactive oxygen species (ROS), with subsequent cell cycle checkpoint arrest, apoptosis, and stress- related responses.

[0004] Tissue injuries induced by ionizing radiation differ depending on the target organ and cell type. Organs and cells with high sensitivity to radiation include the immune system, the skin, the hematopoietic system, the gut, the lungs, the kidneys, the spermatogenic cells and the vascular system.

[0005] In particular, acute radiation syndrome (ARS) (also known as radiation sickness or radiation poisoning) is a potentially fatal condition that results from total- or partial-body exposure to high levels of radiation (above about 1 Gray (Gy) in humans) over a relatively short time period. Symptoms of ARS may include, but are not limited to, nausea, vomiting, diarrhea, loss of appetite, fatigue, skin damage, hair loss, fever, diminished organ function, seizures, coma, and death. The symptoms of ARS typically develop within several days/weeks/months following exposure to ionizing radiation depending on the radiation dose.

[0006] A number of treatments for ARS are under development. Treatment options that have or are being investigated include cytokine therapy, stem cell therapy, and the administration of various chemical and natural agents that act as antioxidants or immunomodulators.

[0007] WF10 (often referred to in older literature as tetrachlorodecaoxide or TCDO) is an intravenous (i.v.) aqueous solution containing the anions chlorite (0.425% w/v), chlorate (0.15% w/v), chloride (0.2% w/v), and sulfate (0.07% w/v) with sodium as the cation. The active principle of WF10 has been reported to be chlorite (McGrath ef al. (2002), Curr. Opin. Investig. Drugs, 3(3):365-373; PCT patent application publication no. 2007/009245). WF10 is sold under the trade name Immunokine^® in Thailand where it is approved as an adjunctive treatment for cancer patients suffering from post-radiation syndromes. Its effect on local and total-body irradiation in animals has also been studied (Kempf ef al. (1994), Oncology 51 :510-514; Mason et al. (1993), Radiation Research 136:229-235; Breiter et al. (1989), The British journal of Radiology 62:381-383; Sassy ef al. (1991), Onkol. 167:191-193). Ivankovic et al. studied the acute effect of i.v. administered WF10 after total-body irradiation of BD IX rats with an LD₅₀ (11 Gy) dose of cobalt γ rays (Radiation Research (1988), 115:115-123). In a follow-up experiment, Kempf et al. exposed 2 groups of rats to either 9 Gy or 1 1 Gy of total-body irradiation; the animals in each group were treated intravenously with either WF10 or saline after exposure (Radiation Research (1994), 139:226-231). in both the Ivankovic et al. and Kempf et al. studies, enhanced survival was attributed to treatment of animals with WF10.

[0008] However, toxicological characteristics including hemolytic anemia, hemoglobinuria, loss of weight, weakness and lethargy are attributed to higher doses of WF10 (Ivankovic et al.). In addition, side effects such as increases in methemoglobin levels and reductions in RBC glutathione reductase levels are seen in patients receiving greater than 0.5 ml_ kg WF10 which is, therefore, considered to be the maximum tolerated dose (see Raffanti, S.P., Schaffner, W., Federspiel, C.F., Blackwell, R.B., Ah Ching, O., Kiihne, F.W, Randomized, double blind, placebo-controlled trial of the immune modulator WF10 in patients with advanced AIDS. Infection, Vol. 26, 4, 201-206 (1998)). Furthermore, WF10 contains a carbonate buffer to maintain alkaline environment (pH of >10) to maintain the stability of the active chlorite ion. Thus, administering a highly basic solution, such as WF10, by intravenous infusion can result in phlebitis (inflammation of the vein) unless the infusion is performed slowly, and only after WF10 is diluted using about 250 - 500 mL of saline, For this reason a WF10 infusion might typically be administered over a period such as 1.5 hours resulting in patient inconvenience and significant utilization of medical resources. As such, administration of WF10 by i.v. requires clinical supervision and eliminates its use as an "at home" remedy.

Summary of the Application

[0009J The present application is directed to the use of chlorate as an effective agent in the treatment of subjects who have been exposed to radiation. The present application includes compositions and uses of chlorate that are expected to have a wider therapeutic index than currently approved radiation treatments. For example, chlorate has a more favorable toxicological profile than chlorite, the reported active principle in WF10 (Bureau EC-EC. lUCLID Dataset-Substance ID: 7758-19-2. European Comission - European Chemicals Bureau; 2000. p. 56; Health Canada. Guidelines for Canadian Drinking Water Quality: Guideline Technical Document — Chlorite and Chlorate. Water Quality and Health Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario. Health Canada 2008). The lower toxicity of chlorate is evidenced by the fact that the median lethal dose (LD₅₀) of sodium chlorate is almost 20-fold higher than that of sodium chlorite. The LD₅₀ of sodium chlorate and sodium chlorite have been reported to be 2228.6 and 1 12.8 mg/kg body weight in rats, respectively, after intravenous administration [See, Jeng DK, Woodworth AG. Chlorine dioxide gas sterilization of oxygenators in an industrial scale sterilizer: a successful model. Artificial organs. 1990 Oct;14(5):361-8]. Additionally, oral dosage forms are accessible for the compositions of the present application which, due to the high reactivity of chlorite (particularly in the acidic conditions of the gut), are not suitable forms for WF10. Further unlike chlorite, which has been demonstrated to decompose within 30 seconds after contact with whole bfood, chlorate has been shown to be bioavailable after oral administration (Hakk et al. (2007), J. Agric. Food Chem. 55:2034-2042; Oliver et ai. (2007) J Vet Pharmacol Ther. 30(4):358-65). Moreover chlorate-based formulations are suitable for long-term storage and administration to animals under neutral pH conditions, whereas formulations containing chlorite tend to be unstable unless stored at high pH and special precautions, such as long infusion times, may be necessary to administer such high pH formulations to an animal if side effects such as phlebitis are to be avoided.

[0010] The present application includes compositions comprising chlorate for the treatment of radiation exposure. In particular, the present application includes compositions comprising chlorate for treating a condition arising from radiation exposure such as acute radiation syndrome.

