Methods for treatment of diseases

Abstract

To provide methods of treating a range of diseases or conditions, involving administration of a superoxide dismutase mimetic to a subject.SOLUTION: A unit dose formulation comprises at least 50 mg of a superoxide dismutase mimetic in a container, the superoxide dismutase mimetic corresponding to the following formula (GC4419), wherein X and Y are independently neutral or negatively charged ligands.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates generally to methods of treating (including inhibiting) various diseases and conditions. The methods of the present invention involve the administration of superoxide dismutase (SOD) mimetics. [Background technology]

[0002] The enzyme superoxide dismutase catalyzes the conversion of superoxide to oxygen and hydrogen peroxide according to formula (I) (a process often referred to herein and in the art as dismutation). [ka]

[0003] Reactive oxygen metabolites derived from superoxide have been demonstrated to contribute to tissue pathology in many inflammatory diseases and disorders, such as reperfusion injury to ischemic myocardium, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, hypertension, metastatic reactions, psoriasis, organ transplant rejection, radiation-induced injury, asthma, influenza, stroke, burns, and trauma. See, for example, Simic, MG, et al., Oxygen Radicals in Biology and Medicine, BASIC LIFE SCIENCES, vol. 49, Plenum Press, New York and London, 1988; Weiss, J, Cell. Biochem., 1991 Suppl. 15C, 216 Abstract C110 (1991); Petkau, A., Cancer Treat. Rev. 13, 17 (1986); McCord, J. Free Radicals Biol. Med., 2, 307 (1986); and Bannister, JV, et al., Crit. Rev. Biochem., 22, 11 1 (1987). In certain circumstances, cells lack natural SOD activity. For example, this SOD activity deficiency can occur due to heart attack, organ transplantation, or even cancer (cancer cells are often SOD-deficient). This can increase superoxide levels and cause damage to surrounding tissues.

[0004] It is known that superoxide is involved in the breakdown of endothelium-derived vascular relaxing factor (EDRF), which has been identified as nitric oxide (NO), and that superoxide dismutase prevents the breakdown of EDRF. This suggests a central role for superoxide-derived reactive oxygen species in the pathogenesis of hypertension, vasospasm, thrombosis, and atherosclerosis. See, for example, Gryglewski, RJ et al., "Superoxide Anion is Involved in the Breakdown of Endothelium-Derived Vascular Relaxing Factor," Nature, Vol. 320, pp. 454-56 (1986) and Palmer, RMJ et al., "Nitric Oxide Release Accounts for the Biological Activity of Endothelium-Derived Relaxing Factor," Nature, Vol. 327, pp. 523-526 (1987).

[0005] Clinical trials and animal studies have been completed or are underway using native, recombinant, and engineered superoxide dismutase enzymes to demonstrate the therapeutic benefit of reducing superoxide levels in the above conditions. However, several problems have arisen in using this enzyme as a potential therapeutic agent, including lack of oral activity (a common problem with polypeptides), short in vivo half-life, immunogenicity of non-human enzymes, and poor tissue distribution.

[0006] In an attempt to overcome the problems associated with superoxide dismutase enzymes, several investigations have been conducted into the design of nonproteinaceous catalysts for superoxide dismutation and their use in treating superoxide-related mild diseases. One group of catalysts that have demonstrated catalytic efficiencies similar to those of natural superoxide dismutase enzymes are manganese and iron complexes of pentaazacyclopentadecane ligands, as described in U.S. Patent Nos. 5,610,293, 5,637,578, and 5,874,421. These ligands contain a pentaazacyclopentadecane macrocycle with various substituents on the macrocycle carbons or cyclic or heterocyclic structures attached to the macrocycle carbons. Some of these complexes possess potent catalytic superoxide dismutation activity, produce anti-inflammatory activity, and prevent oxidative damage in vivo. Additionally, these compounds (sometimes referred to as SOD mimetics) have been shown to have analgesic properties and to reduce inflammation and edema in the rat forepaw carrageenan hyperalgesia model (see, e.g., U.S. Patent No. 6,180,620).

[0007] One particular compound that has been demonstrated to be an effective catalyst for superoxide dismutation is the following pentaazacyclopentadecane compound, which has been described in the prior art under the names SC-72325, M40403, KM40403, and GC4403 (referred to herein as GC4403). [ka]

[0008] wherein X and Y are independently a neutral or negatively charged ligand. It is generally known that superoxide dismutase mimics can be used as anticancer drugs themselves (see, for example, Simic, MG, et al., supra; Weiss, supra; Petkau, A., supra; etc.). Additionally, it has been reported that combined therapy of superoxide dismutase mimic KM4403 with interleukin-2 (IL-2) enhances the antitumor effect of IL-2. See Samlowski, WE, et al., Nature Medicine (2003) 9:750-755.

[0009] Although GC4403 has shown efficacy in treating inflammatory conditions such as oral mucositis, there remains room for other superoxide dismutase mimetics and treatment methods. Summary of the Invention

[0010] Among other aspects of the disclosure, there is provided a method of treating various diseases and conditions, comprising administering to a patient a superoxide dismutase mimetic according to formula (GC4419). [ka]

[0011] wherein X and Y are independently a neutral or negatively charged ligand. Pharmaceutical compositions, unit dose formulations, articles of manufacture, and kits are also described herein.

[0012] Briefly, therefore, the present disclosure is directed to a unit dose formulation comprising at least 50 mg of a superoxide dismutase mimetic corresponding to formula (GC4419) in a container.

[0013] Another aspect of the present disclosure is directed to an article of manufacture comprising packaging material containing a parenteral formulation in a patient in need thereof for treating a disease or condition or protecting tissue from damage resulting from exposure to the patient's cancer treatment, the parenteral formulation comprising a unit dose formulation according to the present invention, and the packaging material comprising a label or package insert with instructions for parenterally administering the dosage to the patient.

[0014] Another aspect of the present disclosure is directed to a pharmaceutical composition in the form of a solution, the pharmaceutical composition comprising about 0.25 mg / mL to about 3.5 mg / mL of a superoxide dismutase mimetic corresponding to formula (GC4419), wherein a unit dose of the pharmaceutical composition is contained in a container for intravenous administration.

[0015] Also described herein are various methods of treatment involving the administration of a superoxide dismutase mimetic according to formula (GC4419).

[0016] Accordingly, another aspect of the present disclosure is directed to a method of treating tissue damage in a human patient resulting from the administration of radiation therapy or chemotherapy to the patient, the method comprising administering to the patient a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419).

[0017] Another aspect of the present disclosure is directed to a method of treating tissue damage in a human patient resulting from exposure to radiation, comprising administering to the patient a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419).

[0018] Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method of treatment comprising administering to the patient at least 25 mg of a superoxide dismutase mimetic corresponding to formula (GC4419) within a 15-minute period. Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method of treatment comprising administering to the patient at least 50 mg of a superoxide dismutase mimetic corresponding to formula (GC4419) within a 15-minute period. Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method of treatment comprising administering to the patient at least 50 mg of a superoxide dismutase mimetic corresponding to formula (GC4419) within a 30-minute period. Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method of treatment comprising administering to the patient at least 100 mg of a superoxide dismutase mimetic corresponding to formula (GC4419) within a 60-minute period.

[0019] Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method of treatment comprising administering to the patient a superoxide dismutase mimetic at a rate of at least 100 mg / hour, wherein the superoxide dismutase mimetic corresponds to formula (GC4419). For example, at least 25 mg of the superoxide dismutase mimetic may be administered to the patient at a rate of at least 100 mg / hour.

[0020] Another aspect of the present disclosure is directed to a method of treating a disease or condition in a human patient, the method of treatment comprising administering to the patient a superoxide dismutase mimetic such that the patient has an exposure, as measured using area under the curve (AUC), of at least 4,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient, wherein the superoxide dismutase mimetic corresponds to formula (GC4419).

[0021] Other objects and features will be in part apparent and in part pointed out hereinafter. [Brief explanation of the drawings]

[0022] [Figure 1] 1 is an Ortep diagram of the GC4403 complex based on single crystal X-ray diffraction, showing ellipsoids with a 50% probability of presence of non-hydrogen atoms and hydrogen atoms bound to secondary amines (see Example 1). [Figure 2] 1 is an Ortep diagram of the GC4419 complex based on single crystal X-ray diffraction, showing ellipsoids with a 50% probability of presence of non-hydrogen atoms and hydrogen atoms bound to secondary amines (see Example 1). [Figure 3] 1 is a graph showing the dose-dependent decrease in proliferation of HEK-293 cells when treated with GC4403 or GC4419. [Figure 4] 1 is a graph showing the effects of GC4403 and GC4419 on radiation-induced oral mucositis in hamsters. [Figure 5] 1 is a graph showing the effect of GC4403 and GC4419 on TNFα levels in mice with collagen-induced arthritis. DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description The present disclosure is generally directed to methods and pharmaceutical compositions for treating various diseases and conditions. The methods of treatment involve administering a superoxide dismutase mimetic to a subject in need of treatment, more preferably, administering a pharmaceutical composition containing a superoxide dismutase mimetic to the subject. In addition, pharmaceutical compositions and formulations (e.g., unit dose formulations) containing a superoxide dismutase mimetic and, optionally, a pharmaceutically acceptable carrier are also described herein. The superoxide dismutase mimetic (e.g., a compound corresponding to the following formula (GC4419)) administered according to the methods described herein is structurally similar to certain superoxide dismutase mimetics known in the art. Specifically, the chemical structure of GC4403 (e.g., the dichloro complex form described in Riley, DP, Schall, OF, 2007, Advances in Inorganic Chemistry, 59: 233-263) and the compound of formula (GC4419) described herein (e.g., the dichloro complex form of formula (GC4419)) are identical except that they have mirror image chirality, i.e., the enantiomeric structures are not superimposable. [ka]

[0024] As shown in the structures above, the dichloro complex form of GC4403 has four chiral carbon centers present in the R-absolute configuration, whereas the dichloro complex form of GC4419 has four chiral carbon atoms in the S-absolute configuration.

[0025] As detailed in the description and examples herein, these two compounds have nearly identical physicochemical properties, including stability, reactivity with achiral reagents, electronic spectrum, solubility in achiral media, and reactivity with superoxide (see Example 3 below). For example, in vitro activity, such as antiproliferative activity in cell culture media, of GC4403 and GC4419 is also similar (see Example 4 below). Despite these similarities, however, it has been unexpectedly discovered that the compound of formula (GC4419) exhibits a superior safety profile (approximately five-fold improvement) compared to its mirror image, GC4403. For example, the compound of formula (GC4419) can be administered to subjects at least two times faster and at five times the dose of GC4403 without any significant adverse events. Furthermore, because the compound of formula (GC4419) is at least as potent as GC4403, this improved safety does not come at the expense of efficacy (see Examples 5-9 below).

[0026] Superoxide production can be increased in cells (e.g., tumor cells) that have reduced expression of natural superoxide dismutases, resulting in increased accumulation of superoxide. Superoxide dismutase mimetics according to formula (GC4419) can replace or supplement natural superoxide dismutases to catalyze the conversion of superoxide to hydrogen peroxide, which can provide therapeutic or other beneficial effects. As described in further detail below, in certain embodiments, administration of a superoxide dismutase mimetic according to formula (GC4419) can increase the ability of cells to dismutate superoxide.

[0027] In various embodiments described herein, a superoxide dismutase mimetic corresponding to Formula (GC4419) may be administered alone or in combination with another (e.g., one or more) pharmaceutically active agent or compound. According to certain preferred embodiments, a superoxide dismutase mimetic corresponding to Formula (GC4419) is administered to a subject as the sole pharmaceutically active agent. Thus, in one embodiment, for example, a pharmaceutical composition or formulation consists essentially of a superoxide dismutase mimetic corresponding to Formula (GC4419), and optionally (but preferably) includes a pharmaceutically acceptable carrier or excipient. In other embodiments, a superoxide dismutase mimetic corresponding to Formula (GC4419) is administered to a subject in combination with another pharmaceutically active agent or compound. Thus, according to certain methods described herein, a superoxide dismutase mimetic corresponding to Formula (GC4419) and an additional pharmaceutically active agent or compound are administered in combination, i.e., they may be administered simultaneously (concurrently) or sequentially.

[0028] Superoxide dismutase mimics The superoxide dismutase mimetic compounds administered in accordance with the methods described herein are capable of converting the superoxide radical O2 -● A superoxide dismutase mimetic is a non-protein molecule that catalyzes the conversion of superoxide to molecular oxygen and hydrogen peroxide. For example, according to one embodiment, a superoxide dismutase mimetic is administered to a subject to increase the ability of cells (e.g., cancer cells) in the subject to dismutate superoxide.

[0029] The superoxide dismutase mimetics used in the methods, compositions, and formulations disclosed herein have the ability to selectively catalyze the conversion of superoxide to oxygen and hydrogen peroxide, but do not exhibit any significant activity against hydrogen peroxide. For example, the selective superoxide dismutase mimetics shown below, corresponding to formula (GC4419), exhibit no detectable activity against hydrogen peroxide, whereas non-selective superoxide dismutase mimetics, such as mangafodipir, copper[II]diisopropylsalicylate (CuDIPS), and manganese[III]tetrakis-(5,10,15,20)-benzoic acid porphyrin (MnTBAP), etc., exhibit significant activity against hydrogen peroxide. Generally, the potency of the superoxide dismutase mimetics used in the methods described herein tends to decrease as the activity of the superoxide dismutase mimetics against hydrogen peroxide increases. Thus, it is preferred that the ratio of the activity of the superoxide dismutase mimic towards superoxide to the activity of the superoxide dismutase mimic towards hydrogen peroxide is at least 10:1 (activity towards superoxide:activity towards hydrogen peroxide). More preferably, the ratio of the activity of the superoxide dismutase mimic towards superoxide to the activity of the superoxide dismutase mimic towards hydrogen peroxide is at least 100:1 (activity towards superoxide:activity towards hydrogen peroxide). Even more preferably, the ratio of the activity of the superoxide dismutase mimic towards superoxide to the activity of the superoxide dismutase mimic towards hydrogen peroxide is at least 1000:1 (activity towards superoxide:activity towards hydrogen peroxide). In a particularly preferred embodiment, the superoxide dismutase mimic exhibits no detectable activity towards hydrogen peroxide.

[0030] Thus, in various aspects of the disclosure, the methods described herein involve the administration of a superoxide dismutase mimetic corresponding to the following formula (GC4419): [ka] In formula (GC4419), X and Y are independently a neutral ligand or a negatively charged ligand.

[0031] As above, X and Y represent suitable neutral or negatively charged ligands derived from monodentate or polydentate ligands or ligand systems, or their corresponding anions (e.g., benzoic acid or benzoate anions, phenol or phenoxide anions, alcohol or alkoxide anions). For example, X and Y can be independently selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkylamino, heterocycloarylamino, amine oxide, hydrazine, alkylhydrazine, arylhydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, arylnitrile, alkylisonitrile, arylisonitrile, nitrate, nitrite, azide, alkylsulfonic acid, arylsulfonic acid, alkylsulfoxide, arylsulfoxide, alkylarylsulfoxide, alkylsulfenic acid, arylsulfenic acid, alkylsulfinic acid, arylsulfinic acid, alkylthiolcarboxylic acid, arylthiolcarboxylic acid, alkylthiolthiocarboxylic acid, azide. Aryl thiol thiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea, alkyl urea, aryl urea, alkylaryl urea, thiourea, alkyl thiourea, aryl thiourea, alkylaryl thiourea, sulfate, sulfite, bisulfite, hydrogen sulfite, thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphine sulfide, alkylaryl phosphine sulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, aryl guanidino, alkylaryl guanidino, alkyl carbamate,Anions of aryl carbamates, alkylaryl carbamates, alkylthiocarbamates, arylthiocarbamates, alkylarylthiocarbamates, alkyldithiocarbamates, aryldithiocarbamates, alkylaryldithiocarbamates, bicarbonates, carbonates, perchlorates, chlorates, chlorites, hypochlorites, perbromates, bromates, bromites, hypobromites, tetrahalomanganates, tetrafluoroborates, hexafluoroantimonates, hypophosphites, iodates, periodates, metaborates, tetraarylborates, tetraalkylborates, tartrates, salicylates, succinates, citrates, ascorbates, saccharates, amino acids, hydroxamic acids, thiotosylates, and ion exchange resins, or their corresponding anions, among other possibilities.

[0032] In one embodiment, X and Y are independently selected from monodentate ligands. For example, in one preferred embodiment, X and Y are independently selected from the group consisting of aquo ligands, halo ligands (e.g., chloro, iodo, fluoro), carboxylato ligands (e.g., formato, acetato), thiocyanato ligands, and bicarbonato ligands. In another preferred embodiment, X and Y are independently selected from aquo ligands and halo ligands. In another preferred embodiment, X and Y are independently halo ligands, and more preferably in this embodiment, X and Y are chloro ligands.

[0033] In a particularly preferred embodiment, the superoxide dismutase mimetic used in the methods and compositions described herein corresponds to the dichloro complex form of the following formula (GC4419): [ka]

[0034] It will be appreciated that when the superoxide dismutase mimics described herein are dissolved or dispersed in a solution such as water, saline, or the like, a dynamic and rapid equilibrium is typically established in which ligands (e.g., chloro ligands) can dissociate from axial coordination sites occupied by solvent (e.g., water) molecules to form both monoaquo (monocationic) and bisaquo (dicationic) complexes. As a result, it is difficult to accurately represent the compounds in solution with a single structural formula. This dissociation reaction generally proceeds according to the following reaction scheme (which also uses chloro and aquo ligands as illustrative examples): [ka]

[0035] When the ligands are defined by some specific structure (e.g., X and Y are chloro ligands, X is aquo and Y is chloro, X and Y are aquo, etc.), the complex is enclosed in parentheses for clarity and the net charge is displayed. The exchange rate of the bound / coordinated water / ligand is measured by NMR relaxation techniques and is very fast (e.g., about 10 +7 s -1 ). It will be appreciated that, due at least in part to the rapid exchange rate of the X and Y ligands in solution, the ligands present at the X and Y positions at any given time will depend on the ligands initially present at the X and Y positions of the superoxide dismutase mimetic (e.g., halo such as chloro, carboxylato such as formato or acetate, or bicarbonate) and the ligands present in the solution in which the compound is dissolved (e.g., water (aquo ligands), saline (chloro anion), etc.). Thus, for example, in one embodiment, a solution containing the dichloro complex form of Formula (GC4419) dissolved in buffered saline is expected to contain a mixture of at least the following complexes in equilibrium: [ka]

[0036] As a further example, a solution containing the diacetate complex form of formula (GC4419) dissolved in buffered saline is expected to contain a mixture of at least the following complexes in equilibrium: [ka]

[0037] Preferably, the enantiomeric purity of the superoxide dismutase mimetic compound is greater than 95%, more preferably greater than 98%, more preferably greater than 99%, and most preferably greater than 99.5%. As used herein, the term "enantiomeric purity" refers to the amount of a compound having the indicated absolute stereochemistry, expressed as a percentage of the total amount of the indicated compound and its enantiomers. Preferably, the diastereomeric purity of the superoxide dismutase mimetic compound is greater than 98%, more preferably greater than 99%, and most preferably greater than 99.5%. As used herein, the term "diastereomeric purity" refers to the amount of a compound having the indicated absolute stereochemistry, expressed as a percentage of the total amount of the indicated compound and its diastereomers. Methods for measuring diastereomeric purity and enantiomeric purity are well known in the art. Measurement of diastereomeric purity can be performed by any analytical technique capable of quantitatively distinguishing between a compound and its diastereomers, such as high-performance liquid chromatography (HPLC). Similarly, measurement of enantiomeric purity can be performed by any analytical technique capable of quantitatively distinguishing between a compound and its enantiomers. Examples of suitable analytical techniques for determining enantiomeric purity include, but are not limited to, rotation of plane polarized light using a polarimeter, and HPLC using chiral column packings.

[0038] Also, preferably, the superoxide dismutase mimic is chemically pure. Preferably, the chemical purity of the superoxide dismutase mimic compound is greater than 95%, more preferably greater than 98%, and most preferably greater than 99%. Chemical purity can be confirmed, for example, by high pressure liquid chromatography.

[0039] High-dose / high-dose superoxide dismutase mimetics and improved pharmacokinetic parameters The actual dosage level of the superoxide dismutase mimetic active ingredient in the pharmaceutical compositions and formulations described herein may be varied to obtain an effective amount of the active compound to achieve the desired therapeutic response for a particular patient, composition, and method of administration. The selected dosage level will generally depend, for example, on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of one in the art to start administering the compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0040] When used in these or other treatments, the superoxide dismutase mimetic compounds may be administered as pharmaceutical compositions or unit dose formulations containing the compound of interest, typically in combination with one or more pharmaceutically acceptable carriers. It will be understood that a therapeutically effective amount of a superoxide dismutase mimetic (or other compound described herein) includes a sufficient quantity of the compound to treat a disease or condition, at a reasonable benefit / risk ratio applicable to any treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for a particular subject will depend on a variety of factors, including the disease or disorder being treated and the severity of the disease or disorder; the activity of the particular compound used; the particular composition used; the age, weight, general health, sex, and diet of the subject; the time, route of administration, and excretion rate of the particular compound used; the duration of treatment; other drugs used in combination or concomitantly with the particular compound used; and similar factors well known in the medical arts. For example, it is well within the skill of one in the art to start administering the compound at levels lower than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0041] Administration of the superoxide dismutase mimetic(s) may occur in a single dose or over the course of treatment. For example, the superoxide dismutase mimetic may be administered daily (including multiple doses per day), weekly, every two weeks, or monthly. For treatment of acute conditions, the course of treatment may be at least several minutes, hours, or days. Depending on the condition, treatment may extend from several days to several weeks. For example, the treatment period may be one week, two weeks, three weeks, etc. For more chronic conditions, the treatment period may be several weeks to several months, a year or more, or for the lifetime of the subject in need of such treatment. Alternatively, the superoxide dismutase mimetic may be administered daily, weekly, biweekly, or monthly as a preventative or suppressive measure for several weeks, months, years, or the lifetime of the mammal.