[0011] The present application further includes a method for treating radiation exposure comprising administering an effective amount of chlorate to a subject in need thereof. In particular, the present application includes a method for treating a condition arising from radiation exposure, for example, acute radiation syndrome, comprising administering an effective amount of chlorate to a subject in need thereof. In other embodiments the condition is an acute radiation sub-syndrome associated with one or more of, the blood, the immune system, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain. In further embodiments, the acute radiation sub-syndrome is neutropenia, thrombocytopenia or injury to the hematopoetic system or immune system.

[0012] In some embodiments of the application, the chlorate is in an aqueous solution. In other embodiments, the chlorate is in a solid, semi-solid, gel, paste, liquid, crystalline or encapsulated form. In further embodiments, the chlorate is an enteral composition, including an oral or rectal composition or a parenteral composition including a dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, subcutaneous, sublingual, topical, inhalative or transdermal composition.

[0013] In some embodiments, the composition comprises, or consists essentially of, chlorate as the sole active ingredient, in another embodiment, the composition is chlorite-free. In a further embodiment, the composition is sulfate-free. In yet a further embodiment, the composition is carbonate-, bicarbonate-, and/or carbonic acid-free. In still a further embodiment, the composition is chloride-free. In another embodiment, the composition is carbonate-, bicarbonate-, carbonic acid-, sulfate-, chloride-, and/or chlorite- free. In yet a further embodiment the chlorate treatment is effected by administering to a subject a dosage form which is essentially free of water.

[0014] In some embodiments, the composition comprises about 0.01 % to about 100% w/w of a chlorate salt. In other embodiments, the composition is an oral composition comprising about 0.05% to about 80% w/v chlorate ion. In further embodiments, the composition is an aqueous solution comprising about 0.1 % to 2.5% or about 1.5% w/v chlorate ion.

[0015] In an embodiment, the chlorate composition is formulated as a pharmaceutical composition for administration to subjects. In another embodiment, the pharmaceutical composition comprises, or consists essentially of chlorate, as the sole active ingredient. In another embodiment, the pharmaceutical composition is chlorite-free. In a further embodiment the pharmaceutical composition is sulfate-free. In yet a further embodiment, the pharmaceutical composition is carbonate-, bicarbonate-, and/or carbonic acid- free. In still another embodiment, the pharmaceutical composition is chloride- free or anhydrous. In further embodiments, the pharmaceutical compositions of the application are sold as ready-to-use unit doses or require dilution (e.g. with water or saline) prior to use. In yet further embodiments, for ease of manufacturing, the pharmaceutical compositions are concentrated prior to packaging and delivery to a pharmacist.

[0016] In further embodiments, the chlorate is administered at least once a day, at least once every second day, at least once every third day, at least once every fourth day, or as required to treat a subject. In other embodiments the chlorate is administered twice, three times or four times a day or as needed. Optionally, the chlorate is administered starting at least 2, 3, 4 or 5 days following radiation exposure. In further embodiments, subjects are treated with more than one cycle, for example, at least two, three, four or five cycles.

[0017] In further embodiments, the chlorate is administered enterally, including orally or rectaily, or a parenterally including including dermally, intradermal^, intragastrally, intracutaneously, intravasally, intravenously, intramuscularly, intraperitoneally, intranasally, intravaginally, intrabuccally, percutaneously, subcutaneously, sublingually, topically, inhalatively or transdermally. In one embodiment, the chlorate is administered intravenously, In another embodiment, the chlorate is administered orally.

[0018] In other embodiments, the subject has been exposed to at least 0.5 or 1 Gray of radiation within one hour, one day, one week or one month.

[0019] The application also includes a use of an effective amount of chlorate for treating a subject who has been exposed to radiation. The appiication further includes a use of an effective amount of chlorate for treating a condition arising from radiation exposure. In some embodiments, the condition is acute radiation syndrome. In other embodiments the condition is an acute radiation sub-syndrome associated with one or more of, the blood, the immune system, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain. In other embodiments the condition is an acute radiation sub-syndrome associated with one or more of neutropenia, thrombocytopenia, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain. In further embodiments, the acute radiation sub-syndrome is neutropenia, thrombocytopenia or injury to the hematopoetic system or immune system.

[0020] In particular embodiments, the composition is for use in treating a subject and comprises about 0.01 % to about 100% w/w of a chlorate salt. In other embodiments, the composition is an oral composition comprising about 0.05% to about 80% w/v chlorate ion. In further embodiments, the composition is in an aqueous solution comprising about 0.1 % to about 2.5% or about 1.5% w/v chlorate ion. In further embodiments, the composition comprises, or consists essentially of, chlorate as the sole active ingredient. In another embodiment, the composition is chlorite-free. In a further embodiment the composition is sulfate-free. In yet a further embodiment, the composition is carbonate-, bicarbonate-, and/or carbonic acid-free, in still another embodiment, the composition is chloride-free or anhydrous,

[0021] In one embodiment, the chlorate is for use at least once a day, at least once every second day, at least once every third day or at least once every fourth day, or as required to treat a subject. In other embodiments the chlorate is administered twice, three times or four times a day or as needed. In other embodiments, the chlorate is for use starting at least 2, 3, 4 or 5 days following radiation exposure. In further embodiments, the chlorate is for use in more than one cycle, for example, at least two, three, four or five cycles.

[0022] In yet another embodiment, the chlorate is for enteral, including oral and rectal use, or parenteral use including dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, subcutaneous, sublingual, topical, inhaltive, or transdermal use. In particular, the chlorate is for intravenous or oral use.

[0023] The application also includes a composition for use in treating a subject who has been exposed to radiation, the composition comprising an effective amount of chlorate. [0024] In one embodiment, the composition further comprises a pharmaceutically acceptable carrier. In other embodiments, the chlorate is in an aqueous solution, or a solid, semi-solid, gel, paste, liquid, crystalline or encapsulated form. In another embodiment, the composition comprises, or consists essentially of, chlorate as the sole active ingredient. In another embodiment, the composition is chlorite-free. In a further embodiment the composition is sulfate-free. In yet a further embodiment, the composition is carbonate-, bicarbonate-, and/or carbonic acid-free. In still another embodiment, the composition is chloride-free or anhydrous.