[0042] As noted above, it has been unexpectedly discovered that the superoxide dismutase mimetics described herein can be administered to a subject in need thereof in relatively high doses (including single doses and unit doses) at rapid administration rates, as compared to, for example, compounds of similar structure, such as enantiomers of the mimetics (e.g., formula (GC4419) as compared to prior art compound (GC4403)).

[0043] Thus, generally, the methods described herein involve administering a superoxide dismutase mimetic corresponding to formula (GC4419) at a relatively high dose and / or at a relatively rapid time interval. In accordance with the treatment methods described herein for cancer therapy or other tissue damage resulting from radiation exposure, the superoxide dismutase mimetic may be administered in various amounts (e.g., at least 25 mg, 50 mg, 100 mg, etc., or another amount based on patient weight) within a specific time frame, such as 15 minutes, 30 minutes, 45 minutes, 60 minutes, or more than 60 minutes. Thus, for example, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic according to formula (GC4419) may be administered within a time frame of 15 minutes, 30 minutes, 45 minutes, 60 minutes, or more than 60 minutes.

[0044] For example, in one embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient at a rate of at least 100 mg / hour. According to this embodiment, for example, the amount may be administered at a rate of at least 150 mg / hour, at least 200 mg / hour, at least 250 mg / hour, at least 300 mg / hour, at least 350 mg / hour, at least 400 mg / hour, at least 450 mg / hour, at least 500 mg / hour, at least 550 mg / hour, or at least 600 mg / hour. Thus, for example, the administered amount can be at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic corresponding to formula (GC4419).

[0045] For example, in one embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 15 minute time frame. According to this embodiment, the administered amount can be, for example, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 25 mg may be administered to a patient within a 15 minute time frame; at least 50 mg may be administered to a patient within a 15 minute time frame; at least 75 mg may be administered to a patient within a 15 minute time frame; at least 100 mg may be administered to a patient within a 15 minute time frame; at least 125 mg may be administered to a patient within a 15 minute time frame; or at least 150 mg may be administered to a patient within a 15 minute time frame. In accordance with these embodiments, one suitable superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0046] For example, in another embodiment, an amount of a superoxide dismutase mimetic according to formula (GC4419) is administered to a patient within a 30 minute time frame. According to this embodiment, the administered amount can be, for example, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic according to formula (GC4419). Thus, for example, at least 50 mg may be administered to a patient within a 30 minute time frame; at least 75 mg may be administered to a patient within a 30 minute time frame; at least 100 mg may be administered to a patient within a 30 minute time frame; at least 125 mg may be administered to a patient within a 30 minute time frame; at least 125 mg may be administered to a patient within a 30 minute time frame; at least 150 mg may be administered to a patient within a 30 minute time frame; at least 175 mg may be administered to a patient within a 30 minute time frame; at least 200 mg may be administered to a patient within a 30 minute time frame; at least 225 mg may be administered to a patient within a 30 minute time frame; at least 250 mg may be administered to a patient within a 30 minute time frame; at least 275 mg may be administered to a patient within a 30 minute time frame; or at least 300 mg may be administered to a patient within a 30 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0047] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 45 minute time frame. According to this embodiment, the administered amount can be, for example, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, or at least 450 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 50 mg may be administered to a patient within a 45 minute time frame; at least 75 mg may be administered to a patient within a 45 minute time frame; at least 100 mg may be administered to a patient within a 45 minute time frame; at least 125 mg may be administered to a patient within a 45 minute time frame; at least 125 mg may be administered to a patient within a 45 minute time frame; at least 150 mg may be administered to a patient within a 45 minute time frame; at least 175 mg may be administered to a patient within a 45 minute time frame; at least 200 mg may be administered to a patient within a 45 minute time frame; at least 225 mg may be administered to a patient within a 45 minute time frame. Preferably, at least 250 mg may be administered to the patient within a 45 minute time frame; at least 275 mg may be administered to the patient within a 45 minute time frame; at least 300 mg may be administered to the patient within a 45 minute time frame; at least 325 mg may be administered to the patient within a 45 minute time frame; at least 350 mg may be administered to the patient within a 45 minute time frame; at least 375 mg may be administered to the patient within a 45 minute time frame; at least 400 mg may be administered to the patient within a 45 minute time frame; at least 425 mg may be administered to the patient within a 45 minute time frame; or at least 450 mg may be administered to the patient within a 45 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0048] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 60 minute time frame. According to this embodiment, for example, the administered amount can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419).Thus, for example, at least 50 mg may be administered to a patient within a 60 minute time frame; at least 75 mg may be administered to a patient within a 60 minute time frame; at least 100 mg may be administered to a patient within a 60 minute time frame; at least 125 mg may be administered to a patient within a 60 minute time frame; at least 125 mg may be administered to a patient within a 60 minute time frame; at least 150 mg may be administered to a patient within a 60 minute time frame; at least 175 mg may be administered to a patient within a 60 minute time frame; at least 200 mg may be administered to a patient within a 60 minute time frame; at least 225 mg may be administered to a patient within a 60 minute time frame; at least 250 mg may be administered to a patient within a 60 minute time frame; at least 275 mg may be administered to a patient within a 60 minute time frame; at least 300 mg may be administered to a patient within a 60 minute time frame. Preferably; at least 325 mg may be administered to the patient within a 60 minute time frame; at least 350 mg may be administered to the patient within a 60 minute time frame; at least 375 mg may be administered to the patient within a 60 minute time frame; at least 400 mg may be administered to the patient within a 60 minute time frame; at least 425 mg may be administered to the patient within a 60 minute time frame; at least 450 mg may be administered to the patient within a 60 minute time frame; at least 475 mg may be administered to the patient within a 60 minute time frame; at least 500 mg may be administered to the patient within a 60 minute time frame; at least 525 mg may be administered to the patient within a 60 minute time frame; at least 550 mg may be administered to the patient within a 60 minute time frame; at least 575 mg may be administered to the patient within a 60 minute time frame; or at least 600 mg may be administered to the patient within a 60 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0049] For example, in other embodiments, at least 0.67 mg / kg of patient body weight; at least 1.0 mg / kg of patient body weight; at least 1.5 mg / kg of patient body weight; at least 2.0 mg / kg of patient body weight; at least 2.5 mg / kg of patient body weight; at least 3.0 mg / kg of patient body weight; at least 3.5 mg / kg of patient body weight; at least 4.0 mg / kg of patient body weight; at least 5.0 mg / kg of patient body weight; at least 6.0 mg / kg of patient body weight; at least 7.5 mg / kg of patient body weight; or at least 10.0 mg / kg of patient body weight of a superoxide dismutase mimetic according to formula (GC4419) is administered to a patient within a particular time frame (e.g., 15 minutes, 30 minutes, 45 minutes, or 60 minutes). Thus, for example, at least 0.67 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 0.67 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame. may be administered to a patient within a 30 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 3.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 3.5 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 4.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 5.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 6.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 7.5 mg may be administered to a patient within a 30 minute time frame; at least 0.67 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; At least 3.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 3.5 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 4.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 5.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 6.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; or at least 7.5 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame. At least 0.67 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 3.0 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame. may be administered to a patient within a 60 minute time frame; at least 3.5 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 4.0 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 5.0 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 6.0 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 7.5 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; or at least 10.0 mg may be administered to a patient within a 60 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419):

[0050] For example, in other embodiments, the dosage (i.e., the dosage without regard to time of administration) is at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). For example, in other embodiments, the dosage (i.e., the dosage without taking into account the time of administration) is at least 0.67 mg / kg of patient body weight; at least 1.0 mg / kg of patient body weight; at least 1.5 mg / kg of patient body weight; at least 2.0 mg / kg of patient body weight; at least 2.5 mg / kg of patient body weight; at least 3.0 mg / kg of patient body weight; at least 3.5 mg / kg of patient body weight; at least 4.0 mg / kg of patient body weight; at least 5.0 mg / kg of patient body weight; at least 6.0 mg / kg of patient body weight; at least 7.5 mg / kg of patient body weight; or at least 10.0 mg / kg of patient body weight; or at least 10.0 mg / kg of patient body weight.

[0051] If desired, the effective dose may be divided into multiple doses for purposes of administration. Thus, a single dose of a composition may contain an effective dose, or any fraction thereof that makes up the effective dose.

[0052] Additionally, some aspects of the present disclosure relate to improved pharmacokinetic profiles of the superoxide dismutase mimetics described herein when administered to a subject. Due, at least in part, to the improved safety profile of superoxide dismutase mimetics according to formula (GC4419) (e.g., the dichloro complex of formula (GC4419)), administration of such compounds results in greater patient exposure as measured by AUC (i.e., the area under the curve of a graph of plasma compound concentration over time) compared to related superoxide dismutase mimetics (e.g., the mirror image compound GC4403 described above).

[0053] For example, in one embodiment, the methods described herein include administering to a patient a superoxide dismutase mimetic corresponding to formula (GC4419) to achieve an exposure, as measured by area under the curve (AUC), of at least 4,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient. Accordingly, the AUC values, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient, can be at least 5,000 ng-hr / mL; at least 7,500 ng-hr / mL; at least 10,000 ng-hr / mL; at least 12,500 ng-hr / mL; at least 15,000 ng-hr / mL; at least 17,500 ng-hr / mL; at least 20,000 ng-hr / mL; at least 22,500 ng-hr / mL; at least 25,000 ng-hr / mL; The superoxide dismutase mimic may be at least 27,500 ng-hr / mL; at least 30,000 ng-hr / mL; at least 32,500 ng-hr / mL; at least 35,000 ng-hr / mL; at least 37,500 ng-hr / mL; at least 40,000 ng-hr / mL; at least 42,500 ng-hr / mL; at least 45,000 ng-hr / mL; at least 47,500 ng-hr / mL; or at least 50,000 ng-hr / mL. According to these embodiments, one suitable superoxide dismutase mimic is the dichloro complex form of formula (GC4419).

[0054] Methods and Indications The superoxide dismutase mimetics described herein (e.g., superoxide dismutase mimetics corresponding to Formula (GC4419)) can be used to treat a variety of diseases and conditions regulated by tissue damage and / or superoxide. Typically, such tissue damage, diseases, and conditions can be treated by controlling superoxide levels in a subject, and preferably, such tissue damage, diseases, and conditions can be treated by administering a compound corresponding to Formula (GC4419), alone or in combination with another active agent, for example, as part of a therapeutic or prophylactic regimen. Treatment of the diseases and conditions described herein (including tissue damage) generally involves not only inhibiting the disease (i.e., arresting further development of the pathology and / or symptoms) in a patient experiencing or exhibiting the pathology or symptoms of the disease or condition, but also ameliorating the disease or condition (i.e., reversing the pathology and / or symptoms) in a patient experiencing or exhibiting the pathology or symptoms of the disease or condition. Treating a human patient for a disease or condition described herein (e.g., tissue damage resulting from the administration of radiotherapy or chemotherapy or radiation exposure) may also result in inhibiting or preventing such damage in a patient who is not necessarily experiencing or exhibiting the pathology or symptoms of the disease or condition.

[0055] The methods of the present disclosure may be advantageously used to treat (e.g., inhibit, reverse, or alleviate) various diseases or conditions in various subjects (i.e., patients). The subject may be a mammal, such as, for example, a bovine, avian, canine, equine, feline, ovine, porcine, or primate (including humans and non-human primates). Subjects also include mammals of importance because they are endangered or economically important, such as animals raised on farms for human consumption, or animals of social importance to humans (e.g., animals kept as pets or in zoos). Examples of such animals include, but are not limited to, cats, dogs, porcines, ruminants, or ungulates, such as cattle, oxen, sheep, giraffes, deer, goats, bison, camels, and horses. In one embodiment, the subject is a bovine, avian, canine, equine, feline, ovine, porcine, or non-human primate. In a preferred embodiment, the subject is a human patient.

[0056] Treating tissue damage According to one aspect of the present disclosure, described herein is a method for treating tissue damage resulting from cancer treatment (e.g., radiation therapy or chemotherapy) administered to a subject in need of treatment. According to another aspect of the present disclosure, described herein is a method for treating tissue damage in a human patient resulting from radiation exposure. Thus, for example, in various embodiments, radiation exposure can be accidental, unintentional, or intentional. As noted above, treating tissue damage as described herein can include both inhibiting (i.e., preventing) and reversing tissue damage that may result from any event or activity. Generally, the method of treatment involves administering to the subject a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419). In a preferred embodiment, the superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0057] Treatment of cancer therapy or other tissue damage resulting from radiation exposure according to the methods described herein involves administering a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419). Generally, various therapeutically effective amounts may be used, depending, for example, on the compound selected and its safety and efficacy, the type, location, and severity of the tissue damage, among other factors.

[0058] In some embodiments, treating tissue damage according to the methods described herein involves administering a superoxide dismutase mimetic corresponding to formula (GC4419) at a relatively high dose and / or at a relatively rapid time interval. According to the treatment methods described herein for tissue damage resulting from cancer treatment or other radiation exposure, the superoxide dismutase mimetic may be administered in various amounts (e.g., at least 25 mg, 50 mg, 100 mg, etc., or another amount based on patient weight) within a specific time frame, e.g., 15 minutes, 30 minutes, 60 minutes, or more than 60 minutes. According to these embodiments, one suitable superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0059] For example, in one embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 15 minute time frame. According to this embodiment, the administered amount can be, for example, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 25 mg may be administered to a patient within a 15 minute time frame; at least 50 mg may be administered to a patient within a 15 minute time frame; at least 75 mg may be administered to a patient within a 15 minute time frame; at least 100 mg may be administered to a patient within a 15 minute time frame; at least 125 mg may be administered to a patient within a 15 minute time frame; or at least 150 mg may be administered to a patient within a 15 minute time frame. In accordance with these embodiments, one suitable superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0060] For example, in another embodiment, an amount of a superoxide dismutase mimetic according to formula (GC4419) is administered to a patient within a 30 minute time frame. According to this embodiment, the administered amount can be, for example, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic according to formula (GC4419). Thus, for example, at least 50 mg may be administered to a patient within a 30 minute time frame; at least 75 mg may be administered to a patient within a 30 minute time frame; at least 100 mg may be administered to a patient within a 30 minute time frame; at least 125 mg may be administered to a patient within a 30 minute time frame; at least 125 mg may be administered to a patient within a 30 minute time frame; at least 150 mg may be administered to a patient within a 30 minute time frame; at least 175 mg may be administered to a patient within a 30 minute time frame; at least 200 mg may be administered to a patient within a 30 minute time frame; at least 225 mg may be administered to a patient within a 30 minute time frame; at least 250 mg may be administered to a patient within a 30 minute time frame; at least 275 mg may be administered to a patient within a 30 minute time frame; or at least 300 mg may be administered to a patient within a 30 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0061] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 45 minute time frame. According to this embodiment, the administered amount can be, for example, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, or at least 450 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 50 mg may be administered to a patient within a 45 minute time frame; at least 75 mg may be administered to a patient within a 45 minute time frame; at least 100 mg may be administered to a patient within a 45 minute time frame; at least 125 mg may be administered to a patient within a 45 minute time frame; at least 125 mg may be administered to a patient within a 45 minute time frame; at least 150 mg may be administered to a patient within a 45 minute time frame; at least 175 mg may be administered to a patient within a 45 minute time frame; at least 200 mg may be administered to a patient within a 45 minute time frame; at least 225 mg may be administered to a patient within a 45 minute time frame. Preferably, at least 250 mg may be administered to the patient within a 45 minute time frame; at least 275 mg may be administered to the patient within a 45 minute time frame; at least 300 mg may be administered to the patient within a 45 minute time frame; at least 325 mg may be administered to the patient within a 45 minute time frame; at least 350 mg may be administered to the patient within a 45 minute time frame; at least 375 mg may be administered to the patient within a 45 minute time frame; at least 400 mg may be administered to the patient within a 45 minute time frame; at least 425 mg may be administered to the patient within a 45 minute time frame; or at least 450 mg may be administered to the patient within a 45 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0062] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 60 minute time frame. According to this embodiment, for example, the administered amount can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419).Thus, for example, at least 50 mg may be administered to a patient within a 60 minute time frame; at least 75 mg may be administered to a patient within a 60 minute time frame; at least 100 mg may be administered to a patient within a 60 minute time frame; at least 125 mg may be administered to a patient within a 60 minute time frame; at least 125 mg may be administered to a patient within a 60 minute time frame; at least 150 mg may be administered to a patient within a 60 minute time frame; at least 175 mg may be administered to a patient within a 60 minute time frame; at least 200 mg may be administered to a patient within a 60 minute time frame; at least 225 mg may be administered to a patient within a 60 minute time frame; at least 250 mg may be administered to a patient within a 60 minute time frame; at least 275 mg may be administered to a patient within a 60 minute time frame; at least 300 mg may be administered to a patient within a 60 minute time frame. Preferably; at least 325 mg may be administered to the patient within a 60 minute time frame; at least 350 mg may be administered to the patient within a 60 minute time frame; at least 375 mg may be administered to the patient within a 60 minute time frame; at least 400 mg may be administered to the patient within a 60 minute time frame; at least 425 mg may be administered to the patient within a 60 minute time frame; at least 450 mg may be administered to the patient within a 60 minute time frame; at least 475 mg may be administered to the patient within a 60 minute time frame; at least 500 mg may be administered to the patient within a 60 minute time frame; at least 525 mg may be administered to the patient within a 60 minute time frame; at least 550 mg may be administered to the patient within a 60 minute time frame; at least 575 mg may be administered to the patient within a 60 minute time frame; or at least 600 mg may be administered to the patient within a 60 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0063] In other embodiments, at least 0.67 mg / kg of patient body weight; at least 1.0 mg / kg of patient body weight; at least 1.5 mg / kg of patient body weight; at least 2.0 mg / kg of patient body weight; at least 2.5 mg / kg of patient body weight; at least 3.0 mg / kg of patient body weight; at least 3.5 mg / kg of patient body weight; at least 4.0 mg / kg of patient body weight; at least 5.0 mg / kg of patient body weight; at least 6.0 mg / kg of patient body weight; at least 7.5 mg / kg of patient body weight; or at least 10.0 mg / kg of patient body weight of a superoxide dismutase mimetic according to formula (GC4419) is administered to the patient within a particular time frame (e.g., 15 minutes, 30 minutes, 45 minutes, or 60 minutes). Thus, for example, at least 0.67 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 0.67 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame. may be administered to a patient within a 30 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 3.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 3.5 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 4.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 5.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 6.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 7.5 mg may be administered to a patient within a 30 minute time frame; at least 0.67 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; At least 3.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 3.5 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 4.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 5.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 6.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; or at least 7.5 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame. At least 0.67 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 3.0 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame. may be administered to a patient within a 60 minute time frame; at least 3.5 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 4.0 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 5.0 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 6.0 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 7.5 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; or at least 10.0 mg may be administered to a patient within a 60 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419):

[0064] For example, in other embodiments, the dosage (i.e., the dosage without regard to time of administration) is at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). For example, in other embodiments, the dosage (i.e., the dosage without taking into account the time of administration) is at least 0.67 mg / kg of patient body weight; at least 1.0 mg / kg of patient body weight; at least 1.5 mg / kg of patient body weight; at least 2.0 mg / kg of patient body weight; at least 2.5 mg / kg of patient body weight; at least 3.0 mg / kg of patient body weight; at least 3.5 mg / kg of patient body weight; at least 4.0 mg / kg of patient body weight; at least 5.0 mg / kg of patient body weight; at least 6.0 mg / kg of patient body weight; at least 7.5 mg / kg of patient body weight; or at least 10.0 mg / kg of patient body weight; or at least 10.0 mg / kg of patient body weight.

[0065] If desired, the effective dose may be divided into multiple doses for purposes of administration. Thus, a single dose of a composition may contain an effective dose, or any fraction thereof that makes up the effective dose.

[0066] Additionally, some aspects of the present disclosure relate to improved pharmacokinetic profiles of the superoxide dismutase mimetics described herein when administered to a subject. Due, at least in part, to the improved safety profile of superoxide dismutase mimetics (e.g., GC4419) corresponding to formula (GC4419), administration of such compounds results in greater patient exposure as measured by AUC (i.e., the area under the curve of a graph of plasma compound concentration over time) compared to related superoxide dismutase mimetics (e.g., the mirror image compound GC4403 described above).