[0025] !n an embodiment, the composition has a pH of about 4 to about 13, about 5 to about 12, about 6 to about 1 1 , about 7 to about 10, or about 8 to about 9. In a further embodiment, the pH of the composition is adjusted according to an industry-recognized acceptable pH range for a desired route of administration. For example, the composition is adjusted to pH of about 5 to about 9 for administration by infusion (Infusion Nurses Society, Infusion Nursing Standards of Practice Supplement to January/February 201 1 Volume 34, Number 1 S ISSN 1533-1458). When the composition is an aqueous solution, it is optionally unbuffered or buffered. In an embodiment, when the aqueous solution is buffered, the buffer is one that provides a pH of about 7 to about 13, or about 10 to about 13. In another embodiment, when the aqueous solution is buffered, the buffer is one that provides a pH of about 5 to about 1 1 , about 6 to about 10, about 7 to about 9, or about 6.5 to about 10.5. As non-limiting examples of suitable buffers, carbonate buffers, phosphate buffers, acetic acid buffers, citric acid buffers, lactic acid buffers, tartaric acid buffers and maleic acid buffers are included. In an embodiment, the aqueous solution further includes sodium chloride, for example in an amount to render the solution isotonic.

[0026] In further embodiments, the composition is formulated to comprise about 0.01 % to about 100% w/w of a chlorate salt. In other embodiments, the composition is an oral composition comprising about 0.05% to about 80% w/v chlorate ion. In further embodiments, the composition is in an aqueous solution comprising about 0.1% to about 2.5% or about 1.5% w/v chlorate ion. In other embodiments, the composition is formulated for enteral administration, including oral or rectal administration, or parenteral administration including dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccai, percutaneous, subcutaneous, sublingual, topical, inhalative or transdermal administration. In particular embodiments, the chlorate is formulated for intravenous or oral administration.

[0027] The present application describes ARS treatment options that are expected to be safe, effective, inexpensive and well-tolerated. For example, the treatments are conveniently distributed and administered in a mass casualty situation and effective when administered after radiation exposure. This is desirable because exposure of a military or civilian population to radiation exposure may not be known or predictable in advance. {0028] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only. The scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

Brief description of the drawings

[0029] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0030] Figure 1 shows the percent survival of irradiated mice treated with a chlorate solution versus a saline solution. Irradiated mice treated with chlorate solution show a higher percent survival in the 32 days following treatment.

[0031] Figure 2 shows the "score" of irradiated mice treated with a chlorate solution versus a saline solution. [0032] Figure 3 shows lower weight loss in irradiated mice treated with a with a chlorate solution versus a saline solution.

Detailed Description of the Application

I. Definitions

[0033] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the application herein described for which they are suitable as would be understood by a person skilled in the art.

[0034] The terms "a," "an," or "the" as used herein not only include aspects with one member, but also includes aspects with more than one member. For example, an embodiment including "a pharmaceutically acceptable carrier" should be understood to present certain aspects with one pharmaceutically acceptable carrier or two or more additional pharmaceutically acceptable carriers.

[0035] The term "and/or" as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that "at least one of or "one or more" of the listed items is used or present. For example the expression carbonate, carbonic acid and/or bicarbonate means that at least one, or one or more of, carbonate, carbonic acid and bicarbonate are present or used.

[0036] In compositions comprising an "additional" or "second" component, the second component as used herein is chemically different from the other components or first component. A "third" component is different from the other, first, and second components, and further enumerated or "additional" components are similarly different.

[0037] The term "agent" as used herein indicates a compound or mixture of compounds that, when added to a composition, tend to produce a particular effect on the composition's properties. As used herein, chlorate is an active agent. [0038] The term "active agent" as used herein means a compound or mixture of compounds having a pharmacological effect, in particular in treating radiation exposure.

[0039] The term "sole active agent" as used herein means that the listed agent is the only compound or mixture of compounds having a pharmacological effect in a composition.

[0040] The term "chlorite-free" as used herein means that the composition comprises no detectable levels chlorite or that the amount of chlorite present in the sample is small compared to the amount of chlorate. For example the weight of chlorite in the composition comprises less than 5%, 4%, 3%, 2% or 1 % of the weight of chlorate.

[0041] The term "sulfate-free" as used herein means that the composition comprises no detectable levels of sulfate or that the amount of sulfate present in the sample is small compared to the amount of chlorate. For example, the weight of sulfate in the composition comprises less than 5%, 4%, 3%, 2% or 1 % of the weight of chlorate.

[0042] The term "chloride-free" as used herein means that the composition comprises no detectable levels of chloride or that the amount of chloride present in the sample is small compared to the amount of chlorate. For example, the weight of chloride in the composition comprises less than 5%, 4%, 3%, 2% or 1 % of the weight of chlorate.

[0043] The phrase "carbonate-, bicarbonate-, and/or carbonic acid- free", means that the composition comprises no detectable levels of carbonate-, bicarbonate-, and/or carbonic acid or that the amount of these substances present in the sample is small compared to the amount of chlorate . For example, the weight of these substances in the composition comprises less than 5%, 4%, 3%, 2% or 1 % of the weight of chlorate.

[0044] The term "aqueous solution" as used herein means a solution wherein the solvent is primarily water, although small amounts, for example, less than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 % (v/v) of a non-aqueous solvent may be present.

[0045] "Composition" and "pharmaceutical composition" as used herein are equivalent terms referring to a composition of matter for pharmaceutical use.

[0046] The term "parenteral" as used herein means taken into the body or administered in a manner other than through the gastrointestinal tract.

[0047] The term "effective amount" as used herein means an amount sufficient to achieve the desired result and accordingly will depend on the ingredient and its desired result. Nonetheless, once the desired effect is known, determining the effective amount is within the skill of a person skilled in the art. For example, as used herein an "effective amount of chlorate" is optionally the amount of chlorate that is sufficient to treat a subject who has been exposed to radiation or who is suffering from the effects of radiation exposure or acute radiation syndrome.

[0048] The term "water" as used herein as an ingredient in the compositions of the application refers to pharmaceutically-acceptable water.

[0049] The term "w/v" as used herein means the number of grams of a substance in 100 mL of a composition.

[0050] The term "w/w" as used herein means the number of grams of a substance in 100 g of a composition.

[0051] The term "v/v" as used herein means the number of mL of a substance in 100 mL of a composition.

[0052] The term "pharmaceutically acceptable" means compatible with the treatment of animals, in particular, humans.

[0053] The term "treating" or "treatment" as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilizing (i.e. not worsening) the state of disease, prevention of disease spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. "Treating" and "treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. "Treating" and "treatment" as used herein also include prophylactic treatment. Treatment methods comprise administering to a subject a therapeutically effective amount of an active agent and optionally consists of a single administration, or alternatively comprises a series of applications. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active ingredient or agent, the activity of the compositions described herein, and/or a combination thereof, It will also be appreciated that the effective dosage of the agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required, For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.

[0054] The term "cycle" or "treatment cycle" as used herein refers to a part of a treatment method that comprises a period of treatment with active agent followed by a period of no treatment or treatment with placebo. For example, one treatment cycle can comprise administration or use of an active agent for 1 to 20 days followed by no administrations or administration or use of a placebo for 1 to 20 days. The periods of treatment and no treatment/placebo need not be the same in duration or amounts.

[0055] The term "subject" as used herein includes all members of the animal kingdom, including mammals, and suitably refers to humans.

[0056] The term "radiation exposure" as used herein refers to being subjected or exposed to ionizing radiation. Radiation exposure can occur as a result of a catastrophic event such as a nuclear accident, the explosion of an atomic bomb, exposure to a sterilization irradiator or interplanetary travel. Radiation exposure includes both whole body radiation exposure and radiation exposure to only part of the body. Optionally, radiation exposure comprises exposure to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of radiation over a time frame of less than 1 minute, or up to 5 minutes, 10 minutes, 30 minutes, 60 minutes, 1 hour, 6 hours, 12 hours, 24 hours, two days, one week, two weeks, three weeks or one month. In other embodiments, radiation exposure comprises exposure to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of radiation over a time frame of more than one month or one year.

[0057] As used herein, the term "condition arising from radiation exposure" refers to any medical symptom, disease, illness, injury, condition or syndrome that results from radiation exposure. The condition may arise directly or indirectly from radiation exposure. In one embodiment, a condition arising from radiation exposure is acute radiation syndrome.

[0058] As used herein, the term "acute radiation syndrome (ARS)" refers to an acute illness caused by irradiation of a significant portion of the body to a high dose of penetrating radiation in a short period of time. In some embodiments, acute radiation syndrome is caused by exposure to at least 1 Gray of radiation within less than an hour. ARS is also known as radiation toxicity, radiation poisoning or radiation sickness.

[0059] As used herein "LD50/30" means the median dose of radiation necessary to kill 50% of an animal in a 30 day observation period following acute radiation injury.

[0060] In understanding the scope of the present disclosure, the term "comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives. The term "consisting" and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The term "consisting essentially of , as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and/or steps.

[0061] Terms of degree such as "substantially", "about" and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least +5% of the modified term if this deviation would not negate the meaning of the word it modifies.

II. Chlorate Compositions

[0062] The present application includes compositions, in particular pharmaceutical compositions, comprising chlorate, and methods and uses thereof for treating radiation exposure.

[0063] In some embodiments, the chlorate is comprised in a compound of the formula X_m(CI0₃)_n, where X is a cationic moiety and m and n are integers necessary to provide a net valency of 0. While these compounds are in solution, free chlorate "CIO3^"" is formed. In some embodiments, the chlorate source is in the form of an alkaline or alkaline earth metal salt, non-limiting examples of which include sodium chlorate (NaCI0₃), calcium chlorate and magnesium chlorate. In one embodiment, the chlorate source is sodium chlorate. In another embodiment, the chlorate source is in the form of an acid, a non-limiting example of which is chloric acid, wherein chlorate is derived from the acid through neutralization. [0064] In an embodiment, the composition has a pH of about 4 to about 13, about 5 to about 12, about 6 to about 1 1 , about 7 to about 10, or about 8 to about 9. In a further embodiment, the pH of the composition is adjusted according to an industry-recognized acceptable pH range for a desired route of administration. For example, the composition is adjusted to pH of about 5 to about 9 for administration by infusion (Infusion Nursing Standards of Practice Supplement to January/February 2011 Volume 34, Number 1 S ISSN 533- 1458). In further embodiments of the present application, chlorate is used as an aqueous composition comprising chlorate. In some embodiments, the composition is an unbuffered aqueous solution. In other embodiments, the composition is a buffered aqueous solution, In an embodiment, when the aqueous solution is buffered, the buffer is one that provides a pH of about 7 to about 13, or about 10 to about 13. In another embodiment, when the aqueous solution is buffered, the buffer is one that provides a pH of about 5 to about 1 1 , about 6 to about 10, about 7 to about 9, or about 6.5 to about 10.5. As non-limiting examples of suitable buffers, carbonate buffers, phosphate buffers, acetic acid buffers, citric acid buffers, lactic acid buffers, tartaric acid buffers and maleic acid buffers are included. In an embodiment, the aqueous solution further includes sodium chlonde, for example in an amount to render the solution isotonic. In an embodiment, the aqueous composition is ready-to- use or is diluted (e.g. with water or saline) prior to administration. In particular embodiments, the aqueous composition is used for i.v. infusion, i.v. push or is administered subcutaneously or intramuscularly.

[0065] In other embodiments, the chlorate is used as an oral composition. The compositions for oral administration include, but are not limited to, solid, semi-solid, gel, paste, liquid, crystalline or encapsulated forms. Non-limiting examples of these forms include capsules, tablets, suspensions, powders, modified-release formulations, solutions, emulsions and syrups. In further embodiments, the chlorate is used as an inhalant or suppository. [0066] In some embodiments, the composition comprises about 0.01 % to about 100% w/w of a chlorate salt. In another embodiment, the composition includes about 0.1 % to about 80%, about 0.2% to about 50%, about 0.25% to about 20%, about 0.5% to about 10%, about 1 % to about 5%, about 1.25% to about 2.5% or about 1.5% w/v chlorate ion. In further embodiments, the compositions of the present application include about 1 %, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% w/v chlorate ion.

[0067] In some embodiments, the composition comprises, or consists essentially of, chlorate as the sole active ingredient. In further embodiments, the compositions are chlorite-free. In further embodiments, the compositions are sulfate-free and/or chloride-free. In yet a further embodiment, the composition is carbonate-, bicarbonate-, and/or carbonic acid-free.