[0067] For example, in one embodiment, the methods described herein include administering to a patient a superoxide dismutase mimetic corresponding to formula (GC4419) to achieve an exposure, as measured by area under the curve (AUC), of at least 4,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient. Accordingly, the AUC values, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient, can be at least 5,000 ng-hr / mL; at least 7,500 ng-hr / mL; at least 10,000 ng-hr / mL; at least 12,500 ng-hr / mL; at least 15,000 ng-hr / mL; at least 17,500 ng-hr / mL; at least 20,000 ng-hr / mL; at least 22,500 ng-hr / mL; at least 25,000 ng-hr / mL; The superoxide dismutase mimic may be at least 27,500 ng-hr / mL; at least 30,000 ng-hr / mL; at least 32,500 ng-hr / mL; at least 35,000 ng-hr / mL; at least 37,500 ng-hr / mL; at least 40,000 ng-hr / mL; at least 42,500 ng-hr / mL; at least 45,000 ng-hr / mL; at least 47,500 ng-hr / mL; or at least 50,000 ng-hr / mL. According to these embodiments, one suitable superoxide dismutase mimic is the dichloro complex form of formula (GC4419).

[0068] Generally, the time aspect of administration of a superoxide dismutase mimetic may depend, for example, on the specific compound, the selected radiotherapy or chemotherapy, and the type, nature, and / or duration of radiation exposure. Other considerations include the disease or disorder to be treated and the severity of the disease or disorder; the activity of the specific compound used; the specific composition used; the age, weight, overall health, sex, and diet of the subject; the administration time, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used; and similar factors. For example, in various embodiments, a superoxide dismutase mimetic may be administered before, during, and / or after the administration of a cancer treatment (e.g., radiotherapy or chemotherapy). As another example, in various embodiments, a superoxide dismutase mimetic may be administered before, during, and / or after radiation exposure.

[0069] For example, in one embodiment, a superoxide dismutase mimic is administered to a patient before or simultaneously with cancer treatment. For example, in another embodiment, a superoxide dismutase mimic is administered to a patient before cancer treatment, but not after cancer treatment. In yet another embodiment, a superoxide dismutase mimic is administered to a patient at least 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more before cancer treatment. For example, in yet another embodiment, a superoxide dismutase mimic is administered to a patient after cancer treatment. Thus, for example, the superoxide dismutase mimetic may be administered up to 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more after cancer treatment. According to these embodiments, one suitable superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0070] For example, in another embodiment, the superoxide dismutase mimic is administered to the patient before or simultaneously with radiation exposure. For example, in another embodiment, the superoxide dismutase mimic is administered to the patient before radiation exposure but not after radiation exposure. In yet another embodiment, the superoxide dismutase mimic is administered to the patient at least 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more before radiation exposure. For example, in yet another embodiment, the superoxide dismutase mimic is administered to the patient after radiation exposure. Thus, for example, the superoxide dismutase mimetic may be administered up to 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more after radiation exposure. According to these embodiments, one suitable superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0071] For example, in one embodiment, cancer treatment involves the administration of radiation therapy (e.g., intentional exposure to radiation). According to this embodiment, administering to the patient a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419) provides a safe and effective method of treating radiation damage and inhibiting or reversing radiation-associated cancer or radiation-associated tissue damage in a patient in need thereof.

[0072] In another embodiment, the exposure to radiation is accidental or unintentional. For example, radiation exposure may occur due to a wide variety of commercial and non-commercial activities, including, but not limited to, utilities, power, oil / gas / petrochemical, chemicals / plastics, automatic ventilation controls (e.g., cooking, smoking), heavy industrial manufacturing, environmental toxicology and remediation, biomedical, cosmetics / fragrance, pharmaceuticals, transportation, emergency response and law enforcement, military or terrorist activity, detection (e.g., leaks or spills of hazardous materials), etc. For example, in one embodiment, radiation exposure may occur due to excavation and / or remediation of radioactive materials from air, groundwater, surface water, sediments, and / or soil.

[0073] In various embodiments, the radiation source can be electromagnetic radiation (including visible light, ultraviolet light) or nuclear radiation (including alpha, beta, gamma, and cosmic rays). Types of injury can include, but are not limited to, various forms of dermatological or mucosal injury, such as mucositis, esophagitis, as well as internal cell loss, fibrosis, cyst formation, neuropathy, and various benign and malignant tumors.

[0074] Additionally or alternatively, in another embodiment, cancer treatment includes the administration of a chemotherapeutic agent. The method according to this embodiment provides a safe and effective way to treat, ameliorate, or inhibit chemotherapy-induced toxicity to normal tissues in a patient in need of such treatment or who has been unintentionally or intentionally administered a chemical agent having a free radical toxic component by administering to the patient a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419). The methods described herein are useful for reducing the toxicity of chemical agents having a free radical component, including fluoropyrimidines, pyrimidine nucleosides, purines, platinum analogs, anthracyclines, podophyllotoxins, camptothecin, hormones and hormone analogs, enzymes, proteins and antibodies, vinca alkaloids, taxanes, and the like, among others. The toxicity reduction method of the present invention can be applied to any chemotherapeutic agent, and representative examples include irinotecan, FU, paclitael, docetaxel, cisplatin, doxorubicin, oxaliplatin, cyclophosphamide, EGF and VGF inhibitors, acemannan, acetaminophen, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxacalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon α, daunorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gemcitabine, gemtuzumab zogamicin (gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination drug, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, IL-2, imiquimod, interferon alpha, interferon alpha, natural type, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-N3, interferon alfacon-1, interferon alpha, natural type, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural type interferon gamma-1a, interferon gamma-1b, interleukin-1beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, promotion of de novo erythropoiesis Protein, NSC631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon α-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon α-2a, porfimer sodium, raloxifene, raltitrexed, rasburicase, rhenium Re186 etidronate, RII retinamide, rituximab, romurtide, lexidronam samarium (153 Sm), sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyroid-stimulating hormone alpha, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, Rilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, native, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE941 (Eterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diazicon, EL532 (Elan), EM800 (Andrecherche), eniluracil, etanidazole, fenretinide, filgrastim SDO1 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-17 gene therapy (Bical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytolan), interleukin-2, iproxifen, LDI200 (Milk House), relidistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Nihon Yakuhin Kaihatsu), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-itrim 90 MAb (Antizoma), marimastat, menogaril, mitumomab, motexafin, gadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU5416 (Sugen), SU6668 (Sugen), These include TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, ethyl etiopurpurin tin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), and valspodar.

[0075] Treatment of Diseases and Conditions Described herein, according to another aspect of the present disclosure, are methods of treating various superoxide-regulated diseases and conditions in a subject in need thereof. As noted above, treatment of the diseases and conditions described herein can include both inhibition (i.e., prevention) and amelioration of the disease or condition. Generally, the methods of treatment involve administering to the subject a therapeutically effective amount of a superoxide dismutase mimetic corresponding to formula (GC4419). In a preferred embodiment, the superoxide dismutase mimetic is a dichloro complex of formula (GC4419).

[0076] Treatment of diseases and conditions according to the methods described herein involves administering a superoxide dismutase mimetic corresponding to formula (GC4419) at relatively high doses and / or at relatively rapid time intervals. According to the treatment methods described herein for cancer treatment or other tissue damage resulting from radiation exposure, the superoxide dismutase mimetic may be administered in various amounts (e.g., at least 25 mg, 50 mg, 100 mg, etc., or another amount based on patient weight) within a specific time frame, such as 15 minutes, 30 minutes, 45 minutes, 60 minutes, or more than 60 minutes.

[0077] For example, in one embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 15 minute time frame. According to this embodiment, the administered amount can be, for example, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 25 mg may be administered to a patient within a 15 minute time frame; at least 50 mg may be administered to a patient within a 15 minute time frame; at least 75 mg may be administered to a patient within a 15 minute time frame; at least 100 mg may be administered to a patient within a 15 minute time frame; at least 125 mg may be administered to a patient within a 15 minute time frame; or at least 150 mg may be administered to a patient within a 15 minute time frame. In accordance with these embodiments, one suitable superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0078] For example, in another embodiment, an amount of a superoxide dismutase mimetic according to formula (GC4419) is administered to a patient within a 30 minute time frame. According to this embodiment, the administered amount can be, for example, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, or at least 300 mg of a superoxide dismutase mimetic according to formula (GC4419). Thus, for example, at least 50 mg may be administered to a patient within a 30 minute time frame; at least 75 mg may be administered to a patient within a 30 minute time frame; at least 100 mg may be administered to a patient within a 30 minute time frame; at least 125 mg may be administered to a patient within a 30 minute time frame; at least 125 mg may be administered to a patient within a 30 minute time frame; at least 150 mg may be administered to a patient within a 30 minute time frame; at least 175 mg may be administered to a patient within a 30 minute time frame; at least 200 mg may be administered to a patient within a 30 minute time frame; at least 225 mg may be administered to a patient within a 30 minute time frame; at least 250 mg may be administered to a patient within a 30 minute time frame; at least 275 mg may be administered to a patient within a 30 minute time frame; or at least 300 mg may be administered to a patient within a 30 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0079] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 45 minute time frame. According to this embodiment, the administered amount can be, for example, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, or at least 450 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). Thus, for example, at least 50 mg may be administered to a patient within a 45 minute time frame; at least 75 mg may be administered to a patient within a 45 minute time frame; at least 100 mg may be administered to a patient within a 45 minute time frame; at least 125 mg may be administered to a patient within a 45 minute time frame; at least 125 mg may be administered to a patient within a 45 minute time frame; at least 150 mg may be administered to a patient within a 45 minute time frame; at least 175 mg may be administered to a patient within a 45 minute time frame; at least 200 mg may be administered to a patient within a 45 minute time frame; at least 225 mg may be administered to a patient within a 45 minute time frame. Preferably, at least 250 mg may be administered to the patient within a 45 minute time frame; at least 275 mg may be administered to the patient within a 45 minute time frame; at least 300 mg may be administered to the patient within a 45 minute time frame; at least 325 mg may be administered to the patient within a 45 minute time frame; at least 350 mg may be administered to the patient within a 45 minute time frame; at least 375 mg may be administered to the patient within a 45 minute time frame; at least 400 mg may be administered to the patient within a 45 minute time frame; at least 425 mg may be administered to the patient within a 45 minute time frame; or at least 450 mg may be administered to the patient within a 45 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichlorocomplex form of formula (GC4419).

[0080] For example, in another embodiment, an amount of a superoxide dismutase mimetic corresponding to formula (GC4419) is administered to a patient within a 60 minute time frame. According to this embodiment, for example, the administered amount can be at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419).Thus, for example, at least 50 mg may be administered to a patient within a 60 minute time frame; at least 75 mg may be administered to a patient within a 60 minute time frame; at least 100 mg may be administered to a patient within a 60 minute time frame; at least 125 mg may be administered to a patient within a 60 minute time frame; at least 125 mg may be administered to a patient within a 60 minute time frame; at least 150 mg may be administered to a patient within a 60 minute time frame; at least 175 mg may be administered to a patient within a 60 minute time frame; at least 200 mg may be administered to a patient within a 60 minute time frame; at least 225 mg may be administered to a patient within a 60 minute time frame; at least 250 mg may be administered to a patient within a 60 minute time frame; at least 275 mg may be administered to a patient within a 60 minute time frame; at least 300 mg may be administered to a patient within a 60 minute time frame. Preferably; at least 325 mg may be administered to the patient within a 60 minute time frame; at least 350 mg may be administered to the patient within a 60 minute time frame; at least 375 mg may be administered to the patient within a 60 minute time frame; at least 400 mg may be administered to the patient within a 60 minute time frame; at least 425 mg may be administered to the patient within a 60 minute time frame; at least 450 mg may be administered to the patient within a 60 minute time frame; at least 475 mg may be administered to the patient within a 60 minute time frame; at least 500 mg may be administered to the patient within a 60 minute time frame; at least 525 mg may be administered to the patient within a 60 minute time frame; at least 550 mg may be administered to the patient within a 60 minute time frame; at least 575 mg may be administered to the patient within a 60 minute time frame; or at least 600 mg may be administered to the patient within a 60 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419).

[0081] In other embodiments, for example, at least 0.67 mg / kg of patient body weight; at least 1.0 mg / kg of patient body weight; at least 1.5 mg / kg of patient body weight; at least 2.0 mg / kg of patient body weight; at least 2.5 mg / kg of patient body weight; at least 3.0 mg / kg of patient body weight; at least 3.5 mg / kg of patient body weight; at least 4.0 mg / kg of patient body weight; at least 5.0 mg / kg of patient body weight; at least 6.0 mg / kg of patient body weight; at least 7.5 mg / kg of patient body weight; or at least 10.0 mg / kg of patient body weight of a superoxide dismutase mimetic according to formula (GC4419) is administered to a patient within a particular time frame (e.g., 15 minutes, 30 minutes, 45 minutes, or 60 minutes). Thus, for example, at least 0.67 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to a patient within a 15 minute time frame; at least 0.67 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame. may be administered to a patient within a 30 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 3.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 3.5 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 4.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 5.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 6.0 mg per kg of patient body weight may be administered to a patient within a 30 minute time frame; at least 7.5 mg may be administered to a patient within a 30 minute time frame; at least 0.67 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to a patient within a 45 minute time frame; At least 3.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 3.5 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 4.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 5.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; at least 6.0 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame; or at least 7.5 mg per kg of patient body weight may be administered to the patient within a 45 minute time frame. At least 0.67 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 1.0 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 1.5 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 2.0 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 2.5 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame; at least 3.0 mg per kg of patient body weight may be administered to the patient within a 60 minute time frame. may be administered to a patient within a 60 minute time frame; at least 3.5 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 4.0 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 5.0 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 6.0 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; at least 7.5 mg per kg of patient body weight may be administered to a patient within a 60 minute time frame; or at least 10.0 mg may be administered to a patient within a 60 minute time frame. According to these embodiments, one suitable superoxide dismutase mimetic is the dichloro complex form of formula (GC4419):

[0082] For example, in other embodiments, the dosage (i.e., the dosage without regard to time of administration) is at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). In other embodiments, for example, the dosage (i.e., the dosage without taking into account the time of administration) is at least 0.67 mg / kg of patient body weight; at least 1.0 mg / kg of patient body weight; at least 1.5 mg / kg of patient body weight; at least 2.0 mg / kg of patient body weight; at least 2.5 mg / kg of patient body weight; at least 3.0 mg / kg of patient body weight; at least 3.5 mg / kg of patient body weight; at least 4.0 mg / kg of patient body weight; at least 5.0 mg / kg of patient body weight; at least 6.0 mg / kg of patient body weight; at least 7.5 mg / kg of patient body weight; or at least 10.0 mg / kg of patient body weight; or at least 10.0 mg / kg of patient body weight.

[0083] If desired, the effective dose may be divided into multiple doses for purposes of administration. Thus, a single dose of a composition may contain an effective dose, or any fraction thereof that makes up the effective dose.

[0084] Additionally, some aspects of the present disclosure relate to improved pharmacokinetic profiles of the superoxide dismutase mimetics described herein when administered to a subject. Due, at least in part, to the improved safety profile of superoxide dismutase mimetics according to formula (GC4419) (e.g., the dichloro complexes of formula (GC4419)), administration of such compounds results in greater patient exposure as measured by AUC (i.e., the area under the curve of a graph of plasma compound concentration over time) compared to related superoxide dismutase mimetics (e.g., the mirror image compound GC4403 described above).

[0085] For example, in one embodiment, the methods described herein include administering to a patient a superoxide dismutase mimetic corresponding to formula (GC4419) to achieve an exposure, as measured by area under the curve (AUC), of at least 4,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient. Accordingly, the AUC values, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient, can be at least 5,000 ng-hr / mL; at least 7,500 ng-hr / mL; at least 10,000 ng-hr / mL; at least 12,500 ng-hr / mL; at least 15,000 ng-hr / mL; at least 17,500 ng-hr / mL; at least 20,000 ng-hr / mL; at least 22,500 ng-hr / mL; at least 25,000 ng-hr / mL; The superoxide dismutase mimic may be at least 27,500 ng-hr / mL; at least 30,000 ng-hr / mL; at least 32,500 ng-hr / mL; at least 35,000 ng-hr / mL; at least 37,500 ng-hr / mL; at least 40,000 ng-hr / mL; at least 42,500 ng-hr / mL; at least 45,000 ng-hr / mL; at least 47,500 ng-hr / mL; or at least 50,000 ng-hr / mL. According to these embodiments, one suitable superoxide dismutase mimic is the dichloro complex form of formula (GC4419).

[0086] Generally, the time aspect of administration of a superoxide dismutase mimetic can depend, for example, on the particular compound or the disease or condition being treated. Other considerations include the severity of the disease or condition; the activity of the particular compound used; the particular composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the particular compound used; the duration of treatment; drugs used in combination or simultaneously with the particular compound used; and similar factors.

[0087] As noted above, the disease or condition treated in accordance with the methods described herein can be any disease or condition that is regulated by superoxide. For example, in one embodiment, the disease or condition is selected from cancer, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immunodeficiency disorders, inflammatory disorders, metabolic disorders, neurological disorders, ophthalmological disorders, pulmonary disorders, infectious diseases, and combinations thereof. Examples of uses include the treatment of inflammatory and hyperproliferative skin diseases and cutaneous symptoms of immune-mediated diseases, such as psoriasis, atopic dermatitis, contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, and alopecia greata; various ocular diseases (including autoimmune) such as keratoconjunctivitis, vernal conjunctivitis, Behcet's disease-associated uveitis, keratitis, herpetic keratitis, keratoconus, dystrophia epithelialis corneae, corneal leukoplakia, and ocular pemphigus. In addition, reversible obstructive airway diseases can be treated, prevented, and / or ameliorated according to the methods described herein, including, for example, asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma), particularly chronic or refractory asthma (e.g., late-onset asthma, airway hyperresponsiveness), bronchitis, allergic rhinitis, and the like. Other treatable diseases and conditions include mucosal and vascular inflammation, such as gastric ulcers and vascular injury (resulting from ischemic disease and thrombosis). Furthermore, hyperproliferative vascular diseases, such as intimal smooth muscle cell hyperplasia, restenosis, and vascular obstruction, particularly following biologically or mechanically mediated vascular injury, may also be treated with the compounds described herein.

[0088] Further treatable diseases and conditions include cardiac diseases such as post-myocardial infarction syndrome, pulmonary diseases such as changes and remodeling of lung muscle and chronic obstructive pulmonary disease (COPD); ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, small intestinal inflammation / allergy (e.g., celiac disease), proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, and ulcerative colitis; neurological diseases (e.g., polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuropathy, mononeuropathy, radiculopathy); septic shock and associated refractory hypotension; endocrine diseases (e.g., hyperthyroidism, Graves' disease); arthritis (e.g., rheumatoid arthritis, chronic progressive arthritis, arthritis chronica) progrediente, osteoarthritis), and rheumatic diseases; blood diseases (e.g., pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia); bone diseases (e.g., osteoporosis); respiratory diseases (e.g., sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia); skin diseases (e.g., dermatomyositis) , vitiligo vulgaris, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma); cardiovascular diseases (e.g., arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy); collagen diseases (e.g., scleroderma, Wegener's granulomatosis, Sjogren's syndrome); steatosis; eosinophilic fasciitis; periodontal diseases (e.g., lesions of the gingiva, periodontium, alveolar bone, dental cementum); nephrotic syndrome (e.g., thread Glomerulonephritis); Male pattern baldness or age-related alopecia (treatment by preventing hair loss, promoting hair growth, and / or promoting hair initiation and growth); Muscular dystrophy; Pyoderma, Sézary syndrome; Addison's disease; Oxygen-mediated diseases, such as ischemia-reperfusion injury of organs (e.g., heart, liver, kidneys, gastrointestinal tract) occurring during preservation, transplantation, organ (single or multiple) failure, or ischemic diseases (e.g., thrombosis, myocardial infarction); Movement disorders (e.g., Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesia); Intestinal diseases (e.g., endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation); Renal diseases (e.g., ischemic acute renal failure, chronic renal failure); Pulmonary diseases (e.g., intoxication caused by pulmonary oxygen or drugs (e.g., paracort, bleomycin), lung cancer, emphysema);These include eye diseases (e.g., cataracts, siderosis, retinitis, pigmentary degeneration, age-related macular degeneration, vitreous scarring, and corneal alkali burns); dermatitis (e.g., erythema multiforme, linear IgA bullous dermatitis, and cement dermatitis); and other diseases such as gingivitis, periodontal disease, sepsis, pancreatitis, diseases caused by environmental pollution (e.g., air pollution), aging, carcinogenesis, cancer metastasis, and altitude sickness; diseases caused by the release of histamine or leukotriene-C4; and Behcet's disease (e.g., intestinal, vascular, or neurological Behcet's disease, as well as Behcet's disease affecting the mouth, skin, eyes, vulva, joints, epididymis, lungs, kidneys, etc.). Furthermore, the compounds of the present invention are useful for the treatment and prevention of liver diseases such as immunogenic diseases (e.g., chronic autoimmune liver diseases such as autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, etc.), partial liver resection, acute liver necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock, or anoxia), viral hepatitis B, non-A / non-B hepatitis, cirrhosis (e.g., alcoholic cirrhosis), liver failure (fulminant liver failure, delayed liver failure, "acute in chronic" liver failure (acute liver failure in chronic liver disease)), bacterial or viral infections such as influenza, HIV infection, etc., and further useful in the treatment of chemotherapeutic agents. Due to their beneficial activities, such as enhanced therapeutic efficacy, cytomegalovirus infection, especially HCMV infection, and anti-inflammatory activity, they are useful in a variety of diseases, including sclerosing and fibrotic diseases such as nephrosis, scleroderma, fibrosis (e.g., pulmonary fibrosis including idiopathic fibrosing alveolitis, idiopathic interstitial pneumonia, idiopathic pulmonary fibrosis, idiopathic mediastinal fibrosis, fibrosis associated with anti-tumor therapy, radiation therapy, and chronic infections including tuberculosis, aspergillosis, and other fungal infections), arteriosclerosis, congestive heart failure, ventricular hypertrophy, postoperative adhesions and scarring, stroke, myocardial infarction, and ischemia- and reperfusion-related injuries;

[0089] Administration route The superoxide dismutase mimetics described herein (or pharmaceutical compositions comprising the superoxide dismutase mimetics) can be administered to subjects (e.g., humans and other mammals) by a number of suitable routes of administration, including oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, intrasternal), topical (nasal, transdermal, buccal, intraocular), intravesical, intrathecal, intraintestinal, intrapulmonary, intralymphatic, intracavity, intravaginal, intrarectal, transurethral, ​​intradermal, intraocular, intraaural, intramammary, orthotopic, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual, and intraintestinal administration. In one embodiment, the superoxide dismutase mimetics are introduced into a patient orally or via injection (including intravenous, subcutaneous, intramuscular, intraperitoneal, intraarterial, and intradermal injection). Additionally or alternatively, a superoxide dismutase mimetic described herein (or a pharmaceutical composition comprising a superoxide dismutase mimetic described herein) can be administered to a subject topically (as a patch (e.g., a transdermal patch), powder, lotion, ointment, or drops applied to the skin), bucally, or by inhalation (as an oral or nasal spray). A superoxide dismutase mimetic described herein (or a pharmaceutical composition comprising the superoxide dismutase mimetic) may also be administered rectally or intravaginally to a human or other mammal. In one embodiment, a superoxide dismutase mimetic (or a pharmaceutical composition or unit dose formulation comprising the superoxide dismutase mimetic) is administered parenterally to a subject. Parenteral administration is generally understood to refer to modes of administration including intravenous, intramuscular, intraperitoneal, subcutaneous, and intraarticular. In a preferred embodiment, the superoxide dismutase mimetic (or a pharmaceutical composition or unit dose formulation comprising the superoxide dismutase mimetic) is administered intravenously.