[0068] In other embodiments, the composition includes a chlorate salt, optionally sodium chlorate, which is formulated for administration at a dose of about 0.01 mg/kg to about 40 mg/kg body weight. In further embodiments, the composition is formulated for administration of chlorate at a dose of about 1 mg/kg to about 30 mg/kg, about 3 mg/kg to about 25 mg/kg, or about 5 mg/kg to about 20 mg/kg body weight. In particular embodiments, the composition is formulated for administration of chlorate at a dose of about 0.1 , 0.2, 0.5, 1.0, 2.0, 5.0 or 10.0 mg/kg body weight. In further embodiments, the composition is formulated for administration of chlorate at a fixed dose that is not adjusted for body weight (e.g. 1 , 2.5, 5, 10, 25, 50, 100 or 250 mg/day for an adult).

[0069] In other embodiments, the composition includes a pharmaceutically acceptable carrier, excipient, buffer and/or stabilizer. Suitable pharmaceutically acceptable carriers include essentially chemically inert and nontoxic materials that do not interfere with the effectiveness of the biological activity of the pharmaceutical composition. Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., USA, 2000). Examples of suitable pharmaceutical carriers include, but are not limited to, water, saline solutions, glycerol solutions, ethanol, N-(1 (2,3-dioleyioxy)propyi)N,N, N-trimethyiammonium chloride (DOTMA), diolesylphosphotidyl-ethanolamine (DOPE), and liposomes. Such compositions contain a therapeutically effective amount of the agent, together with a suitable amount of carrier so as to provide the form for direct administration to the patient.

[0O70] In some embodiments, the compositions of the application are formulated for administration to a subject such as a human. In particular embodiments, the compositions are formulated for enteral administration, including oral or rectal administration. Optionally, the compositions are formulated for parenteral administration, including dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, subcutaneous, sublingual, topical, inhalative or transdermal administration.

[0071] In further embodiments, the chlorate is administered, or formulated for administration, or used, intravenously, orally, inhalativeiy, rectally or parenterally including dermally, intradermal^, intragastrally, intracutaneousiy, intravasally, intravenously, intramuscularly, intraperitoneal^, intranasally, intravaginally, intrabuccally, percutaneously, subcutaneously, sublingually, topically or transdermal!y. In one embodiment, the chlorate is administered intravenously. In another embodiment, the chlorate is administered orally.

[0072] In yet another embodiment, the compositions are formulated in oral dosage forms that are modified release, for example immediate release and timed-release (e.g. delayed release or suspended release), formulations. In an embodiment, the oral formulations comprise a coating or other mechanism for releasing the active agent(s) lower down in the digestive track, such as in the large or small intestine. Examples of modified-release formulations include, for example, bolus release, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, suspended release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. In an embodiment, timed-release compositions are formulated, e.g. liposomes or those wherein the active agent is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems, include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes are, for example, formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines

III, Methods and Uses of the Composition

10073] The application includes methods for treating subjects who have been exposed to radiation comprising administering an effective amount of chlorate to a subject in need thereof. The application also includes the use of chlorate for treating subjects who have been exposed to radiation.

10074] The application also includes methods for treating subjects who have been exposed to radiation comprising administering an effective amount of the chlorate compositions described herein to a subject in need thereof. The application also includes the use of the chlorate compositions described herein for treating subjects who have been exposed to radiation.

[0075] Also provided in the present application are methods for treating acute radiation syndrome comprising administering an effective amount of chlorate to a subject in need thereof. The application also includes the use of chlorate for treating subjects who have acute radiation syndrome,

[0076] Also provided in the present application are methods for treating acute radiation syndrome comprising administering an effective amount of the chlorate compositions described herein to a subject in need thereof. The application also includes the use of the chlorate compositions described herein for treating subjects who have acute radiation syndrome. [0077] The present application further includes a methods and uses for treating other conditions arising from radiation exposure, comprising administering an effective amount of chlorate, or the compositions comprising chlorate as described herein, to a subject in need thereof. In embodiments the condition is an acute radiation sub-syndrome associated with one or more of neutropenia, thrombocytopenia, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain.

[0078] In other embodiments the condition is an acute radiation sub- syndrome associated with one or more of, the blood, the immune system, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system, including the brain. In further embodiments, the acute radiation sub-syndrome is neutropenia, thrombocytopenia or injury to the hematopoetic system or immune system.

[0079] Optionally, the methods of the application comprise treating a subject who has been exposed to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of partial- or whole-body radiation. In other embodiments, the methods comprise treating a subject who has been exposed to at least 0.25, 0.5, , 2, 3, 4, 5, 6, 7, 8, 9 or 0 Gray of whole-body radiation.

[0080] In some embodiments, the subject has been exposed to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of radiation over a time frame of less than 1 minute, or up to 5 minutes, 10 minutes, 30 minutes, 60 minutes, 1 hour, 6 hours, 12 hours, 24 hours, two days, one week, two weeks, three weeks or one month. In other embodiments, the subject has been exposed to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of radiation over a time frame of more than one month or one year.

[0081] In an embodiment, the treatment is administered or used once a day. In another embodiment, the treatment is administered or used twice a day. In still another embodiment, the treatment is administered or used three times a day or four times a day. In a further embodiment, the treatment is administered or used at least once a day for one, two, three, four, five, six or seven days. In still a further embodiment, the treatment is administered at least once a day for a longer term such as 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks. In an even further embodiment, the treatment is administered or used at least once a day until the condition has ameliorated to where further treatment is not necessary. The treatment period may also comprise cycles, for example, administration or use once daily for about three to seven days, followed by a period of rest for about 5 to 20 days, to constitute one cycle of treatment. In an embodiment, patients are treated with more than one cycle, for example, at least two, three, four or five cycles, In a further embodiment, the effective dosage of the agent used for the treatment or prophylaxis increases or decreases over the course of a particular treatment or prophylaxis regime. In an embodiment, the effective dosage of the agent decreases over the course of a particular treatment regimen. In some instances, chronic administration is required. For example, the compositions are administered to the subject, or used, in an amount and for a duration sufficient to treat the subject.

[0082] The compositions of the present application are useful and effective when administered to treat radiation exposure. The amount of the chlorate used or that is present in the composition will be the amount that is therapeutically effective, i.e., an amount that will result in the effective treatment of the condition (e.g., radiation exposure) when administered or used. The therapeutically effective amount will vary depending on the subject and the severity of the affliction and can be determined routinely by one of ordinary skill in the art.