[0090] Unit dose formulations and pharmaceutical compositions Another aspect of the present disclosure relates to unit dose formulations and pharmaceutical compositions comprising the compounds described herein, typically in combination with a pharmaceutically acceptable carrier or excipient, and optionally in combination with another pharmaceutically active compound or compounds. The pharmaceutical compositions include a superoxide dismutase mimetic according to formula (GC4419), typically formulated as a pharmaceutical dosage form, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient. For example, in one embodiment, the pharmaceutical composition comprises a compound of formula (GC4419) and a pharmaceutically acceptable carrier or excipient. The unit dose formulations and pharmaceutical compositions according to the present disclosure may be used, for example, to treat various cancers, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immune deficiency disorders, inflammatory disorders, metabolic disorders, neurological disorders, eye disorders, pulmonary disorders, infectious diseases, tissue injuries, and combinations thereof. Specific diseases and conditions include cancer, fibrosis, inflammatory diseases and conditions (including, for example, inflammatory bowel disease, rheumatoid arthritis, asthma, COPD, pancreatitis, etc.), dermatitis, psoriasis, etc., as well as protection from tissue damage resulting from cancer treatment or other radiation exposure.

[0091] One particular aspect of the present disclosure is directed to a unit dose formulation comprising a superoxide dismutase mimetic in a container as described herein. In one embodiment, the superoxide dismutase mimetic corresponds to formula (GC4419). In a preferred embodiment, the superoxide dismutase mimetic is a dichloro complex form of formula (GC4419).

[0092] Preferably, a unit dose formulation according to the present disclosure contains at least 50 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). For example, in various embodiments, the unit dose formulation contains at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg, at least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg, at least 400 mg, at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg of a superoxide dismutase mimetic corresponding to formula (GC4419). In some of these embodiments, the superoxide dismutase mimetic is a dichlorocomplex form of formula (GC4419).

[0093] Another specific embodiment of the present disclosure is directed to a pharmaceutical composition in solution form, where the pharmaceutical composition is in a unit dose form for intravenous administration. For example, according to this embodiment, the pharmaceutical composition includes a superoxide dismutase mimetic and a pharmaceutically acceptable carrier contained in an IV (intravenous) bag for administration to a patient. Typical unit-dose IV bags are glass or plastic containers with inlet and outlet means and standard volumes (e.g., 50 mL, 100 mL, and 150 mL). Typically, a concentrate of reconstituted lyophilized superoxide dismutase mimetic (described in more detail below) is added to an IV (intravenous) container containing a suitable aqueous carrier. Useful carriers are described herein (e.g., sterile water, sterile saline, etc.). Typically, the pharmaceutical composition contains about 0.25 mg / mL to about 3.5 mg / mL of a superoxide dismutase mimetic described herein (e.g., a superoxide dismutase mimetic corresponding to formula (GC4419)). Alternatively, higher or lower concentrations of the superoxide dismutase mimic may be present depending on the intended use, packaging and shipping considerations, whether one or multiple IV bags are used, etc. In one embodiment, a concentrated amount of lyophilized superoxide dismutase mimic is added to an IV bag to form a solution pharmaceutical composition containing about 0.25 mg / mL, about 0.5 mg / mL, about 0.75 mg / mL, about 1.0 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2.0 mg / mL, about 2.25 mg / mL, about 2.5 mg / mL, about 2.75 mg / mL, about 3.0 mg / mL, about 3.25 mg / mL, or about 3.5 mg / mL of the superoxide dismutase mimic.

[0094] The superoxide dismutase mimics may be dispersed in a pharmaceutically acceptable carrier before administration to a mammal. A carrier, known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is generally a substance that is pharmaceutically inert, provides the composition with an appropriate consistency or form, and does not reduce the efficacy of the compound. A carrier that does not produce unacceptable adverse, allergic, or other untoward reactions when administered to a mammal (especially a human) is generally considered to be "pharmaceutically or pharmacologically acceptable."

[0095] Pharmaceutically acceptable carriers are also selected in part depending on the route of administration. Generally, the compositions described herein can be formulated for any route of administration according to the conventional route of administration of the component (e.g., superoxide dismutase mimetic compound), as long as the blood circulation is accessible via the route of administration. For example, suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, intrasternal), topical (intranasal, transdermal, buccal, intraocular), intravesical, intrathecal, intestinal, intrapulmonary, intralymphatic, intracavity, intravaginal, intrarectal, transurethral, ​​intradermal, intraocular, intraaural, intramammary, orthotopic, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual, and intraintestinal administration.

[0096] Pharmaceutically acceptable carriers for use in conjunction with the compounds and compositions of the present disclosure are well known to those of skill in the art and are selected based on a number of factors, including the particular compound and drug used, its / their concentration, stability, and intended bioavailability; safety; the subject; their age, size, and general condition; and the route of administration. Examples of suitable pharmaceutically acceptable non-aqueous polar solvents include, but are not limited to, water, alcohols having 2 to 30 carbon atoms; fatty acid esters of alcohols; amides; esters; ketones; sulfoxides; aliphatic, alicyclic, or aromatic hydrocarbons having 4 to 30 carbon atoms; mineral oil, vegetable oil, animal oil, essential oil, or synthetic oil.

[0097] In one embodiment, the pharmaceutically acceptable carrier is in the form of a solution. For example, the solution may include water. In another example, the solution may include saline. Examples of suitable carriers for use in formulating liquid dosage forms for parenteral administration include pharmaceutically acceptable non-aqueous polar solvents, such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons, and mixtures thereof, as well as water, saline (e.g., USP and isotonic saline solutions), dextrose solutions (e.g., D5W), electrolyte solutions, or other aqueous pharmaceutically acceptable liquids. In a preferred embodiment, the pharmaceutical composition is in the form of an aqueous solution comprising a superoxide dismutase mimetic according to Formula (GC4419) and saline (e.g., normal saline, i.e., a sterile solution of 0.9% w / v NaCl in water). In these and other embodiments, for example, the saline is preferably a physiologically buffered saline solution (i.e., buffered saline). A buffering agent is used to provide a suitable buffering capacity of about pH 7-8.5, about pH 7.8, or within the range of pH 7.3-8. Preferably, the buffer is chemically inert and physiologically and pharmaceutically acceptable. Representative examples of buffers include phosphate-based buffers, carbonate-based buffers, Tris-based buffers, amino acid-based buffers (e.g., arginine, lysine, and other natural amino acids), and citrate-based buffers. Carbonate-based buffers (e.g., sodium carbonate buffer, calcium carbonate buffer, or bicarbonate buffer) may be particularly useful in some embodiments due to their ready availability, high buffering capacity, and compatibility. A particularly preferred buffer is sodium bicarbonate. For example, in a preferred embodiment, the pharmaceutically acceptable carrier comprises a buffered saline solution; more preferably, in this embodiment, the buffered saline solution is a saline solution buffered with carbonated water. In a particularly preferred embodiment, the solution is formulated using 10 mg / mL GC4419 in an aqueous solution containing 0.9% by weight NaCl, the aqueous solution containing 26 mM sodium bicarbonate, and the pH range of the solution is 7.6 to 8.3. In one preferred embodiment, the superoxide dismutase mimetic is a dichloro complex of formula (GC4419).As noted above, it will be appreciated that when the chloro (or other) ligands of superoxide dismutase mimics are in solution, they can dissociate from the axial coordination sites occupied by solvent water molecules to form both monoaquo (monocationic) and bisaquo (dicationic) complexes, i.e., the ligand bonds can be swapped apart and occupied by other molecules (e.g., solvent water molecules) present in solution.

[0098] Pharmaceutical formulations are also preferably sterile. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use. The compositions of the present invention may be provided, prepared, stored, or transported in any container suitable for maintaining sterility. The container may incorporate a means for dispensing an aqueous composition (e.g., a pierceable or removable seal). The compositions of the present invention may be dispensed, for example, by withdrawing them with a syringe or by injecting the composition directly into a device for patient administration (e.g., a syringe, IV bag, or machine). Other means of providing, preparing, storing, transporting, and dispensing sterile pharmaceutical compositions are known to those skilled in the art.

[0099] In another embodiment, the superoxide dismutase mimic may be used, and more typically, stored, as a lyophilized powder. Those skilled in the art will recognize that lyophilization is a freeze-drying process in which water sublimes from a composition after freezing. The advantages associated with the freeze-drying process are, among others, the ability to dry biologics and pharmaceuticals without elevated temperatures (thereby eliminating potentially harmful thermal effects) and subsequently store them in a dry state with relatively few (or at least fewer) stability issues. Methods for providing lyophilized powders or particles are known to those skilled in the art. The use of bulking agents or solidifying agents in lyophilized formulations is useful, for example, to enhance product precision and prevent bursting. Bulking agents provide structural strength to the lyophilized cake, and examples of bulking agents include sucrose, trehalose, dextran, lactose, cyclodextrin, chitosan, mannitol, and glycine. In one embodiment, the bulking agent is dextran. Buffers may be included in the solution prior to lyophilization, if desired, to affect the relationship between the compound and the solvent (e.g., water or saline) in the solution. Suitable buffers are described elsewhere herein, and examples include phosphate-based buffers, carbonate-based buffers, Tris-based buffers, amino acid-based buffers (e.g., arginine, lysine, and other natural amino acids), and citrate-based buffers. Thus, by way of example, the lyophilized forms described herein may include a superoxide dismutase mimic, a bulking agent, and a buffering agent, or may include only a superoxide dismutase mimic and a bulking agent. In one specific example, the lyophilized form includes a superoxide dismutase mimic and dextran. In another specific example, the lyophilized form includes a superoxide dismutase mimic, dextran, and arginine (as a buffering agent). In another specific example, the lyophilized form includes a superoxide dismutase mimic, dextran, and lysine (as a buffering agent). In another specific example, the lyophilized form comprises a superoxide dismutase mimetic, dextran, and Tris (tris(hydroxymethyl)-aminomethane) (as a buffering agent).

[0100] When a lyophilized form of a superoxide dismutase mimic described herein is employed (e.g., for storage or shipping), the lyophilized form typically must be reconstituted before administration to a patient. Any pharmaceutically acceptable carrier solution (e.g., water or saline) described herein may be used to reconstitute the lyophilized cake. If a buffer was included in the pre-lyophilization solution, it is not necessary to include a buffer in the reconstitution solution. On the other hand, if a buffer was not included in the pre-lyophilization solution, it is preferable that a buffer be included in the reconstitution solution for the reasons described above.

[0101] In some embodiments, oils or non-aqueous solvents may be used in the formulation, e.g., to put one or more compounds into solution, e.g., because of the presence of a large lipophilic moiety. Alternatively, emulsions, suspensions, or other preparations (e.g., liposomal formulations) may be used. For example, with respect to liposomal preparations, any known method for preparing liposomes may be used. See, e.g., Bangham et al., J. Mol. Biol, 23: 238-252 (1965) and Szoka et al., Proc. Natl. Acad. Sci 75: 4194-4198 (1978), which are incorporated herein by reference. Thus, in one embodiment, one or more compounds are administered in the form of a liposome delivery system (e.g., small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles). Liposomes can be formed from various phospholipids (e.g., cholesterol, stearylamine, phosphatidylcholine, etc.). For example, ligands may be attached to liposomes in order to target these compositions to a specific site of action.

[0102] Other pharmaceutically acceptable solvents for use in the pharmaceutical compositions described herein are well known to those skilled in the art and are set forth in the following references: The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, DC, and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., eds., 3rd ed.) (Marcel Dekker, Inc., New York, NY, 1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.) (Marcel Dekker, Inc., New York, NY, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), and AJ Spiegel et al., Use of Nonaqueous Solvents in Parenteral Products, Journal of Pharmaceutical Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

[0103] Formulations containing superoxide dismutase mimetics may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as aerosols, capsules, creams, emulsions, foams, gels / jellies, lotions, ointments, pastes, powders, soaps, solutions, sprays, suppositories, suspensions, sustained-release formulations, tablets, tinctures, transdermal patches, etc., preferably in unit dosage forms suitable for convenient administration of precise doses. When formulated as fixed doses, such pharmaceutical compositions or formulations preferably employ a superoxide dismutase mimetic within the dosage ranges described above.

[0104] Generally, specific formulations for superoxide dismutase mimetics are also known in the art and are generally described in, for example, U.S. Patent Nos. 5,610,293, 5,637,578, 5,874,421, 5,976,498, 6,084,093, 6,180,620, 6,204,259, 6,214,817, 6,245,758, 6,395,725, and 6,525,041 (each of which is incorporated by reference herein in its entirety).

[0105] In certain embodiments, the pharmaceutical composition administered to a subject in accordance with the methods described herein consists essentially of a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. In other embodiments, the pharmaceutical composition comprises a superoxide dismutase mimetic, a pharmaceutically acceptable carrier, and one or more additional pharmaceutically active agents or compounds. In these embodiments, the pharmaceutical compositions described herein are products resulting from mixing or combining multiple active ingredients, and include both fixed and loose combinations of multiple active ingredients. A fixed combination is one in which both active ingredients (e.g., a superoxide dismutase mimetic and another pharmaceutically active agent or compound described herein) are administered to a patient simultaneously in the form of a single entity or dose. A non-fixed combination is one in which the active ingredients (e.g., a superoxide dismutase mimetic and another pharmaceutically active agent or compound) are administered to a patient as separate entities simultaneously, concurrently, or sequentially with no specific intervening time limit, whereby this administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy (e.g., administration of three or more active ingredients).

[0106] When co-forming a superoxide dismutase mimetic with one or more additional pharmaceutically active agents or compounds, it is contemplated that conventional formulation techniques may be used for these components individually, or alternative formulation routes may be used for these components together, provided compatibility and efficacy of the various components exist.

[0107] Additional pharmaceutically active agents As noted above, the methods and pharmaceutical compositions (including superoxide dismutase mimetics) described herein may additionally include the administration of one or more pharmaceutically active agents or components. The superoxide dismutase mimetics described herein may be administered as the sole active pharmaceutical agent or may be used in combination with one or more compounds of the present invention or other agents. When administered in combination, the therapeutic agents may be formulated as separate compositions administered simultaneously or sequentially at different times (e.g., one to several hours or days apart), or the therapeutic agents may be provided as a single composition. Thus, the present disclosure is intended to encompass sequential administration of each agent in a regimen that provides the beneficial effect of the combined drug, and also contemplates substantially simultaneous coadministration of these agents (e.g., in a single capsule containing a fixed ratio of the active agents, or in separate capsules for each agent).

[0108] Suitable examples of suitable pharmaceutically active agents or compounds that may be included in the methods and compositions of the present disclosure include analgesics, anti-arthritics, anti-asthmatics, anti-emetics, anesthetics (e.g., local anesthetics), antiglaucoma agents, antimalarials, antihypertensives, anti-anxiety agents, anticoagulants, anticonvulsants, hypoglycemic agents, decongestants, antihistamines, antitussives, antipyretics, anticholinergics, antiulcer agents, antineoplastic agents, beta-blockers, beta-2 agonists, beta-agonists, anti-inflammatory agents, antipsychotics, nootropics, cholesterol-lowering agents, and the like. hypocholesterolemic agents, anti-obesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, anti-migraine agents, antibacterial agents, amoebicides or trichomoniacides, hypnotics, anti-Parkinson's disease agents, anti-Alzheimer's disease agents, antibiotics, antiparasitic agents, antidepressants, antivirals, bronchodilators, central nervous system acting agents, cardiovascular agents, contraceptives, cell growth inhibitors, diuretics, bactericides, H-2 blockers, hormones, hypnotics, cardiac stimulants, muscle relaxants, muscle contractants, psychiatric stimulants energizers, sedatives, sympathomimetics, vasodilators, vasoconstrictors, tranquilizers, electrolyte supplements, vitamins, counterirritants, stimulants, antihormones, drug antagonists, lipid regulating agents, uricosurics, cardiac glycosides, expectorants, laxatives, contrast materials, radiopharmaceuticals, imaging agents, peptides, enzymes, growth factors, etc. As noted above, the components of such combinations may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations.

[0109] Examples of antihypertensive agents include prazosin, nifedipine, amlodipine besylate, trimazosin, and doxazosin; examples of hypoglycemic agents include glipizide and chlorpropamide; examples of antiimpotence agents include sildenafil and sildenafil citrate; examples of antineoplastic agents include chlorambucil, lomustine, and echinomycin; an example of an imidazole-type antineoplastic agent is tubulazole; and examples of antihypercholesterolemic agents include atorvastatin and atorvastatin calcium. specific examples of anti-anxiety agents include hydroxyzine hydrochloride and doxepin hydrochloride; specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin, piroxicam, valdecoxib, carprofen, celecoxib, flurbiprofen, and (+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hydroxyurea; a specific example of a barbiturate is phenobarbital; specific examples of antiviral agents include acyclovir, nelfinavir, and virazol; vitamins / nutrients Examples of nutritional agents include retinol and vitamin E; examples of beta-blockers include timolol and nadolol; an example of an emetic is apomorphine; examples of diuretics include chlorthalidone and spironolactone; an example of an anticoagulant is dicumarol; examples of cardiac inotropes include digoxin and digitoxin; examples of androgens include 17-methyltestosterone and testosterone; an example of a mineralocorticoid is desoxycorticosterone; an example of a steroidal hypnotic / anesthetic is alpha- specific examples of anabolic agents include fluoxymesterone and methanstenolone; specific examples of antidepressants include sulpiride, [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine, 3,5-dimethyl-4-(3'-pentoxy)-2-(2',4',6'-trimethylphenoxy)pyridine, pyroxidine, fluoxetine, paroxetine, venlafaxine, and sertraline;specific examples of antibiotics include carbenicillin indanyl sodium, bacampicillin hydrochloride, troleandomycin, doxycycline hyclate, ampicillin, amoxicillin, and penicillin G; specific examples of anti-infectives include benzalkonium chloride and chlorhexidine; specific examples of coronary vasodilators include nitroglycerin and miofurazine; a specific example of a hypnotic is etomidate; and specific examples of carbonic anhydrase inhibitors include acetazolamide and chlorzolamide. specific examples of antifungal agents include econazole, terconazole, fluconazole, voriconazole, and griseofulvin; a specific example of an antiprotozoal agent is metronidazole; specific examples of anthelmintics include thiabendazole, oxfendazole, and morantel; specific examples of antihistamines include astemizole, levocabastine, cetirizine, decarboethoxyloratadine, and cinnarizine; specific examples of antipsychotics include ziprasidone, olanzapine, and fluconazole. specific examples of gastrointestinal agents include loperamide and cisapride; specific examples of serotonin antagonists include ketanserin and mianserin; a specific example of an anesthetic is lidocaine; a specific example of a hypoglycemic agent is acetohexamide; a specific example of an antiemetic is dimenhydrinate; a specific example of an antibacterial agent is cotrimoxazole; and a specific example of a dopamine agonist is L-DOPA specific examples of anti-Alzheimer's agents include THA and donepezil; specific examples of anti-ulcer agents / H2 antagonists include famotidine; specific examples of sedatives / hypnotics include chlordiazepoxide and triazolam; specific examples of vasodilators include alprostadil; specific examples of platelet inhibitors include prostacyclin; specific examples of ACE inhibitors / antihypertensive agents include enalapril, quinapril, and lisinopril; specific examples of tetracycline antibiotics include oxytetracycline and minocycline;Specific examples of macrolide antibiotics include erythromycin, clarithromycin, and spiramycin; a specific example of an azalide antibiotic is azithromycin; specific examples of glycogen phosphorylase inhibitors include [R--(R'S')]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamide and 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-o-oxypropyl]amide; and specific examples of cholesterol ester transfer protein inhibitors include include [2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, [2R,4S]-4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, and [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0110] Other specific examples include anti-inflammatory drugs such as ibuprofen, indomethacin, naproxen, nalorphine, etc.; anti-Parkinson's drugs such as bromocriptine, biperidine, benzhexol, benztropine, etc.; antidepressants such as imipramine, nortriptyline, protriptyline, etc.; antibiotics such as clindamycin, erythromycin, fusidic acid, gentamicin, mupirocin, amfomycin, etc. ), neomycin, metronidazole, sulfamethizole, bacitracin, framycetin, polymyxin B, acitromycin, etc.; antifungal agents such as miconazole, ketoconaxole, clotrimazole, amphotericin B, nystatin, mepyramine, econazole, fluconazole, flucytosine, griseofulvin, bifonazole, amorofine, mycostatin, itraconazole, terbina antibacterial agents such as metronidazole, tetracycline, oxytetracycline, penicillin, etc.; antiemetics such as metoclopramide, droperidol, haloperidol, promethazine, etc.; antihistamines such as chlorpheniramine, terfenadine, triprolidine, etc.; antimigraine drugs such as dihydroergotamine, ergotamine, pizofylline, etc.; coronary, cerebral, or peripheral vasodilators such as nifedipine , diltiazem, etc.; antianginal drugs, such as glyceryl nitrate, isosorbide dinitrate, molsidomine, verapamil, etc.; calcium channel blockers, such as verapamil, nifedipine, diltiazem, nicardipine, etc.; hormonal drugs, such as estradiol, estrone, estriol, polyesterradiol, polyester, dienestrol, diethylstilbestrol, progesterone, dihydroprogesterone, cyprosterone, danazol, testosterone, etc.;Contraceptives, such as ethinylestradiol, lynestrenol, ethynodiol, norethisterone, mestranol, norgestrel, levonorgestrel, desodestrel, medroxyprogesterone, etc.; antithrombotic drugs, such as heparin, warfarin, etc.; diuretics, such as hydrochlorothiazine, flunarizine, minoxidil, etc.; antihypertensive drugs, such as propanolol, metoprolol, clonidine, pindolol, etc.; corticosteroids, such as beclomethasone, betamethasone, betamethasone-17-valerate, etc. , betamethasone dipropionate, clobetasol, clobetasol-17-butyrate, clobetasol propionate, desonide, desoximetasone, dexamethasone, diflucortolone, flumethasone, flumethasone pivalate, fluocinolone acetonide, fluocinoid, hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone buteprate, methylprednisolone, triamcinolone acetonide, halcinonide, fluprednide acetate, dipropionate alclometasone furoate, fluocortolone, fluticasone propionate, mometasone furoate, desoximetasone, diflurason diacetate, halquinol, clioquinol, chlorquinaldol, fluocinolone acetonide, etc.; dermatological drugs such as nitrofurantoin, dithranol, clioquinol, hydroxyquinoline, isotretinoin, Methoxsalen, methotrexate, trethionin, trioxalen, salicylic acid, penicillamine, etc.; steroid drugs, such as estradiol, progesterone, norethindrone, levonorgestrel, ethynodiol, levonorgestrol, norgestimate, gestanin, desogestrel, 3-ketone-desogesterel, demegestone, promethestrol, testosterone, spironolactone, esters thereof, etc.;Nitro compounds, such as amyl nitrate, nitroglycerin, isosorbide dinitrate, etc.; opioids, such as morphine, buprenorphine, oxymorphone, hydromorphone, codeine, tramadol, etc.; prostaglandins, such as members of the PGA, PGB, PGE, or PGF series, such as minoprostol, dinoprostone, carboprost, eneprostil, etc.; peptides, such as growth hormone-releasing factor, growth factors (e.g., epidermal growth factor (EGF), nerve growth factor (NGF), T GF, PDGF, insulin growth factor (IGF), fibroblast growth factor (aFGF, bFGF, etc.), somatostatin, calcitonin, insulin, vasopressin, interferon, IL-2, etc., urokinase, serratiopeptidase, superoxide dismutase, thyrotropin-releasing hormone, luteinizing hormone-releasing hormone (LH-RH), corticotropin-releasing hormone; growth hormone-releasing hormone (GHRH), oxytodin, erythropoietin (EPO), colony-stimulating factor (CSF), etc.;

[0111] Further forms of the compound With respect to the compounds described herein, such as, for example, the superoxide dismutase mimetics corresponding to formula (GC4419), and other pharmaceutically active agents or compounds that may be included in pharmaceutical compositions, these compounds may exist in various forms, and each of these forms, as well as other forms, is contemplated in the present disclosure.

[0112] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by known methods (e.g., chromatography and / or fractional crystallization). In one embodiment, enantiomers can be separated by chiral chromatography columns. In other embodiments, enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a salt), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to their corresponding pure enantiomers. As noted above, all such isomers (including diastereomers, enantiomers, and mixtures thereof) are considered to be part of the compounds and compositions described herein.

[0113] It will be understood that the methods and formulations described herein also include the use of crystalline forms (also called polymorphs) or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds, which possess the same or similar types of activity. Additionally, the compounds described herein may exist in unsolvated or solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0114] The compounds described herein also include isotopically labeled compounds. Isotopically labeled compounds are identical to the compounds listed in the various compounds, structures, and formulas herein except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, and 54 Mn. Certain isotopically labeled compounds described herein, such as3 H, 14 Compounds incorporating radioactive isotopes such as 3C may be useful in drug and / or substrate tissue distribution assays. Additionally, deuterium (i.e. 2 Substitution with isotopes such as 3H may offer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).

[0115] Reference to a pharmaceutically acceptable salt should be understood to include its solvent addition forms or crystalline forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent, and solvates may be formed during the crystallization process using a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms in the compounds and methods provided herein. Polymorphs include multiple different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystalline shapes, optical and electrical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, and storage temperature may cause a single crystalline form to dominate.

[0116] The compounds described herein may also exist in various forms, including, but not limited to, amorphous, crushed, and nanoparticulate forms.

[0117] Kit / manufactured product Kits and articles of manufacture are also described for use in the therapeutic applications described herein. Such kits may include a carrier, package, or container compartmentalized to receive one or more containers, such as vials, tubes, etc., each of which contains one of the individual components (e.g., a superoxide dismutase mimetic, a pharmaceutically acceptable carrier, or an additional pharmaceutically active agent or compound, either alone or in combination) used in the methods described herein. Examples of suitable containers include bottles, vials, syringes, and test tubes. Containers can be formed from a variety of materials, such as glass or plastic.

[0118] The articles of manufacture provided herein include packaging materials. Packaging materials used to package pharmaceutical products are well known to those skilled in the art. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252, each of which is incorporated herein by reference. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material appropriate for the selected formulation and intended mode of administration and treatment. As noted above, a wide variety of formulations of the compounds and compositions provided herein are contemplated, as there are a variety of treatments for diseases, disorders, or conditions that may benefit from treatment with the superoxide dismutase mimetics described herein.

[0119] Thus, for example, a container may contain one or more compounds described herein, optionally in the form of a composition or in combination with other agents disclosed herein. The container may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). In one embodiment, such a kit comprises a compound (e.g., a superoxide dismutase mimetic) associated with identifying contents or labeling or instructions for use in the methods described herein. The kit may further comprise a pharmaceutically acceptable carrier or diluent for combination with the active compound. For example, in one embodiment, the kit comprises a sterile solution comprising a superoxide dismutase mimetic corresponding to formula (GC4419). For example, in another embodiment, the kit comprises a superoxide dismutase mimetic corresponding to formula (GC4419) in lyophilized powder form. In these and other embodiments, the kit may further include a solution (e.g., sterile saline solution) for diluting the superoxide dismutase mimetic, for example, in an infusion bag (which itself may be included in the kit).

[0120] Kits typically include one or more additional containers, each with various materials (e.g., reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for using the compounds described herein. Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes; carriers, packages, containers, vials, bags, and / or tube labels listing the contents and / or instructions for use; and package inserts with the instructions. A set of instructions is typically included in various embodiments and may be in the form of a separate sheet or booklet, or may be printed on one or more of the packages, containers, or vials (either directly printed or printed on a label, as described below).

[0121] A label may be affixed to or associated with the kit or one or more containers contained in the kit. A label may be affixed to a container when letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself. A label may be associated with a container when the label is present in a receptacle or carrier that also holds the container (e.g., as a package insert). A label may be used to indicate that the contents are intended for a particular therapeutic use. A label may also provide directions or instructions for use of the contents, for example, according to the methods described herein.

[0122] In some embodiments, the pharmaceutical compositions may be presented in a pack or dispenser device that may contain one or more unit dosage forms containing one or more compounds and agents provided herein. The pack may contain, for example, metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container that is in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals and that indicates approval by that agency of the drug form for administration to humans or animals. Such notice may be, for example, labeling approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMEA) for prescription drugs, or an approved package insert.

[0123] Compositions containing one or more compounds provided herein (e.g., a superoxide dismutase mimetic, or another additional pharmaceutically active agent or compound) formulated in a compatible pharmaceutical carrier may be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0124] According to one aspect, an article of manufacture includes packaging material containing a parenteral formulation, the parenteral formulation being for treating a disease or condition in a patient in need thereof, or for protecting tissue from damage resulting from exposure to a cancer treatment in the patient, as described herein. According to this embodiment, the parenteral formulation includes a unit dose formulation described herein, and the packaging material includes a label or package insert with instructions for parenterally administering the dosage to the patient. For example, the parenteral formulation may be in the form of a solution and stored in a suitable vial or container.

[0125] Generally, parenteral solutions can contain about 5 mg / mL to about 20 mg / mL of a superoxide dismutase mimetic described herein in a unit dose form in a suitable container. Alternatively, higher or lower concentrations of the superoxide dismutase mimetic can be present depending on the intended use, packaging and shipping considerations, whether single or multiple vials are used, etc. In one embodiment, the parenteral formulation is a solution containing about 20 mg / mL, about 17.5 mg / mL, about 15 mg / mL, about 12.5 mg / mL, about 10 mg / mL, about 7.5 mg / mL, or about 5 mg / mL of the superoxide dismutase mimetic in a single container. In another embodiment, the parenteral formulation is a solution comprising about 20 mg / mL, about 17.5 mg / mL, about 15 mg / mL, about 12.5 mg / mL, about 10 mg / mL, about 7.5 mg / mL, or about 5 mg / mL of the superoxide dismutase mimetic in multiple containers (e.g., two or more, three or more, four or more, etc.).