[0083] In particular embodiments, compositions comprising about 0.1 % to about 80%, about 0.2% to about 50%, about 0.25% to about 20%, about 0.5% to about 10%, about 1 % to about 5%, about 1.25% to about 2.5% or about 1.5% w/v chlorate ion are administered to the subject. In further embodiments, compositions comprising about 1 %, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% w/v chlorate ion are administered to the subject or used. In other embodiments, compositions that are chlorite-, sulfate-, chloride- carbonate-, bicarbonate-, and/or carbonic acid-free are administered to the subject or used. . In other embodiments, compositions comprising, or consisting essentially of, chlorate as the sole active ingredient are administered to the subject or used.

[0084] In other embodiments, the treatment is administered or used at least one day or at least one week after radiation exposure. In other embodiment, the treatment is administered or used 2, 3, 4, 5, or 6 days, optionally 4 days, after radiation exposure.

[0085] In some embodiments, the treatment is administered or used at a dose of about 0.01 mg/kg to about 40 mg/kg body weight of chlorate. In further embodiments, the treatment is administered or used at a dose of about 1 mg/kg to about 30 mg/kg, about 3 mg/kg to about 25 mg/kg, or about 5 mg/kg to about 20 mg/kg body weight. In particular embodiments, treatment is administered or used at a dose of about 0.1 , 0.2, 0.5, 1.0, 2.0, 5.0 or 10.0 mg/kg body weight of chlorate. In alternate embodiments, the treatment is administered or used at a fixed dose that is not adjusted for body weight (e.g. 1 , 2.5, 5, 10, 25, 50, 100 or 250 mg/day for an adult).

[0086] In particular embodiments, the treatment is administered or used sequentially at the same dose. In alternate embodiments, the treatment is administered or used sequentially at different doses (e.g. step regimen). In further embodiments, the treatment is administered or used at least once a day, at least once every second day, at least once every third day, at least once every fourth, or as required to treat the subject. Optionally, the treatment is administered or used starting at least 2, 3, 4 or 5 days following radiation exposure. Subjects may also be treated with more than one cycle, for example, at least two, three, four or five cycles.

[0087] The application also includes methods for treating chronic radiation syndrome. Chronic radiation syndrome is caused by months or years of chronic exposure to ionizing radiation. In one embodiment, a subject with chronic radiation exposure has been exposed to between 0.5 to 2.0 Gray of radiation at a dose rate of at least 0.1 , 0.2, 0.3, 0.4, 0.5, 1 , 1.5 or 2 Gray per year.

[0088] The application additionally includes methods for treating Delayed Effects of Acute Radiation Exposure ("DEARE"). DEARE includes for example leukemia and other malignancies as well as radiation cystitis, mucocitis and proctitis which may occur months to years after an acute exposure to radiation.

[0089] Also contemplated within the present application is the use of chlorate or a chlorate composition as a preventive or prophylactic measure against radiation exposure. In some embodiments, the chlorate or chlorate compositions are administered to a subject prior to radiation exposure. Optionally, the subject is a radiation worker, a clinician or patient that may be exposed to radiation during a medical procedure, or personnel at risk of being exposed to radiation during military operations. In other embodiments, the chlorate or chlorate compositions are administered to military or civilian populations after a nuclear attack with either an atomic bomb or a dirty bomb as part of a post-exposure treatment or "radiation countermeasure". Also contemplated is the use of chlorate or chlorate compositions to treat subjects exposed to radiation in the event of a nuclear accident at a power plant.

[0090] The application also includes methods for treating subjects who are suspected of being exposed to radiation or who may have been exposed to radiation comprising administering to the subjects an effective amount of chlorate or the chlorate compositions described herein. The subject may or may not display symptoms of radiation exposure. IV. Examples

[0091] The following non-limiting examples are illustrative of the present application:

Example 1: Preparation of Chlorate Solution

[0092] An aqueous solution was prepared by dissolving 97.5 mg of A.C.S. grade sodium chlorate (Aldrich) in water for injection to make a total volume of 50.0 mL. The mixture was swirled or shaken to obtain a homogenous solution. The concentration of chlorate in the solution was 1528 ppm (0.15% w/v). Unbuffered sodium chlorate solutions have a pH of approximately 4.5 to 8.5 depending, for example, on the amount of dissolved CO₂ in the solution.

Example 2: Treatment of Induced Acute Radiation Syndrome (ARS) in Mice

Summary

[0093] Twenty-eight female Balb/C mice were irradiated and treated with either an unbuffered sodium chlorate (NaCIO^"3) solution (14 mice) or a saline (NaCI) solution (14 mice). The mice were injected intraperitoneally with chlorate (0.15% w/v, Example 1) or saline solution for 5 consecutive days following radiation exposure with treatment commencing 4 days after radiation insult. The sodium chlorate solution was diluted with saline before administration such that the total injection volume was about 200 microliters. The sterile isotonic saline solution was injected at the same volume (about 200 microliters). Percent survival, weight loss and other measureable factors were assessed following treatment.

irradiation

[0094] Balb/C mice, 9-10 weeks old, were subjected to 7 Gray of whole-body X-irradiation. The mice were removed from their cages and placed in a PLEXIGLAS box of size 22 cm X 4.5 cm X 30 cm (each individual mouse chamber was 3cm x 3.5cm x 7cm). The animals were irradiated in the PLEXIGLAS box operably connected to an orthovoltage unit (Serial No., D3225; Gulmay Medical Ltd., Surrey, UK), operating at 200 kV. A filter comprising 2.0mm Cu and 0.3mm Al was used in the irradiator between the X-ray tube and the animals. The 7 Gray dose was provided in approximately 6.02 minutes of irradiation.

Treatment

[0095] The irradiated mice were injected intraperitonealty with 0.25 mlJkg body weight of the chlorate treatment solution (Example 1) diluted with isotonic saline to a volume of approximately 200μΙ_ (14 mice) or approximately 200μΙ_ of the placebo solution (14 mice) for 5 consecutive days commencing on the fourth day following radiation exposure. The treatment solution contained 0.15% w/v chlorate. The p!acebo was a saline solution. Percent survival, weight loss and other measureable factors were assessed following treatment.

Percent survival

[0096] The percent survival of mice treated with the chlorate solution was higher than the percent survival of mice treated with saline over the 32 days following treatment (Figure 1 ). Mice in the control group succumbed to the effects of radiation more rapidly than the animals receiving chlorate and in a Cox regression model a mouse without treatment was calculated to be 1.42 times as likely to die at any time as a mouse receiving the chlorate solution. Score

[0097] The mice were assigned a "score" based on bearing, ability, skin quality and fur quality according to the following evaluation procedure.

Evaluation Procedure:

1.1 Inspect mice two times a day within an interval of 7 hours.

1.2 Measure the body weight using a scale (0.1 g precision) once a day.

1.3 Rate symptoms of ARS with regard to Table 1 once a day. For each parameter a rank has to be given for each animal.

1.4 Sum the ranks for each parameter to receive a score for each animal (max. score: 8/day).

1.5 Calculate a daily mean value for each group throughout the period of the experiment. [0098] Animals with characteristics most similar to untreated (healthy) mice received a lower score. As shown in Figure 2, animals treated with the chlorate solutions had lower scores than those treated with saline in the 17 days following irradiation.

Weight loss

[0099] In addition, the mice treated with saline showed a higher degree of weight loss over the 32 days following treatment than mice treated with the chlorate solution (Figure 3).

Example 3: Future Studies

[00100] The inventors have studied the treatment of induced Acute Radiation Syndrome in mice using a chlorate solution (see Example 2). Sensitivity to radiation appears to be species-dependent [See for example Radionuclides in the Arctic Seas from the Former Soviet Union: Potential Health and Ecological Risks, D. Layton, R, Edson, M. Varela and B. Napier, November 1 , 1997 US Department of Energy, Lawrence Livermore National Laboratory page B-2]. There are also other factors that can influence radiation sensitivity in a single species such as genetic strain, age, sex, environment and radiation quality and intensity [See for example Storer J.B. Acute Responses to Ionizing Radiation, Chapter 22 in Biology of the Laboratory Mouse second edition ed. Green, E.L.] Thus a study to determine species- specific LD5030 can be conducted in advance of the treatment study to identify appropriate ranges of irradiation for each animal model.

A. LD50/30 Determination without Chlorate Treatment

[00101] Eight groups of C3H/HenCrl mice are irradiated at 5.0, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0 Gy (n=~10). Irradiation is performed as generally described in Example 2, except at the radiation values indicated above. Mice are injected intraperitoneally with a sterile, isotonic saline (NaCI) solution on days 4, 5, 6, 7, 8, 9, 10 and 11 following radiation insult. The total injection volume is about 200 microliters. LDsoy3o is estimated by fitting the survival data with a logistic function using a maximum likelihood approach. B. Comparison of the Effects on Survival of Two Chlorate Solutions versus Saline in ARS

[00102] Mice are irradiated and assigned to receive one of the following sterile aqueous solutions post insult (i) sodium chlorate 0.15% w/v (including a carbonate buffer and sufficient NaCI to make the solution isotonic, pH 11.4 - 12.7), (ii) sodium chlorate 0.15% w/v (including NaCI sufficient to render the solution isotonic, pH 7.0) or (iii) an isotonic saline solution (pH 7.0). Irradiation is performed as generally described in Example 2, using a single fixed radiation value selected in the range from about 5.0 to about 9.0 Gy. The mice are injected intraperitoneal^ with either the chlorate or saline solutions for 8 consecutive days following radiation exposure commencing 4 days after radiation insult. The sodium chlorate solutions are diluted with saline prior to administration such that the total injection volume is about 200 microliters. The isotonic saiine solution in the control group is injected at the same volume (about 200 microliters). The chlorate solutions are administered at 1 mL/kg on days 4, 5, 6 following radiation exposure and then at 0.5 mL/kg on days 7, 8, 9, 10 and 1 1 after radiation exposure. The effects of the chlorate solutions versus saiine on the survival curves of the mice to day 30 are assessed, including differences in overall survival at day 30.

C. Dose Modification Factor Experiment

100103] The dose modification factor can be defined as the ratio of LD50/30 radiation level with and without treatment and is a recommended measurement to determine the effectiveness of a radiation medical countermeasure. [See for example Williams JP, Brown SL, Georges GE, Hauer-Jensen M, Hill RP, Huser AK, Kirsch DG, Macvittie TJ, Mason KA, Medhora MM, Moulder JE, Okunieff P, Otterson MF, Robbins ME, Smathers JB, McBride WH. Animal models for medical countermeasures to radiation exposure. Radiat Res. 2010 Apr;173(4):557-78.] To determine the dose modification factor for a chlorate solution versus a control solution, best estimates for LD₅₀/₃o with and without chlorate treatment are developed using results from Experiments A and B. Groups of mice (n=~10) are irradiated and are treated with either a sodium chlorate 0.15% w/v or an isotonic saline solution at four irradiation levels separated by 0.5 Gy centered about the corresponding estimated LD₅₀/3o value. Irradiation is performed as generally described in Example 2, except at the stepped radiation values described in the preceding sentence. The mice are injected intraperitonealiy with the chlorate or saline solutions for 8 consecutive days following radiation exposure commencing 4 days after radiation insult. The sodium chlorate solutions are diluted with saline prior to administration such that the total injection volume is about 200 microliters. The isotonic saline solution is injected at the same volume (about 200 microliters). The chlorate solution is administered at 1 mL/kg body weight on days 4, 5, 6 following radiation exposure and then at 0.5 mL/kg body weight on days 7, 8, 9, 10 and 1 1. LD50/30 and other measureable factors with and without chlorate treatment are assessed and a dose modification factor is computed.

Example 4: Alternate Method of LD5030 Determination - Selection of Radiation Level

[00104] Six groups of 6 mice receive radiation at different doses followed by treatment with saline. Irradiation is performed as generally described in Example 2, except at the radiation values indicated below. The levels of radiation are 5.0, 6.0, 7.0, 7.5, 8.0 and 9.0 Gy. Saline is administered i.p. in an amount of 200 pL/day on days 4, 5, 6, 7, 8, 9, 10 and 1 1. The percent of animals surviving at 30 days past radiation exposure is then plotted vs radiation level (or analyzed numerically) to determine the LD50/30 radiation dose.