[0126] The following listed embodiments are presented to illustrate certain aspects of the present invention and are not intended to limit the scope of the invention: 1. A unit dose formulation comprising at least 50 mg of a superoxide dismutase mimetic in a container, wherein the superoxide dismutase mimetic has the formula (GC4419): [ka] and X and Y are independently neutral or negatively charged ligands. 2. A unit dose formulation according to embodiment 1, comprising at least 75 mg of a superoxide dismutase mimetic. 3. A unit dose formulation according to embodiment 1, comprising at least 100 mg of a superoxide dismutase mimetic. 4. A unit dose formulation according to embodiment 1, comprising at least 125 mg of a superoxide dismutase mimetic. 5. A unit dose formulation according to embodiment 1, comprising at least 150 mg of a superoxide dismutase mimetic. 6. The unit dose formulation of embodiment 1, comprising at least 175 mg of a superoxide dismutase mimetic. 7. The unit dose formulation of embodiment 1, comprising at least 200 mg of a superoxide dismutase mimetic. 8. The unit dose formulation of embodiment 1, comprising at least 225 mg of a superoxide dismutase mimetic. 9. The unit dose formulation of embodiment 1, comprising at least 250 mg of a superoxide dismutase mimetic. 10. The unit dose formulation of embodiment 1, comprising at least 275 mg of a superoxide dismutase mimetic. 11. The unit dose formulation of embodiment 1, comprising at least 300 mg of a superoxide dismutase mimetic. 12. The unit dose formulation of embodiment 1, comprising at least 325 mg of a superoxide dismutase mimetic. 13. The unit dose formulation of embodiment 1, comprising at least 350 mg of a superoxide dismutase mimetic. 14. The unit dose formulation of embodiment 1, comprising at least 375 mg of a superoxide dismutase mimetic. 15. The unit dose formulation of embodiment 1, comprising at least 400 mg of a superoxide dismutase mimetic. 16. The unit dose formulation of embodiment 1, comprising at least 425 mg of a superoxide dismutase mimetic. 17. The unit dose formulation of embodiment 1, comprising at least 450 mg of a superoxide dismutase mimetic. 18. The unit dose formulation of embodiment 1, comprising at least 475 mg of a superoxide dismutase mimetic. 19. The unit dose formulation of embodiment 1, comprising at least 500 mg of a superoxide dismutase mimetic. 20. The unit dose formulation of embodiment 1, comprising at least 525 mg of a superoxide dismutase mimetic. 21. The unit dose formulation of embodiment 1, comprising at least 550 mg of a superoxide dismutase mimetic. 22. The unit dose formulation of embodiment 1, comprising at least 575 mg of a superoxide dismutase mimetic. 23. The unit dose formulation of embodiment 1, comprising at least 600 mg of a superoxide dismutase mimetic. 24. A unit dose formulation described in any of embodiments 1 to 23, wherein the superoxide dismutase mimetic is in the form of a lyophilized powder. 25. The unit dose formulation of any of embodiments 1 to 24, wherein the container further comprises a pharmaceutically acceptable carrier. 26. The unit dose formulation of embodiment 25, wherein the pharmaceutically acceptable carrier is in the form of a solution. 27. The unit dose formulation of embodiment 25, wherein the pharmaceutically acceptable carrier is a solution comprising water. 28. The unit dose formulation of embodiment 25, wherein the pharmaceutically acceptable carrier is a solution comprising saline. 29. The unit dose formulation of any of embodiments 25-28, wherein the pharmaceutically acceptable carrier comprises buffered saline. 30. The unit dose formulation of any of embodiments 25-28, wherein the pharmaceutically acceptable carrier comprises bicarboxylate buffered saline. 31. The unit dose formulation of any of embodiments 1-30, wherein X and Y are independently selected from monodentate ligands. 32. The unit dose formulation of any of embodiments 1-31, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 33. The unit dose formulation of any of embodiments 1-32, wherein X and Y are independently selected from aquo ligands and halo ligands. 34. The unit dose formulation of any of embodiments 1-33, wherein X and Y are independently halo ligands. 35. The unit dose formulation of any of embodiments 1-34, wherein X and Y are chloro ligands. 36. A superoxide dismutase mimetic having the formula (GC4419): [ka] 36. The unit dose formulation of any of embodiments 1-35, wherein the dichloro complex form of 37. The unit dose formulation of any of embodiments 1-36, wherein the formulation is stored in a container for storage or for administration to a patient. 38. The unit dose formulation of any of embodiments 1-37, wherein the container is a vial, a syringe, or an IV bag or IV bottle. 39. A method of treating a human patient for tissue damage resulting from the use of radiation therapy or chemotherapy in the patient, comprising administering to the patient a compound of formula (GC4419): [ka] wherein X and Y are independently neutral or negatively charged ligands. 40. The method of embodiment 39, wherein the therapeutically effective amount is at least 0.67 mg / kg of patient body weight. 41. The method of embodiment 39, wherein the therapeutically effective amount is at least 1.0 mg / kg of patient body weight. 42. The method of embodiment 39, wherein the therapeutically effective amount is at least 1.5 mg per kg of patient body weight. 43. The method of embodiment 39, wherein the therapeutically effective amount is at least 2.0 mg / kg of patient body weight. 44. The method of embodiment 39, wherein the therapeutically effective amount is at least 2.5 mg per kg of patient body weight. 45. The method of embodiment 39, wherein the therapeutically effective amount is at least 3.0 mg / kg of patient body weight. 46. ​​The method of embodiment 39, wherein the therapeutically effective amount is at least 3.5 mg per kg of patient body weight. 47. The method of embodiment 39, wherein the therapeutically effective amount is at least 4.0 mg / kg of patient body weight. 48. The method of embodiment 39, wherein the therapeutically effective amount is at least 5.0 mg per kg of patient body weight. 49. The method of embodiment 39, wherein the therapeutically effective amount is at least 6.0 mg per kg of patient body weight. 50. The method of embodiment 39, wherein the therapeutically effective amount is at least 7.5 mg per kg of patient body weight. 51. The method of embodiment 39, wherein the therapeutically effective amount is at least 10.0 mg / kg of patient body weight. 52. The method of embodiment 39, wherein the therapeutically effective amount is at least 50 mg. 53. The method of embodiment 39, wherein the therapeutically effective amount is at least 75 mg. 54. The method of embodiment 39, wherein the therapeutically effective amount is at least 100 mg. 55. The method of embodiment 39, wherein the therapeutically effective amount is at least 125 mg. 56. The method of embodiment 39, wherein the therapeutically effective amount is at least 150 mg. 57. The method of embodiment 39, wherein the therapeutically effective amount is at least 175 mg. 58. The method of embodiment 39, wherein the therapeutically effective amount is at least 200 mg. 59. The method of embodiment 39, wherein the therapeutically effective amount is at least 225 mg. 60. The method of embodiment 39, wherein the therapeutically effective amount is at least 250 mg. 61. The method of embodiment 39, wherein the therapeutically effective amount is at least 275 mg. 62. The method of embodiment 39, wherein the therapeutically effective amount is at least 300 mg. 63. The method of embodiment 39, wherein the therapeutically effective amount is at least 325 mg. 64. The method of embodiment 39, wherein the therapeutically effective amount is at least 350 mg. 65. The method of embodiment 39, wherein the therapeutically effective amount is at least 400 mg. 66. The method of embodiment 39, wherein the therapeutically effective amount is at least 425 mg. 67. The method of embodiment 39, wherein the therapeutically effective amount is at least 450 mg. 68. The method of embodiment 39, wherein the therapeutically effective amount is at least 475 mg. 69. The method of embodiment 39, wherein the therapeutically effective amount is at least 500 mg. 70. The method of embodiment 39, wherein the therapeutically effective amount is at least 525 mg. 71. The method of embodiment 39, wherein the therapeutically effective amount is at least 550 mg. 72. The method of embodiment 39, wherein the therapeutically effective amount is at least 575 mg. 73. The method of embodiment 39, wherein the therapeutically effective amount is at least 600 mg. 74. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 0.67 mg per kg of patient body weight within a period of 15 minutes. 75. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 1.0 mg per kg of patient body weight within a period of 15 minutes. 76. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 1.5 mg per kg of patient body weight within a period of 15 minutes. 77. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 2.0 mg per kg of patient body weight within a period of 15 minutes. 78. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 2.5 mg per kg of patient body weight within a period of 15 minutes. 79. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 3.0 mg per kg of patient body weight within a period of 15 minutes. 80. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 1.5 mg per kg of patient body weight within a 30 minute period. 81. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 2.0 mg per kg of patient body weight within a 30 minute period. 82. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 2.5 mg per kg of patient body weight within a 30 minute period. 83. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 3.0 mg per kg of patient body weight within a 30 minute period. 84. The method of embodiment 39, wherein the superoxide dismutase mimetic is administered in an amount of at least 1.5 mg per kg of patient body weight within a period of 60 minutes. 85. The method of embodiment 39, wherein at least 25 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 86. The method of embodiment 39, wherein at least 50 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 87. The method of embodiment 39, wherein at least 50 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 88. The method of embodiment 39, wherein at least 100 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 89. The method of any one of embodiments 39-88, wherein the superoxide dismutase mimetic is administered to the patient prior to or simultaneously with radiation therapy or chemotherapy. 90. The method of any one of embodiments 39-88, wherein the superoxide dismutase mimetic is administered to the patient before radiation therapy or chemotherapy but not after. 91. The method of any one of embodiments 39-88, wherein the superoxide dismutase mimetic is administered to the patient at least 30 minutes before radiation therapy or chemotherapy. 92. The method of any one of embodiments 39-88, wherein the superoxide dismutase mimetic is administered to the patient up to 3 days after radiation therapy or chemotherapy. 93. The method of any one of embodiments 39-88, wherein the superoxide dismutase mimetic is administered to the patient after radiation therapy or chemotherapy. 94. The method of any one of embodiments 39-88, wherein the superoxide dismutase mimetic is administered up to one week after radiation therapy or chemotherapy. 95. The method of any one of embodiments 39-88, wherein the superoxide dismutase mimetic is administered to the patient up to 6 weeks after radiation therapy or chemotherapy. 96. The method of any one of embodiments 39-88, wherein the superoxide dismutase mimetic is administered to the patient up to 12 weeks after radiation therapy or chemotherapy. 97. The method of any one of embodiments 39 to 96, wherein the superoxide dismutase mimetic is administered parenterally. 98. The method of any one of embodiments 39 to 96, wherein the superoxide dismutase mimetic is administered intravenously. 99. The method of any one of embodiments 39-98, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. 100. The method of any one of embodiments 39-99, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation described in any one of embodiments 1-38. 101. The method of any of embodiments 39-99, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution containing about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic and is contained in an IV bag. 102. The method of any one of embodiments 39-101, wherein X and Y are independently selected from monodentate ligands. 103. The method of any of embodiments 39-102, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 104. The method of any one of embodiments 39-103, wherein X and Y are independently selected from aquo ligands and halo ligands. 105. The method of any one of embodiments 39-104, wherein X and Y are independently halo ligands. 106. The method of any one of embodiments 39-105, wherein X and Y are chloro ligands. 107. A superoxide dismutase mimetic having the formula (GC4419): [ka] 107. The method of any one of embodiments 39 to 106, wherein the dichloro complex form of 108. A method of treating a human patient for tissue damage resulting from radiation exposure, comprising administering to a patient a compound of formula (GC4419): [ka] wherein X and Y are independently neutral or negatively charged ligands. 109. The method of embodiment 108, wherein the therapeutically effective amount is at least 0.67 mg per kg of patient body weight. 110. The method of embodiment 108, wherein the therapeutically effective amount is at least 1.0 mg per kg of patient body weight. 111. The method of embodiment 108, wherein the therapeutically effective amount is at least 1.5 mg per kg of patient body weight. 112. The method of embodiment 108, wherein the therapeutically effective amount is at least 2.0 mg per kg of patient body weight. 113. The method of embodiment 108, wherein the therapeutically effective amount is at least 2.5 mg / kg of patient body weight. 114. The method of embodiment 108, wherein the therapeutically effective amount is at least 3.0 mg per kg of patient body weight. 115. The method of embodiment 108, wherein the therapeutically effective amount is at least 3.5 mg per kg of patient body weight. 116. The method of embodiment 108, wherein the therapeutically effective amount is at least 4.0 mg per kg of patient body weight. 117. The method of embodiment 108, wherein the therapeutically effective amount is at least 5.0 mg per kg of patient body weight. 118. The method of embodiment 108, wherein the therapeutically effective amount is at least 6.0 mg per kg of patient body weight. 119. The method of embodiment 108, wherein the therapeutically effective amount is at least 7.5 mg per kg of patient body weight. 120. The method of embodiment 108, wherein the therapeutically effective amount is at least 10.0 mg per kg of patient body weight. 121. The method of embodiment 108, wherein the therapeutically effective amount is at least 50 mg. 122. The method of embodiment 108, wherein the therapeutically effective amount is at least 75 mg. 123. The method of embodiment 108, wherein the therapeutically effective amount is at least 100 mg. 124. The method of embodiment 108, wherein the therapeutically effective amount is at least 125 mg. 125. The method of embodiment 108, wherein the therapeutically effective amount is at least 150 mg. 126. The method of embodiment 108, wherein the therapeutically effective amount is at least 175 mg. 127. The method of embodiment 108, wherein the therapeutically effective amount is at least 200 mg. 128. The method of embodiment 108, wherein the therapeutically effective amount is at least 225 mg. 129. The method of embodiment 108, wherein the therapeutically effective amount is at least 250 mg. 130. The method of embodiment 108, wherein the therapeutically effective amount is at least 275 mg. 131. The method of embodiment 108, wherein the therapeutically effective amount is at least 300 mg. 132. The method of embodiment 108, wherein the therapeutically effective amount is at least 325 mg. 133. The method of embodiment 108, wherein the therapeutically effective amount is at least 350 mg. 134. The method of embodiment 108, wherein the therapeutically effective amount is at least 400 mg. 135. The method of embodiment 108, wherein the therapeutically effective amount is at least 425 mg. 136. The method of embodiment 108, wherein the therapeutically effective amount is at least 450 mg. 137. The method of embodiment 108, wherein the therapeutically effective amount is at least 475 mg. 138. The method of embodiment 108, wherein the therapeutically effective amount is at least 500 mg. 139. The method of embodiment 108, wherein the therapeutically effective amount is at least 525 mg. 140. The method of embodiment 108, wherein the therapeutically effective amount is at least 550 mg. 141. The method of embodiment 108, wherein the therapeutically effective amount is at least 575 mg. 142. The method of embodiment 108, wherein the therapeutically effective amount is at least 600 mg. 143. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 0.67 mg per kg of patient body weight within a period of 15 minutes. 144. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 1.0 mg per kg of patient body weight within a period of 15 minutes. 145. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 1.5 mg per kg of patient body weight within a period of 15 minutes. 146. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 2.0 mg per kg of patient body weight within a period of 15 minutes. 147. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 2.5 mg per kg of patient body weight within a period of 15 minutes. 148. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 3.0 mg per kg of patient body weight within a period of 15 minutes. 149. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 1.5 mg per kg of patient body weight within a 30 minute period. 150. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 2.0 mg per kg of patient body weight within a 30 minute period. 151. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 2.5 mg per kg of patient body weight within a 30 minute period. 152. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 3.0 mg per kg of patient body weight within a 30 minute period. 153. The method of embodiment 108, wherein the superoxide dismutase mimetic is administered in an amount of at least 1.5 mg per kg of patient body weight within a period of 60 minutes. 154. The method of embodiment 108, wherein at least 25 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 155. The method of embodiment 108, wherein at least 50 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 156. The method of embodiment 108, wherein at least 50 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 157. The method of embodiment 108, wherein at least 100 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 158. The method of any one of embodiments 108-157, wherein the superoxide dismutase mimetic is administered to the patient up to 3 days after radiation exposure. 159. The method of any one of embodiments 108-157, wherein the superoxide dismutase mimetic is administered to the patient after radiation exposure. 160. The method of any one of embodiments 108-157, wherein the superoxide dismutase mimetic is administered to the patient up to one week after radiation exposure. 161. The method of any one of embodiments 108-157, wherein the superoxide dismutase mimetic is administered to the patient up to 6 weeks after radiation exposure. 162. The method of any one of embodiments 108-157, wherein the superoxide dismutase mimetic is administered to the patient up to 12 weeks after radiation exposure. 163. The method of any one of embodiments 108-162, wherein the radiation exposure is accidental radiation exposure, unintentional radiation exposure, or intentional radiation exposure. 164. The method of any one of embodiments 108-163, wherein the superoxide dismutase mimetic is administered parenterally. 165. The method of any one of embodiments 108 to 163, wherein the superoxide dismutase mimetic is administered intravenously. 166. The method of any one of embodiments 108-165, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. 167. The method of any one of embodiments 108-166, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation described in any one of embodiments 1-38. 168. The method of any of embodiments 108 to 166, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution containing about 0.25 mg / mL to 3.5 mg / mL of the superoxide dismutase mimetic and placed in an IV bag. 169. The method of any one of embodiments 108-168, wherein X and Y are independently selected from monodentate ligands. 170. The method of any of embodiments 108-169, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 171. The method of any of embodiments 108-170, wherein X and Y are independently selected from aquo ligands and halo ligands. 172. The method of any one of embodiments 108-171, wherein X and Y are independently halo ligands. 173. The method of any one of embodiments 108-172, wherein X and Y are chloro ligands. 174. A superoxide dismutase mimetic having the formula (GC4419): [ka] 174. The method according to any one of embodiments 108 to 173, wherein the compound is in the dichloro complex form of 175. A method of treating a human patient for a disease or condition, comprising administering to a patient a compound of formula (GC4419): [ka] wherein X and Y are independently neutral or negatively charged ligands. 176. The method of embodiment 175, wherein at least 50 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 177. The method of embodiment 175, wherein at least 75 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 178. The method of embodiment 175, wherein at least 100 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 179. The method of embodiment 175, wherein at least 125 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 180. The method of embodiment 175, wherein at least 150 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 181. The method of embodiment 175, wherein at least 175 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 182. The method of embodiment 175, wherein at least 200 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 183. The method of embodiment 175, wherein at least 225 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 184. The method of embodiment 175, wherein at least 250 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 185. The method of embodiment 175, wherein at least 275 mg of the superoxide dismutase mimetic is administered within a 15 minute period. 186. The method of embodiment 175, wherein at least 300 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 187. The method of embodiment 175, wherein at least 0.67 mg per kg of body weight is administered within a period of 15 minutes. 188. The method of embodiment 175, wherein at least 1.0 mg per kg of body weight is administered within a period of 15 minutes. 189. The method of embodiment 175, wherein at least 1.5 mg per kg of body weight is administered within a period of 15 minutes. 190. The method of embodiment 175, wherein at least 2.0 mg per kg of body weight is administered within a period of 15 minutes. 191. The method of embodiment 175, wherein at least 2.5 mg per kg of body weight is administered within a period of 15 minutes. 192. The method of embodiment 175, wherein at least 3.0 mg per kg of body weight is administered within a period of 15 minutes. 193. The method of embodiment 175, wherein at least 1.5 mg per kg of body weight is administered within a 30-minute period. 194. The method of embodiment 175, wherein at least 2.0 mg per kg of body weight is administered within a 30-minute period. 195. The method of embodiment 175, wherein at least 2.5 mg per kg of body weight is administered within a 30-minute period. 196. The method of embodiment 175, wherein at least 3.0 mg per kg of body weight is administered within a 30-minute period. 197. The method of embodiment 175, wherein at least 1.5 mg per kg of body weight is administered within a period of 60 minutes. 198. The method of any one of embodiments 175-197, wherein the superoxide dismutase mimetic is administered parenterally. 199. The method of any one of embodiments 175-197, wherein the superoxide dismutase mimetic is administered intravenously. 200. The method of any of embodiments 175-199, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. 201. The method of any of embodiments 175-200, wherein the disease or condition is selected from cancer, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immune disorders, inflammatory disorders, metabolic disorders, neurological disorders, ophthalmological disorders, pulmonary disorders, infectious diseases, and combinations thereof. 202. The method of any one of embodiments 175-201, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation described in any one of embodiments 1-38. 203. The method of any of embodiments 175-201, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution containing about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic and is contained in an IV bag. 204. The method of any of embodiments 175-203, wherein X and Y are independently selected from monodentate ligands. 205. The method of any of embodiments 175-204, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 206. The method of any of embodiments 175-205, wherein X and Y are independently selected from aquo ligands and halo ligands. 207. The method of any one of embodiments 175-206, wherein X and Y are independently halo ligands. 208. The method of any one of embodiments 175-207, wherein X and Y are chloro ligands. 209. A superoxide dismutase mimetic having the formula (GC4419): [ka] The method according to any one of embodiments 175 to 208, wherein the compound is in the dichloro complex form of 210. A method of treating a human patient for a disease or condition, comprising administering to a patient a compound of formula (GC4419): [ka] and X and Y are independently neutral or negatively charged ligands. 211. The method of embodiment 210, wherein at least 75 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 212. The method of embodiment 210, wherein at least 100 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 213. The method of embodiment 210, wherein at least 125 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 214. The method of embodiment 210, wherein at least 150 mg of the superoxide dismutase mimetic is administered within a 15 minute period. 215. The method of embodiment 210, wherein at least 175 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 216. The method of embodiment 210, wherein at least 200 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 217. The method of embodiment 210, wherein at least 225 mg of the superoxide dismutase mimetic is administered within a 15 minute period. 218. The method of embodiment 210, wherein at least 250 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 219. The method of embodiment 210, wherein at least 275 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 220. The method of embodiment 210, wherein at least 300 mg of the superoxide dismutase mimetic is administered within a period of 15 minutes. 221. The method of embodiment 210, in which at least 0.67 mg per kg of body weight is administered within a period of 15 minutes. 222. The method of embodiment 210, wherein at least 1.0 mg per kg of body weight is administered within a period of 15 minutes. 223. The method of embodiment 210, in which at least 1.5 mg per kg of body weight is administered within a period of 15 minutes. 224. The method of embodiment 210, wherein at least 2.0 mg per kg of body weight is administered within a period of 15 minutes. 225. The method of embodiment 210, in which at least 2.5 mg per kg of body weight is administered within a period of 15 minutes. 226. The method of embodiment 210, wherein at least 3.0 mg per kg of body weight is administered within a period of 15 minutes. 227. The method of any one of embodiments 210-226, wherein the superoxide dismutase mimetic is administered parenterally. 228. The method of any one of embodiments 210-226, wherein the superoxide dismutase mimetic is administered intravenously. 229. The method of any of embodiments 210-228, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. 230. The method of any of embodiments 210-229, wherein the disease or condition is selected from cancer, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immune disorders, inflammatory disorders, metabolic disorders, neurological disorders, ophthalmological disorders, pulmonary disorders, infectious diseases, and combinations thereof. 231. The method of any one of embodiments 210-230, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation described in any one of embodiments 1-38. 232. The method of any of embodiments 210-230, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution containing about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic and contained in an IV bag. 233. The method of any of embodiments 210-232, wherein X and Y are independently selected from monodentate ligands. 234. The method of any of embodiments 210-233, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 235. The method of any of embodiments 210-234, wherein X and Y are independently selected from an aquo ligand and a halo ligand. 236. The method of any one of embodiments 210-235, wherein X and Y are independently halo ligands. 237. The method of any one of embodiments 210-236, wherein X and Y are chloro ligands. 238. A superoxide dismutase mimetic having the formula (GC4419): [ka] 238. The method of any one of embodiments 210 to 237, wherein the compound is in the dichloro complex form of 239. A method of treating a human patient for a disease or condition, comprising administering to a patient a compound of formula (GC4419): [ka] wherein X and Y are independently neutral or negatively charged ligands. 240. The method of embodiment 239, wherein at least 75 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 241. The method of embodiment 239, wherein at least 100 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 242. The method of embodiment 239, wherein at least 125 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 243. The method of embodiment 239, wherein at least 150 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 244. The method of embodiment 239, wherein at least 175 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 245. The method of embodiment 239, wherein at least 200 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 246. The method of embodiment 239, wherein at least 225 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 247. The method of embodiment 239, wherein at least 250 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 248. The method of embodiment 239, wherein at least 275 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 249. The method of embodiment 239, wherein at least 300 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 250. The method of embodiment 239, wherein at least 325 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 251. The method of embodiment 239, wherein at least 350 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 252. The method of embodiment 239, wherein at least 375 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 253. The method of embodiment 239, wherein at least 400 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 254. The method of embodiment 239, wherein at least 425 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 255. The method of embodiment 239, wherein at least 450 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 256: The method of embodiment 239, wherein at least 0.67 mg per kg of body weight is administered within a 30 minute period. 257. The method of embodiment 239, wherein at least 1.0 mg per kg of body weight is administered within a 30-minute period. 258. The method of embodiment 239, wherein at least 1.5 mg per kg of body weight is administered within a 30-minute period. 259. The method of embodiment 239, wherein at least 2.0 mg per kg of body weight is administered within a 30-minute period. 260. The method of embodiment 239, wherein at least 2.5 mg per kg of body weight is administered within a 30-minute period. 261. The method of embodiment 239, wherein at least 3.0 mg per kg of body weight is administered within a 30-minute period. 262. The method of embodiment 239, wherein at least 4.0 mg per kg of body weight is administered within a 30-minute period. 263. The method of embodiment 239, wherein at least 6.0 mg per kg of body weight is administered within a 30-minute period. 264. The method of embodiment 239, wherein at least 10.0 mg per kg of body weight is administered within a 30-minute period. 265. The method of any one of embodiments 239-264, wherein the superoxide dismutase mimetic is administered parenterally. 266. The method of any one of embodiments 239-264, wherein the superoxide dismutase mimetic is administered intravenously. 267. The method of any one of embodiments 239-266, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. 268. The method of any of embodiments 239-266, wherein the disease or condition is selected from cancer, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immune disorders, inflammatory disorders, metabolic disorders, neurological disorders, ophthalmological disorders, pulmonary disorders, infectious diseases, and combinations thereof. 269. The method of any one of embodiments 239-268, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation described in any one of embodiments 1-38. 270. The method of any of embodiments 239-268, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution containing about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic and is contained in an IV bag. 271. The method of any one of embodiments 239-270, wherein X and Y are independently selected from monodentate ligands. 272. The method of any of embodiments 239-271, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 273. The method of any of embodiments 239-272, wherein X and Y are independently selected from aquo ligands and halo ligands. 274. The method of any one of embodiments 239-273, wherein X and Y are independently halo ligands. 275. The method of any one of embodiments 239-274, wherein X and Y are chloro ligands. 276. A superoxide dismutase mimetic having the formula (GC4419): [ka] 276. The method of any of embodiments 239 to 275, wherein the compound is in the dichloro complex form of 277. A method of treating a human patient for a disease or condition, comprising administering to a patient a compound of formula (GC4419): [ka] wherein X and Y are independently neutral or negatively charged ligands. 278. The method of any of embodiments 277, wherein at least 125 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 279. The method of embodiment 277, wherein at least 150 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 280. The method of embodiment 277, wherein at least 175 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 281. The method of embodiment 277, wherein at least 200 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 282. The method of embodiment 277, wherein at least 225 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 283. The method of embodiment 277, in which at least 250 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 284. The method of embodiment 277, wherein at least 275 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 285. The method of embodiment 277, wherein at least 300 mg of the superoxide dismutase mimetic is administered within a 60 minute period. 286. The method of embodiment 277, wherein at least 325 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 287. The method of embodiment 277, wherein at least 350 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 288. The method of embodiment 277, wherein at least 375 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 289. The method of embodiment 277, wherein at least 400 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 290. The method of embodiment 277, wherein at least 425 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 291. The method of embodiment 277, wherein at least 450 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 292. The method of embodiment 277, wherein at least 475 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 293. The method of embodiment 277, wherein at least 500 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 294. The method of embodiment 277, wherein at least 525 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 295. The method of embodiment 277, wherein at least 550 mg of the superoxide dismutase mimetic is administered within a 30-minute period. 296. The method of embodiment 277, wherein at least 575 mg of the superoxide dismutase mimetic is administered within a 30-minute period. 297. The method of embodiment 277, wherein at least 600 mg of the superoxide dismutase mimetic is administered within a 30 minute period. 298. The method of embodiment 277, wherein at least 0.67 mg per kg of body weight is administered within a 60-minute period. 299. The method of embodiment 277, wherein at least 1.0 mg per kg of body weight is administered within a period of 60 minutes. 300. The method of embodiment 277, wherein at least 1.5 mg per kg of body weight is administered within a period of 60 minutes. 301. The method of embodiment 277, wherein at least 2.0 mg per kg of body weight is administered within a 60-minute period. 302. The method of embodiment 277, in which at least 2.5 mg per kg of body weight is administered within a 60-minute period. 303. The method of embodiment 277, in which at least 3.0 mg per kg of body weight is administered within a 60-minute period. 304. The method of embodiment 277, wherein at least 4.0 mg per kg of body weight is administered within a 60-minute period. 305. The method of embodiment 277, in which at least 6.0 mg per kg of body weight is administered within a 60-minute period. 306. The method of embodiment 277, in which at least 10.0 mg per kg of body weight is administered within a 60-minute period. 307. The method of any of embodiments 277-306, wherein the superoxide dismutase mimetic is administered parenterally. 308. The method of any one of embodiments 277-306, wherein the superoxide dismutase mimetic is administered intravenously. 309. The method of any of embodiments 277-309, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. 310. The method of any of embodiments 277-309, wherein the disease or condition is selected from cancer, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immune disorders, inflammatory disorders, metabolic disorders, neurological disorders, ophthalmological disorders, pulmonary disorders, infectious diseases, and combinations thereof. 311. The method of any of embodiments 277-310, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation described in any of embodiments 1-38. 312. The method of any of embodiments 277-310, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution containing about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic and placed in an IV bag. 313. The method of any of embodiments 277-312, wherein X and Y are independently selected from monodentate ligands. 314. The method of any of embodiments 277-313, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 315. The method of any of embodiments 277-314, wherein X and Y are independently selected from aquo ligands and halo ligands. 316. The method of any of embodiments 277-315, wherein X and Y are independently halo ligands. 317. The method of any one of embodiments 277-316, wherein X and Y are chloro ligands. 318. A superoxide dismutase mimetic having the formula (GC4419): [ka] The method according to any one of embodiments 277 to 317, wherein the compound is in the dichloro complex form of 319. A method of treating a disease or condition in a human patient, comprising administering to the patient at least 25 mg of a superoxide dismutase mimetic at a rate of at least 100 mg / hour, wherein the superoxide dismutase mimetic has the formula (GC4419): [ka] and X and Y are independently neutral or negatively charged ligands. 320. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 150 mg / hour. 321. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 200 mg / hour. 322. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 250 mg / hour. 323. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 300 mg / hour. 324. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 350 mg / hour. 325. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 400 mg / hour. 326. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 450 mg / hour. 327. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 500 mg / hour. 328. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 550 mg / hour. 329. The method of embodiment 319, in which the superoxide dismutase mimetic is administered at a rate of at least 600 mg / hour. 330. The method of embodiment 319, in which at least 50 mg of the superoxide dismutase mimetic is administered to the patient. 331. The method of embodiment 319, in which at least 75 mg of the superoxide dismutase mimetic is administered to the patient. 332. The method of embodiment 319, in which at least 100 mg of the superoxide dismutase mimetic is administered to the patient. 333. The method of embodiment 319, in which at least 125 mg of the superoxide dismutase mimetic is administered to the patient. 334. The method of embodiment 319, in which at least 150 mg of the superoxide dismutase mimetic is administered to the patient. 335. The method of embodiment 319, in which at least 175 mg of the superoxide dismutase mimetic is administered to the patient. 336. The method of embodiment 319, in which at least 200 mg of the superoxide dismutase mimetic is administered to the patient. 337. The method of embodiment 319, in which at least 225 mg of the superoxide dismutase mimetic is administered to the patient. 338. The method of embodiment 319, in which at least 250 mg of the superoxide dismutase mimetic is administered to the patient. 339. The method of embodiment 319, in which at least 275 mg of the superoxide dismutase mimetic is administered to the patient. 340. The method of embodiment 319, in which at least 300 mg of the superoxide dismutase mimetic is administered to the patient. 341. The method of embodiment 319, in which at least 325 mg of the superoxide dismutase mimetic is administered to the patient. 342. The method of embodiment 319, in which at least 350 mg of the superoxide dismutase mimetic is administered to the patient. 343. The method of embodiment 319, in which at least 375 mg of the superoxide dismutase mimetic is administered to the patient. 344. The method of embodiment 319, in which at least 400 mg of the superoxide dismutase mimetic is administered to the patient. 345. The method of embodiment 319, in which at least 425 mg of the superoxide dismutase mimetic is administered to the patient. 346. The method of embodiment 319, in which at least 450 mg of the superoxide dismutase mimetic is administered to the patient. 347. The method of embodiment 319, in which at least 475 mg of the superoxide dismutase mimetic is administered to the patient. 348. The method of embodiment 319, in which at least 500 mg of the superoxide dismutase mimetic is administered to the patient. 349. The method of embodiment 319, in which at least 525 mg of the superoxide dismutase mimetic is administered to the patient. 350. The method of embodiment 319, wherein at least 550 mg of the superoxide dismutase mimetic is administered to the patient. 351. The method of embodiment 319, in which at least 575 mg of the superoxide dismutase mimetic is administered to the patient. 352. The method of embodiment 319, in which at least 600 mg of the superoxide dismutase mimetic is administered to the patient. 353. The method of any one of embodiments 319, wherein administration occurs within a 15-minute time frame. 354. The method of any one of embodiments 319, wherein administration occurs within a 30-minute time frame. 355. The method of any one of embodiments 319, wherein administration occurs within a 60-minute time frame. 356. The method of any one of embodiments 319-355, wherein the superoxide dismutase mimetic is administered parenterally. 357. The method of any one of embodiments 319-355, wherein the superoxide dismutase mimetic is administered intravenously. 358. The method of any of embodiments 319-357, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. 359. The method of any of embodiments 319-358, wherein the disease or condition is selected from cancer, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immune disorders, inflammatory disorders, metabolic disorders, neurological disorders, ophthalmological disorders, pulmonary disorders, infectious diseases, and combinations thereof. 360. The method of any one of embodiments 319-359, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation described in any one of embodiments 1-38. 361. The method of any of embodiments 319-359, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution containing about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic and is contained in an IV bag. 362. The method of any of embodiments 319-361, wherein X and Y are independently selected from monodentate ligands. 363. The method of any of embodiments 319-362, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 364. The method of any of embodiments 319-363, wherein X and Y are independently selected from aquo ligands and halo ligands. 365. The method of any one of embodiments 319-364, wherein X and Y are independently halo ligands. 366. The method of any one of embodiments 319-365, wherein X and Y are chloro ligands. 367. A superoxide dismutase mimetic having the formula (GC4419): [ka] 367. The method of any one of embodiments 319 to 366, wherein the dichloro complex is 368. A method of treating a disease or condition in a human patient, comprising administering to the patient a superoxide dismutase mimetic to achieve an exposure, as measured using area under the curve (AUC), of at least 4,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient, wherein the superoxide dismutase mimetic has the formula (GC4419): [ka] and X and Y are independently neutral or negatively charged ligands. 369. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 5,000 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 370. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 7,500 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient. 371. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 10,000 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 372. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 12,500 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 373. The method of embodiment 368, wherein administration results in an exposure, as measured using the area under the curve (AUC), of at least 15,000 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 374. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 17,500 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient. 375. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 20,000 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 376. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 22,500 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 377. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 25,000 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 378. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 27,500 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 379. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 30,000 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 380. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 32,500 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient. 381. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 35,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient. 382. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 37,500 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient. 383. The method of embodiment 368, wherein administration results in an exposure, as measured using the area under the curve (AUC), of at least 40,000 ng-hr / mL, calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 384. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 42,500 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient. 385. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 45,000 ng-hr / mL, calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 386. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 47,500 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 387. The method of embodiment 368, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 50,000 ng-hr / mL, as calculated from measurements of the patient's plasma concentration of the superoxide dismutase mimetic. 388. The method of any of embodiments 368-387, wherein the superoxide dismutase mimetic is administered parenterally. 389. The method of any one of embodiments 368-387, wherein the superoxide dismutase mimetic is administered intravenously. 390. The method of any of embodiments 368-389, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier. 391. The method of any of embodiments 368-390, wherein the disease or condition is selected from cancer, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immune disorders, inflammatory disorders, metabolic disorders, neurological disorders, ophthalmological disorders, pulmonary disorders, infectious diseases, and combinations thereof. 392. The method of any one of embodiments 368-391, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation described in any one of embodiments 1-38. 393. The method of any of embodiments 368-391, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution containing about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic and placed in an IV bag. 394. The method of any of embodiments 368-393, wherein X and Y are independently selected from monodentate ligands. 395. The method of any of embodiments 368-394, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 396. The method of any of embodiments 368-395, wherein X and Y are independently selected from aquo ligands and halo ligands. 397. The method of any one of embodiments 368-396, wherein X and Y are independently halo ligands. 398. The method of any one of embodiments 368-397, wherein X and Y are chloro ligands. 399. A superoxide dismutase mimetic having the formula (GC4419): [ka] 399. The method of any of embodiments 368 to 398, wherein the compound is in the dichloro complex form of 400. An article of manufacture comprising packaging material containing within the packaging material a parenteral formulation for treating a disease or condition or protecting tissue from damage resulting from exposure to a cancer treatment in a patient in need thereof, the parenteral formulation comprising a unit dose formulation of any of embodiments 1-38, and the packaging material comprising a label or package insert with instructions for parenterally administering the dose to the patient. 401. The article of manufacture of embodiment 400, wherein the parenteral formulation is in the form of a solution and comprises about 20 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container. 402. The article of manufacture of embodiment 400, wherein the parenteral formulation is in the form of a solution and comprises about 17.5 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container. 403. The article of manufacture of embodiment 400, wherein the parenteral formulation is in the form of a solution and comprises about 15 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container. 404. The article of manufacture of embodiment 400, wherein the parenteral formulation is in the form of a solution and comprises about 12.5 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container. 405. The article of manufacture of embodiment 400, wherein the parenteral formulation is in the form of a solution and comprises about 10 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container. 406. The article of manufacture of embodiment 400, wherein the parenteral formulation is in the form of a solution and comprises about 7.5 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container. 407. The article of manufacture of embodiment 400, wherein the parenteral formulation is in the form of a solution and comprises about 5 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container. 408. The article of manufacture of any of embodiments 400-407, wherein the disease or condition is selected from cancer, cardiovascular disorders, cerebrovascular disorders, skin disorders, fibrotic disorders, gastrointestinal disorders, immune disorders, inflammatory disorders, metabolic disorders, neurological disorders, ophthalmological disorders, pulmonary disorders, infectious diseases, and combinations thereof. 409. The method of any of embodiments 400-408, wherein X and Y are independently selected from monodentate ligands. 410. The pharmaceutical composition of any of embodiments 400-409, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 411. The pharmaceutical composition of any of embodiments 400-410, wherein X and Y are independently selected from aquo ligands and halo ligands. 412. The pharmaceutical composition of any of embodiments 400-411, wherein X and Y are independently halo ligands. 413. The pharmaceutical composition of any of embodiments 400-412, wherein X and Y are chloro ligands. 414. A superoxide dismutase mimetic having the formula (GC4419): [ka] 414. The article of manufacture of any of embodiments 400 to 413, wherein the dichloro complex form of 415. A pharmaceutical composition in the form of a solution comprising about 0.25 mg / mL to about 3.5 mg / mL of a superoxide dismutase mimetic, the composition being a unit dose in a container for intravenous administration, the superoxide dismutase mimetic being (GC4419): [ka] and X and Y are independently neutral or negatively charged ligands. 416. The pharmaceutical composition of embodiment 415, comprising about 0.25 mg / mL of the superoxide dismutase mimetic. 417. The pharmaceutical composition of embodiment 415, comprising about 0.5 mg / mL of the superoxide dismutase mimetic. 418. The pharmaceutical composition of embodiment 415, comprising about 0.75 mg / mL of the superoxide dismutase mimetic. 419. The pharmaceutical composition of embodiment 415, comprising about 1.0 mg / mL of the superoxide dismutase mimetic. 420. The pharmaceutical composition of embodiment 415, comprising about 1.25 mg / mL of the superoxide dismutase mimetic. 421. The pharmaceutical composition of embodiment 415, comprising about 1.5 mg / mL of the superoxide dismutase mimetic. 422. The pharmaceutical composition of embodiment 415, comprising about 1.75 mg / mL of the superoxide dismutase mimetic. 423. The pharmaceutical composition of embodiment 415, comprising about 2.0 mg / mL of the superoxide dismutase mimetic. 424. The pharmaceutical composition of embodiment 415, comprising about 2.25 mg / mL of the superoxide dismutase mimetic. 425. The pharmaceutical composition of embodiment 415, comprising about 2.5 mg / mL of the superoxide dismutase mimetic. 426. The pharmaceutical composition of embodiment 415, comprising about 2.75 mg / mL of the superoxide dismutase mimetic. 427. The pharmaceutical composition of embodiment 415, comprising about 3.0 mg / mL of the superoxide dismutase mimetic. 428. The method of any one of embodiments 415-427, wherein X and Y are independently selected from monodentate ligands. 429. The pharmaceutical composition of any of embodiments 415-428, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands. 430. A pharmaceutical composition according to any of embodiments 415-429, wherein X and Y are independently selected from aquo ligands and halo ligands. 431. A pharmaceutical composition according to any of embodiments 415-430, wherein X and Y are independently halo ligands. 432. The pharmaceutical composition of any of embodiments 415-431, wherein X and Y are chloro ligands. 433. A superoxide dismutase mimetic having the formula (GC4419): [ka] The pharmaceutical composition according to any of embodiments 415 to 432, wherein the dichloro complex form of