Example 5: Development of Oral Formulations

Formulation 1

[00105] A sachet containing a predetermined amount of sodium chlorate in powder form is prepared. The powder may additionally include a bulking agent such as sodium chloride. In use, the sachet is opened and its contents are dissolved in a specified amount of water. The aqueous solution is consumed orally by the subject. Formulation 2

[00106] A capsule containing a predetermined amount of sodium chlorate is prepared. In use, the capsule is swallowed by the subject. The capsule is designed to release its contents in the gastrointestinal tract of the subject.

[00107] Bioavailability measurements of orally administered chlorate compositions have been performed in animals (Hakk et al. J Agric Food Chem. 2007 Mar 7;55(5):2034-42; Smith et al., J Agric Food Chem. 2005 Sep 7;53(18):7352-60; Smith et al., J Agric Food Chem. 2005 May 18;53{10):4272-80; Oliver et al, J Vet Pharmacol Ther. 2007 Aug;30(4):358- 65; Smith et al., Journal of agricultural and food chemistry. 2006 Nov 1 ;54(22):8648-53; Smith et al, J Vet Pharmacol Ther. 2007 Aug;30(4):358-65; Smith & Taylor, Journal of animal science. 2012 Jun;90{6):2026-34.) These publications demonstrate that orally administered chlorate in mammals becomes bioavailable in the systemic circulation.

[00108] All publications, patents and patent applications cited in the application are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present disclosure is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

Table 1 : Clinical scoring after irradiation¹

Oncology, Carl-Gustav-Carus, Dresden

Claims

Claims:

1. A method for treating radiation exposure comprising administering an effective amount of chlorate or a composition comprising chlorate to a subject in need thereof.

2. A method for treating a condition arising from radiation exposure comprising administering an effective amount of chlorate or a composition comprising chlorate to a subject in need thereof.

3. The method of claim 2, wherein the condition is acute radiation syndrome or an acute radiation sub-syndrome associated with one or more of the blood, the immune system, the gastrointestinal tract, the skin, the pulmonary system, the kidney and the central nervous system.

4. The method of any one of claims 1 to 3, wherein the composition comprising chlorate is an aqueous solution or a solid, semi-solid, gel, paste, liquid, crystalline or encapsulated form, and the aqueous solution and solid, semi-solid, gel, paste, liquid, crystalline and encapsulated forms are formulated for enteral or parenteral administration.

5. The method of claim 4, wherein the composition is an unbuffered aqueous solution.

6. The method of claim 4 or 5 wherein the aqueous solution is ready-to- use or is diluted prior to administration.

7. The method of any one of claims 4 to 6, wherein the composition comprises about 0.1 % to about 2.5% or about 1.5% w/v chlorate ion.

8. The method of any one of claims 1 to 3, wherein the composition comprising chlorate is an oral composition.

9. The method of claim 8, wherein the oral composition is a solid, semi- solid, gel, paste, liquid, crystalline or encapsulated form.

10. The method of claim 9, wherein the oral form is selected from capsules, tablets, suspensions, powders, modified-release formulations, solutions, emulsions and syrups.

1 1. The method of any one of claims 8 to 10 wherein the composition comprises about 1 %, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% w/v chlorate ion.

12. The method of any one of claims 1 to 11 , wherein the chlorate composition comprises, or consists essentially of, chlorate as the sole active ingredient.

13. The method of any one of claims 1 to 11 , wherein the chlorate composition is chlorite-, sulfate-, carbonate-, bicarbonate-, carbonic acid- and/or chloride-free.

14. The method of any one of claims 1 to 13, wherein the chlorate is, or the composition comprises, a chlorate salt which is formulated for administration at a dose of about 0.01 mg/kg to about 40 mg/kg, about 1 mg/kg to about 30 mg/kg, about 3 mg/kg to about 25 mg/kg, or about 5 mg/kg to about 20 mg/kg body weight.

15. The method of any one of claims 1 to 14, wherein the subject has been exposed to at least 0.25, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gray of radiation.

16. The method of claim 15, wherein the radiation is whole body radiation.

17. The method of claim 15 or 16, wherein the subject has been exposed to the radiation over a time frame of less than 1 minute, or up to 5 minutes, 10 minutes, 30 minutes, 60 minutes, 1 hour, 6 hours, 12 hours, 24 hours, two days, one week, two weeks, three weeks, one month or one year.

18. The method of any one of claims 1 to 17, wherein the chlorate or composition comprising chlorate is administered once a day, twice a day, three times a day or four times a day, for one, two, three, four, five, six or seven days.

19. The method of any one of claims 1 to 17, wherein the chlorate or composition comprising chlorate is administered at least once a day for 1 , 2,

3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 weeks.

20. The method of any one of claims 1 to 17, wherein the chlorate or composition comprising chlorate is administered once daily for about three to seven days, followed by a period of rest for about 5 to about 20 days, to constitute one cycle of treatment and the subjects are treated with one or more than one cycle.

21 . A composition comprising chlorate formulated for use in the treatment of radiation exposure or a condition arising from radiation exposure.

22. The composition of claim 21 , wherein the composition is an aqueous solution or a solid, semi-solid, gel, paste, liquid, crystalline or encapsulated form, and the aqueous solution and solid, semi-solid, gel, paste, liquid, crystalline and encapsulated forms are formulated for enteral or parenteral administration.

23. The composition of claim 22, wherein the composition is formulated for oral, rectal, dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, subcutaneous, sublingual, topical, inhalative or transdermal administration.

24. The composition of claim 22, formulated for oral administration and comprising about 1 %, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% w/v chlorate ion.

25. The composition of claim 24, wherein the oral administration forms are selected from capsules, tablets, suspensions, powders, modified-release formulations, solutions, emulsions and syrups.

26. The composition of claim 22, wherein the composition is an aqueous solution comprising about 0.1 % to 2.5% or about 1.5% w/v chlorate ion.

27. The composition of any one of claims 21 to 26, comprising, or consisting essentially of, chlorate as the sole active ingredient.

28. The composition of any one of claims 21 to 26, wherein the composition is chlorite-, sulfate-, carbonate-, bicarbonate-, carbonic acid- and/or chloride-free.

29. The composition of any one of claims 21 to 28, comprising a chlorate salt which is formulated for administration at a dose of about 0.01 mg/kg to about 40 mg/kg, about 1 mg/kg to about 30 mg/kg, about 3 mg/kg to about 25 mg/kg, or about 5 mg/kg to about 20 mg/kg body weight.

30. The composition of claim 26, comprising chloride in an amount to make the composition isotonic.