[0127] The above-described embodiments are for illustrative purposes only and do not represent any limitation on the scope of the present invention. Various modifications and combinations of the disclosed features will be apparent to those skilled in the art based on the above disclosure and are also within the scope of the present invention.

[0128] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention as defined in the appended claims. Furthermore, it should be understood that all embodiments of the present disclosure are provided by way of non-limiting examples. [Example]

[0129] The following non-limiting examples are provided to further illustrate the present invention. Those of skill in the art should understand that the techniques disclosed in the examples which follow represent methods discovered by the inventors to function well in the practice of the invention and, as such, may be considered to constitute exemplary modes of practice thereof. However, those of skill in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. [Example]

[0130] Chemical and crystal structures of GC4403 and GC4419 As noted above, the chemical structures of GC4403 and GC4419 have mirror image chirality; i.e., their enantiomeric structures are identical except that they are non-superimposable. GC4403 has four chiral carbon centers present in the R-absolute configuration, and GC4419 has four chiral carbon centers in the S-absolute configuration: [ka]

[0131] The single crystal X-ray structure of GC4403 has been previously reported in the literature and is shown in Figure 1. Riley, DP, Schall, OF, 2007, Advances in Inorganic Chemistry, 59: 233-263. The single crystal X-ray structure of GC4419 has also been determined and is shown in Figure 2. [Example]

[0132] Synthesis of GC4403 and GC4419 Complexes of GC4403 and GC4419 were synthesized by the template method previously reported for GC4403. In the case of GC4403, the complex was synthesized via a literature-described template route using chiral R,R-1,2-diaminocyclohexane. Salvemini, D., et al., 1999, Science, 286: 304-6; Aston, K., Rath, N., Naik, A., Slomczynska, U., Schall, OF, Riley, DP, 2001, Inorg. Chem., 40(8), 1779-89. The same method was used to synthesize GC4419, except that R,R-1,2-diaminocyclohexane was replaced with chiral S,S-1,2-diaminocyclohexane during the synthesis. [Example]

[0133] Physiochemical properties of GC4403 and GC4419 The complexes of GC4403 and GC4419 have identical physicochemical properties, including stability, reactivity with achiral reagents, electronic spectra, solubility in achiral media, and reactivity with superoxide. The relevant physicochemical properties are summarized in Table 1. Table 1. Physical and chemical characteristics of GC4419 and GC4403 [Table 1] [Example]

[0134] Antiproliferative activity (in vitro) Materials and Methods: HEK-293 (CRL-1573) cells were obtained from ATCC and cultured according to the ATCC instructions. Complete growth medium consisted of RPMI 1640 supplemented with fetal bovine serum (FBS) to 10%. All cell cultures were performed at 37°C in a 95% air:5% CO2 atmosphere. Two days before the start of the growth experiments, 10 cells in the exponential growth phase were cultured. 3HEK-293 cells were seeded into each well of a 96-well plate. To synchronize cell division, cells were maintained in complete growth medium for 24 hours, at which point the cell monolayer was washed once with growth medium without FBS and then cultured overnight in medium without FBS. The following morning, GC4419 or GC4403 in complete growth medium, or growth medium alone, was added. After culturing the plates for 72 hours, cell number was determined using an LDH assay kit. "Cell number" in Figure 3 represents the absorbance at 490 nm.

[0135] Results: Both SOD mimetics, i.e., GC4403 and GC4419, equally reduced the proliferation of HEK-293 cells in a dose-dependent manner (Figure 3). In addition, there was no significant difference in the antiproliferative effects between the compounds. [Example]

[0136] Animal Safety Testing Compared to GC4403, GC4419 achieved similar plasma exposures for similar mass doses and IV infusion rates in animal safety models and human studies, while being significantly safer (i.e., significantly more compound could be administered over a significantly shorter infusion time).

[0137] Safety studies in dogs 7-day IV toxicity of GC4403 GC4403 in 26 mM sodium bicarbonate / 0.9% sodium chloride was administered IV (slow bolus injection over at least 1 minute) to beagle dogs (four dogs / sex / group) at doses of 0, 1, 3, or 6 mg / kg / day for 7 days. No deaths occurred during the study. Clinical signs were observed immediately after doses of 3 mg / kg / day and above and included scratching, mild or moderate facial swelling, red, raised areas on the abdominal body surface, and partial closure of the eyes. At 6 mg / kg / day, animals also had tremors, abnormal posture and gait, inability to stand, and prostration. Generally, clinical signs resolved by 2 hours after dose administration. As the study progressed, some clinical signs (tremors, inability to stand, prostration, and abnormal posture and gait) subsided slightly. Males at 3 mg / kg / day and above and females at 6 mg / kg / day experienced an initial decrease in body weight accompanied by a decrease in food intake during the first 3 days of the study. Males and females at 6 mg / kg / day did not gain weight during the study, compared with animals in other groups that did gain weight throughout the study. At the end of the treatment period, all treatment groups showed trends toward decreases in red blood cell counts, hemoglobin, and hematocrit, as well as decreases in total white blood cell counts. The decreases in white blood cell counts correlated with decreases in absolute neutrophil and eosinophil counts at 3 mg / kg / day and above, but remained within the historical normal range for these parameters. At necropsy, there were no changes in organ weights compared to control animals, as well as no macroscopic or microscopic changes in any organs, except for cardiac fibrosis in one male at 3 mg / kg / day and one male at 6 mg / kg / day.

[0138] Based on the results of this study, the no observed toxic event level (NOTEL) for GC4403 administered IV by slow bolus injection for 7 days in dogs was 3 mg / kg / day.

[0139] 28-day IV toxicity of GC4403 GC4403 was evaluated in beagle dogs in a Good Laboratory Practice (GLP) study. GC4403 was administered intravenously (IV) via slow bolus injection once daily for 28 consecutive days. GC4403 was administered IV (0.5 mL / kg) into the cephalic vein at doses of 1.0, 3.0, and 6.0 mg / kg to three groups of dogs (four animals / sex / group), with a fourth group receiving vehicle (26 mM sodium bicarbonate in normal saline). Tremors, abnormal posture and gait, and inability to stand were observed immediately after administration in the 6.0 mg / kg group; however, no animals died during treatment; however, these clinical signs were short-lived, and the incidence and severity decreased as the study progressed. There were no test article-related differences in group mean hematological, coagulation, or clinical chemistry or urinalysis parameters in any treatment group after 28 days of treatment. At necropsy on Day 29, there were no test article-related gross macroscopic findings or test article-related organ weight differences. There was no test article-related histopathological damage. There were no test article-related electrocardiogram (ECG) effects when evaluated on Day 27.

[0140] Based on the results and observations of this study, the no observed adverse event level (NOTEL) for GC4403 administered IV to beagle dogs for 28 consecutive days was 3.0 mg / kg / day, while the no observed adverse effect level (NOAEL) was 1 mg / kg / day.

[0141] 14-day repeated dose toxicity of GC4419 in dogs GC4419 was evaluated in beagle dogs in a GLP study. Beagle dogs were administered GC4419 intravenously (IV) over 15 minutes once daily for 14 consecutive days. GC4419 was administered IV (4 mL / kg) into the cephalic vein at doses of 2.5, 5.0, and 7.5 mg / kg to three groups of dogs (four animals / sex / group). Group 4 received vehicle (26 mM sodium bicarbonate in normal saline). No animals died during treatment, and GC4419 had minimal effects up to 7.5 mg / kg. However, one male and one female experienced ataxia, and one female experienced convulsions, all in the 7.5 mg / kg group. All animals recovered from these effects. There were no test article-related differences in group mean hematological, coagulation, or clinical chemistry or urinalysis parameters in any treatment group after 14 days of treatment. At necropsy on day 15, there were no test article-related gross macroscopic findings or test article-related organ weight differences. There was no test article-related histopathological damage.

[0142] Based on rare clinical signs at 7.5 mg / kg / day, the no observed adverse effect level (NOAEL) was determined to be 5.0 mg / kg / day.

[0143] Safety studies in rats Seven-day intravenous toxicity of GC4403 in rats GC4403 was tested in a GLP toxicity study in which GC4403 in 26 mM sodium bicarbonate / 0.9% sodium chloride was administered IV (slow bolus at 1 mL / kg / min) to SD rats (10 / sex / group) at doses of 0, 1, 3, or 10 mg / kg / day for 7 days (on Day 1, 1 / 10 of the male rats given 10 mg / kg / day died). Therefore, on Day 2, the dose was reduced to 8 mg / kg / day for all surviving animals, and the original 10 mg / kg / day group was rescheduled as an 8 mg / kg / day group for the remainder of the study. On Day 4, two females from the 8 mg / kg / day group also died. Clinical signs immediately following administration of the 8 mg / kg / day dose included spasms, labored breathing, body drop, and collapse. Animals appeared normal during periodic 1-hour observations. Decreased body weight gain was observed in both males and females given 8 mg / kg / day, with decreased food intake observed in males only. Compared with controls, rats receiving 8 mg / kg / day had significantly higher glucose, alkaline phosphatase, ALT, and triglyceride levels. Calcium levels were significantly higher in males at 3 mg / kg / day and higher and in females at 8 mg / kg / day. Surviving rats were sacrificed, and all sacrificed rats or rats found dead were necropsied. Necropsy revealed no compound-related organ weight changes. There were no macroscopic or microscopic findings in any tissues, and examination of the injection site revealed the compound to be non-irritating.

[0144] Based on the results and observations of this study, the no observed adverse event level (NOTEL) for GC4403 administered IV by slow bolus injection to rats for 7 days was 3 mg / kg / day.

[0145] 28-day IV toxicity of GC4403 in rats GC4403 was evaluated in Sprague-Dawley rats in a 28-day GLP study. GC4403 was administered to rats (10 / sex / group) at doses of 0, 1, 3, or 6 mg / kg / day via slow bolus IV injection for 28 days. The control (zero-dose) group received vehicle (26 mM sodium bicarbonate in normal saline). Evaluation of compound-related effects was based on clinical findings, body weight, food consumption, hematological and clinical chemistry parameters, a functional observation battery, organ weights, and gross and microscopic necropsies. There were no compound-related organ weight differences or macroscopic or microscopic lesions. Based on the results and observations of this study, the no observed adverse event level (NOTEL) for GC4403 when administered as an IV infusion to rats for 28 days was 3 mg / kg / day.

[0146] 7-day IV study of GC4419 in rats A GLP toxicity study was conducted using GC4419 in bicarbonate buffer. Rats (5 / sex / group) were administered GC4419 at 0, 5, 10, or 15 mg / kg as a 15-minute IV infusion (4 mL / kg) for 7 consecutive days. A control group received bicarbonate buffer. Evaluation of compound-related effects was based on clinical findings, body weight, and food consumption. No deaths occurred during the study, and there was no sign of significant effects of the compound at any dose. In male rats given 15 mg / kg / day, some mild weight loss, reaching approximately 10% by day 8, was observed, and a mild decrease in food intake was also observed. NOTE: The effect of GC4419 on the development of GC4419 was not observed in either male or female rats at 15 mg / kg / day.

[0147] A 14-day IV study of GC4419 in rats GC4419 was evaluated in rats in a 14-day GLP study. GC4419 was administered to rats (10 per sex per group) at doses of 0, 5, 10, or 20 (15) mg / kg / day as a 15-minute IV infusion for 14 days. The control group received vehicle (sodium citrate in normal saline). Due to a fatal event at 20 mg / kg / day, the high-dose group was reduced to 15 mg / kg / day on day 3. Evaluation of compound-related effects was based on clinical findings, body weight, food consumption, hematological and clinical chemistry parameters, a functional observation battery, organ weights, and gross and microscopic necropsies. Several rats died on days 1 or 2 at 20 mg / kg, and these deaths were considered compound-related; therefore, the dose level was reduced to 15 mg / kg / day starting on day 3. There were no compound-related changes in organ weights or macroscopic or microscopic lesions. Based on the results and observations of this study, the NOAEL for GC4419 was 15 mg / kg / day when administered as a 15-minute IV infusion to rats for 14 days. [Example]

[0148] Efficacy of SOD mimetics for radiation-induced oral mucositis GC4403 and GC4419 were tested in a hamster model of oral mucositis (OM). Radiation to the hamster cheek pouch induced lesions that were histologically similar to clinically occurring OM and developed and resolved at a rate similar to that of radiation-induced OM in humans. Male Syrian golden hamsters (8 per group) were given intraperitoneal injections of vehicle, GC4403 (30 mg / kg), or GC4419 (3–30 mg / kg) in 26 mM sodium bicarbonate-buffered saline 30 minutes before and 12 hours after irradiation. Animals received a localized 40 Gy radiation dose to the everted cheek pouch and were evaluated every 2 days for the development of inflammation at the irradiated site. Inflammation was graded on a scale from 0 (normal) to 5 (complete cheek ulceration) by trained observers blinded to the treatment protocol.

[0149] All doses of GC4419 administered before irradiation prevented the development of grade 3 or higher OM (Figure 4). GC4419 at 30 mg / kg reduced OM by 57%, and GC4403 at 30 mg / kg reduced grade 3 or higher OM by 52%. All hamsters treated with GC4403 or GC4419 gained weight (approximately 15% compared to vehicle) throughout the duration of the experiment (28 days), likely due to the ease of eating and drinking resulting from reduced pain and inflammation in the oral cavity. [Example]

[0150] Efficacy of SOD mimetics on plasma TNF-α in a collagen-induced arthritis model Male Lewis rats (160-180 g) were used in this study. Collagen-induced arthritis (CIA) was induced as follows: Bovine type II collagen (CII; Sigma) was dissolved in 0.1 M acetic acid at 4°C overnight with stirring to a concentration of 2 mg / mL. Rats were immunized with a 2 mg / mL emulsion of CII in Freund's incomplete adjuvant (IFA; Sigma). This emulsion was prepared by homogenizing CII in IFA at a 1:1 ratio at 4°C. On day 1, rats were injected intradermally at the base of the tail with 100 μL of the emulsion. On day 21, a second injection of CII in IFA was administered at the base of the tail. Fresh GC4403 and GC4419 were prepared and dissolved in 26 mM sodium bicarbonate-buffered saline (vehicle). All drugs were given by intraperitoneal injection at 1 mL / kg. Animals were randomly divided into groups (n=10 per group). GC4403 and GC4419 were administered once daily at 2, 5, and 10 mg / kg from day 25 to day 35.

[0151] A time-course study showed that plasma levels in the CIA model peaked on day 35 and remained elevated for approximately 5–6 days. TNF-α levels were measured from plasma on day 35. The assay was performed using a chromogenic ELISA kit (Calbiochem-Novabiochem) with a detection limit of 5 pg / mL. Values ​​were averaged across 10 observations and expressed as mean ± standard error. Data sets were validated by one-way ANOVA followed by Bonferroni post hoc multiple comparisons. A p value of less than 0.05 was considered significant.

[0152] At day 35, TNF-α levels were significantly elevated in the plasma of vehicle-treated CIA rats. Both GC4403 and GC4419 attenuated TNF-α production similarly (Figure 5). At a dose of 2 mg / kg, the reduction in TNF-α production was not significant. For both agents, doses of 5 mg / kg and 10 mg / kg significantly reduced TNF-α production. [Example]

[0153] Human clinical safety of GC4419 A human clinical trial entitled "A Double-Blind, Placebo-Controlled, Single Ascending-Dose Study to Evaluate the Safety and Tolerability and Determine the Pharmacokinetics of M40419 Administered as a 15-Minute Intravenous Infusion to Healthy Subjects" was conducted in 54 subjects. This was a single-center, randomized, placebo-controlled, sequential panel, single-dose safety, tolerability, and pharmacokinetic study of GC4419 administered as a 75 mL IV infusion over 15 minutes at escalating doses of 10 mg, 15 mg, 22 mg, 33 mg, 50 mg, 75 mg, and 112 mg. The study consisted of two phases: Phase 1 involved dose escalation using six subjects in each cohort (four active, two placebo) to determine the maximum tolerated dose (MTD); Phase 2 involved repeating the MTD dose in 12 subjects (eight active and four placebo) to confirm the safety of the MTD, i.e., the highest dose tested. The study population included 54 healthy male and female subjects (36 males, 18 females) between the ages of 18 and 50 who were deemed eligible based on the inclusion and exclusion criteria. For the dose-escalation phase of the study, four subjects received active drug and two subjects received placebo at each dose level, and for the confirmation MTD phase, eight subjects received active drug and four subjects received placebo.

[0154] All subjects who received a dose of study drug were evaluated for safety. The safety of the drug product was assessed based on treatment-emergent adverse events (TEAEs), clinical laboratory assessments, vital signs, 12-lead electrocardiograms (ECGs), and standard ECG parameters such as PR, QRS, QT, and QTc intervals.

[0155] Of the 54 subjects who were randomized and received study medication, 54 (100%) completed the study according to the study protocol. No subjects discontinued the study prematurely. Protocol deviations were few, and none were considered to affect the pharmacokinetic or safety outcomes of the study. Immediate visual inspection of data regarding demographic and baseline characteristics revealed no clinically relevant differences between treatment groups.

[0156] A total of 125 treatment-emergent adverse events (TEAEs) occurred in 37 subjects after administration. Overall, 7 of 18 subjects (38.9%) who received placebo and 30 of 36 subjects (83.3%) who received study drug experienced at least one TEAE. TEAEs occurred in 12 body systems, with the most common in study drug-treated subjects being nervous system disorders, systemic disorders, administration site conditions, and gastrointestinal disorders. The most common adverse events in study drug-treated subjects were paresthesia, perioral paresthesia, and nausea (an analysis of the causes of the paresthesia side effect is discussed below). The majority of reported TEAEs were mild in severity (104 of 125 events, 83.2%). Nineteen events (19 of 125 events, 15.2%) were moderate in intensity, and two (2 of 125 events, 1.6%) were severe. The two events reported as severe in intensity were nausea, reported in the 75 mg and 112 mg treatment groups. Both events resolved spontaneously. Of the 125 total reported TEAEs, 105 events (84.0%) occurred in 37 of the 54 total subjects and were determined by the investigator to be either uncertainly or probably related to the study drug. Seven of these events (5.6%) occurred in placebo-treated subjects, and 99 of the 105 events (94.3%) occurred in study drug-treated subjects.

[0157] The 50 mg dose was determined to be the MTD after completion of the MTD panel confirmation. Initially, a 75 mg dose was determined to be the MTD during the dose-escalation phase; however, based on the nature and grading of adverse events that occurred during the confirmation MTD phase, it was decided to define the MTD as 50 mg. Although no formal statistical analysis was performed on the data, upon immediate visual inspection of the data, the incidence of AEs appeared to be correlated with the dose of study article.

[0158] No deaths or serious adverse events occurred throughout the study. No subjects discontinued early due to adverse events. Two dose-limiting toxicities (DLTs) occurred, each prompting the identification of the MTD as a lower dose. These DLTs included nausea in a subject receiving 112 mg of test article during the dose-escalation phase (initially defining the MTD as 75 mg) and nausea with mild hypotension in a subject receiving 75 mg of test article during the confirmation MTD phase (defining the final MTD as 50 mg). Both events were deemed by the investigator to be possibly related to the study drug.

[0159] Vital signs, ECGs, and physical examination data did not reveal any clinically significant trends or changes from baseline, nor were there any discernible differences between placebo- and investigational drug-treated subjects at any dose of study drug.

[0160] The overall conclusions of the study are as follows: - GC4419 was excreted unchanged in the urine at less than 20% of the administered dose over 48 hours. The renal route does not appear to be the primary route of GC4419 excretion in humans. A dose of 50 mg of GC4419 (administered as an intravenous infusion over 15 minutes) was determined to be the maximum no effect tolerated dose. Adverse events following GC4419 administration were generally mild. Two dose-limiting toxicities were reported, but did not justify discontinuing dose escalation, ultimately resulting in a maximum tolerated dose of 50 mg. No serious adverse events were reported, and no subjects discontinued due to adverse events. Overall, single intravenous doses of 10mg to 50mg of GC4419 were safe and well tolerated with no adverse events. - In this Phase 1 study, results showed that single doses of GC4419 up to 112 mg were tolerated without serious adverse events in healthy subjects. [Example]

[0161] Human clinical safety of GC4403 In a Phase 1, randomized, double-blind, placebo-controlled, single ascending-dose safety, tolerability, and pharmacokinetic study, 54 healthy male and female subjects received 2.2 to 25 mg of GC4403 administered intravenously over 30 minutes. GC4403 exhibited multi-exponential disposition, with AUC and C decreasing with increasing dose across the dose range studied. max The pharmacokinetics of GC4403 generally increased proportionally. The terminal elimination half-life was approximately 1.5 hours. GC4403 was excreted unchanged in the urine at approximately 9 to 17% of the administered dose. No significant effects on the cardiovascular system or vital signs, significant abnormalities on physical examination, or significant abnormalities in routine clinical laboratory evaluations were observed. Facial tingling, generalized tingling, paresthesia, and facial flushing were reported in a dose-response manner at GC4403 doses of 16.7 and 25 mg. No adverse events labeled as severe or serious adverse events were observed in this study.

[0162] Table 2 summarizes the clinical findings regarding signs and symptoms of toxicity observed in subjects in this Phase 1a trial. Although an official MTD was not established in this trial, given the dose-dependent findings and range of findings at 25 mg, clinical trials with GC4403 continued up to a maximum dose of 20 mg infused over 30 minutes.

[0163] In this initial Phase 1 study, results indicated that single doses of M40403 up to 25 mg were tolerated without serious adverse events in healthy subjects. The number of participants in this study who experienced adverse events, identified by dose, is shown in Table 2; as noted, the maximum tolerated dose (MTD) was not reached. The highest dose administered was 25 mg. No significant cardiovascular effects, significant abnormalities in physical examinations, or significant abnormalities in routine clinical laboratory evaluations were observed. No severe or serious adverse events were reported. One case of conjunctivitis (2.2 mg group), one case of lightheadedness (3.3 mg group), one case of headache (16.7 mg group), and one case of injection site pain (16.7 mg group) were reported as moderate in intensity. All other treatment-emergent adverse events were reported as mild in intensity. Facial flushing, tingling, oral stinging, and paresthesia were all rated as mild in intensity and were reported to occur in a dose-response manner at the 16.7 and 25 mg doses. Facial flushing, tingling, oral stinging, and paresthesia typically began during or shortly after infusion and persisted for up to 3-4 hours. [Table 2] Table 3. Mean Area Under the Curve (AUC) Plasma Exposure in Human Phase 1 Studies [Table 3]

[0164] As part of the Phase 1a clinical trials for GC4403 and GC4419 described in the Examples herein, plasma samples were collected to measure concentrations of the parent compounds (GC4403 and GC4419) following intravenous infusion. Table 3 shows the pharmacokinetic parameter, i.e., area under the curve (AUC), which indicates a subject's total exposure to the drug over time. Importantly, the results demonstrate that in humans, equivalent mass doses of GC4419 and GC4403 should result in essentially equivalent AUC values. Due to the greater safety of GC4419 compared to GC4403 (reflecting safety at the higher doses achieved with GC4419), a nearly four-fold greater AUC was achieved with GC4419 compared to GC4403: 10,350 ng-hr / mL versus 2,556 ng-hr / mL, respectively.

Claims

1. 1. A unit dose formulation comprising at least 50 mg of a superoxide dismutase mimetic in a container, wherein the superoxide dismutase mimetic has the formula (GC4419): 【Chemical 1】 and X and Y are independently neutral or negatively charged ligands.

2. 10. The unit dose formulation of claim 1, comprising at least 75 mg of a superoxide dismutase mimetic.

3. 10. The unit dose formulation of claim 1, comprising at least 150 mg of a superoxide dismutase mimetic.

4. 10. The unit dose formulation of claim 1, comprising at least 300 mg of a superoxide dismutase mimetic.

5. 10. The unit dose formulation of claim 1, comprising at least 600 mg of a superoxide dismutase mimetic.

6. The unit dose formulation of any of claims 1 to 5, wherein the superoxide dismutase mimetic is in the form of a lyophilized powder.

7. The unit dose formulation according to any one of claims 1 to 6, wherein the container further comprises a pharmaceutically acceptable carrier.

8. 8. The unit dose formulation of claim 7, wherein the pharmaceutically acceptable carrier is in the form of a solution.

9. 8. The unit dose formulation of claim 7, wherein the pharmaceutically acceptable carrier is a solution comprising water.

10. 8. The unit dose formulation of claim 7, wherein the pharmaceutically acceptable carrier is a solution comprising saline.

11. The unit dose formulation of any of claims 7 to 10, wherein the pharmaceutically acceptable carrier comprises buffered saline.

12. 11. The unit dose formulation of any of claims 7 to 10, wherein the pharmaceutically acceptable carrier comprises a bicarbonate buffered saline solution.

13. 13. The unit dose formulation of any of claims 1 to 12, wherein X and Y are independently selected from monodentate ligands.

14. 14. The unit dose formulation of any of claims 1 to 13, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands.

15. 15. The unit dose formulation of any of claims 1 to 14, wherein X and Y are independently selected from aquo ligands and halo ligands.

16. 16. The unit dose formulation of any of claims 1 to 15, wherein X and Y are independently halo ligands.

17. 17. The unit dose formulation of any one of claims 1 to 16, wherein X and Y are cyclohexyl ligands.

18. The superoxide dismutase mimetic has the formula (GC4419): 【Chemistry 2】 18. The unit dose formulation according to any one of claims 1 to 17, wherein the compound is in the form of a dichloro complex of

19. 19. The unit dose formulation of any of claims 1 to 18, wherein the formulation is stored in a container for storage or for administration to a patient.

20. 20. The unit dose formulation of any one of claims 1 to 19, wherein the container is a vial, a syringe, or an IV (intravenous injection) bag or bottle.

21. 1. A method of treating a human patient for tissue damage resulting from the use of radiation therapy or chemotherapy, comprising administering to a patient a compound of formula (GC4419): 【Chemistry 3】 wherein X and Y are independently neutral or negatively charged ligands.

22. 22. The method of claim 21, wherein the therapeutically effective amount is at least 0.67 mg / kg of patient body weight.

23. 22. The method of claim 21, wherein the therapeutically effective amount is at least 1.0 mg / kg of patient body weight.

24. 22. The method of claim 21, wherein the therapeutically effective amount is at least 2.0 mg / kg of patient body weight.

25. 22. The method of claim 21, wherein the therapeutically effective amount is at least 4.0 mg / kg of patient body weight.

26. 22. The method of claim 21, wherein the therapeutically effective amount is at least 10.0 mg / kg of patient body weight.

27. 22. The method of claim 21, wherein the therapeutically effective amount is at least 50 mg.

28. 22. The method of claim 21, wherein the therapeutically effective amount is at least 75 mg.

29. 22. The method of claim 21, wherein the therapeutically effective amount is at least 150 mg.

30. 22. The method of claim 21, wherein the therapeutically effective amount is at least 300 mg.

31. 22. The method of claim 21, wherein the therapeutically effective amount is at least 600 mg.

32. The method of any of claims 21 to 31, wherein the superoxide dismutase mimetic is administered to the patient prior to or simultaneously with radiotherapy or chemotherapy.

33. 32. The method of any of claims 21 to 31, wherein the superoxide dismutase mimetic is administered to the patient before but not after radiotherapy or chemotherapy.

34. The method of any of claims 21 to 31, wherein the superoxide dismutase mimetic is administered to the patient at least 30 minutes before radiation therapy or chemotherapy.

35. 32. The method of any of claims 21-31, wherein the superoxide dismutase mimetic is administered to the patient up to three days after radiation therapy or chemotherapy.

36. The method of any of claims 21 to 31, wherein the superoxide dismutase mimetic is administered to the patient after radiation therapy or chemotherapy.

37. 32. The method of any of claims 21-31, wherein the superoxide dismutase mimetic is administered to the patient up to one week after radiation therapy or chemotherapy.

38. 32. The method of any of claims 21 to 31, wherein the superoxide dismutase mimetic is administered to the patient up to 6 weeks after radiation therapy or chemotherapy.

39. 32. The method of any of claims 21 to 31, wherein the superoxide dismutase mimetic is administered to the patient up to 12 weeks after radiation therapy or chemotherapy.

40. 40. The method of any one of claims 21 to 39, wherein the superoxide dismutase mimetic is administered parenterally.

41. The method of any one of claims 21 to 40, wherein the superoxide dismutase mimetic is administered intravenously.

42. The method of any of claims 21 to 40, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier.

43. The method of any one of claims 21 to 42, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation according to any one of claims 1 to 20.

44. 43. The method of any of claims 21-42, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution comprising about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic, and is contained in an IV bag.

45. 45. The method of any one of claims 21 to 44, wherein X and Y are independently selected from monodentate ligands.

46. 46. ​​The method of any of claims 21 to 45, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands.

47. The method of any one of claims 21 to 46, wherein X and Y are independently selected from aquo ligands and halo ligands.

48. The method of any one of claims 21 to 47, wherein X and Y are independently halo ligands.

49. 49. The method of any one of claims 21 to 48, wherein X and Y are chloro ligands.

50. The superoxide dismutase mimetic has the formula (GC4419): 【Chemistry 4】 The method according to any one of claims 21 to 49, wherein the compound is in the form of a dichloro complex of

51. 1. A method of treating a human patient for tissue damage resulting from radiation exposure, comprising administering to a patient a compound of formula (GC4419): 【Chemistry 5】 wherein X and Y are independently neutral or negatively charged ligands.

52. 52. The method of claim 51, wherein the therapeutically effective amount is at least 0.67 mg / kg of patient body weight.

53. 52. The method of claim 51, wherein the therapeutically effective amount is at least 1.0 mg / kg of patient body weight.

54. 52. The method of claim 51, wherein the therapeutically effective amount is at least 2.0 mg / kg of patient body weight.

55. 52. The method of claim 51, wherein the therapeutically effective amount is at least 4.0 mg / kg of patient body weight.

56. 52. The method of claim 51, wherein the therapeutically effective amount is at least 10.0 mg / kg of patient body weight.

57. 52. The method of claim 51, wherein the therapeutically effective amount is at least 50 mg.

58. 52. The method of claim 51, wherein the therapeutically effective amount is at least 75 mg.

59. 52. The method of claim 51, wherein the therapeutically effective amount is at least 150 mg.

60. 52. The method of claim 51, wherein the therapeutically effective amount is at least 300 mg.

61. 52. The method of claim 51, wherein the therapeutically effective amount is at least 600 mg.

62. 62. The method of any of claims 51-61, wherein the superoxide dismutase mimetic is administered to the patient up to three days after radiation exposure.

63. 62. The method of any of claims 51-61, wherein the superoxide dismutase mimetic is administered after radiation exposure.

64. 62. The method of any of claims 51-61, wherein the superoxide dismutase mimetic is administered to the patient up to one week after radiation exposure.

65. 62. The method of any of claims 51-61, wherein the superoxide dismutase mimetic is administered to the patient up to 6 weeks after radiation exposure.

66. 62. The method of any of claims 51-61, wherein the superoxide dismutase mimetic is administered to the patient up to 12 weeks after radiation exposure.

67. 67. The method of any one of claims 51 to 66, wherein the radiation exposure is accidental radiation exposure, unintentional radiation exposure, or intentional radiation exposure.

68. 68. The method of any of claims 51-67, wherein the superoxide dismutase mimetic is administered parenterally.

69. 68. The method of any of claims 51-67, wherein the superoxide dismutase mimetic is administered intravenously.

70. 70. The method of any of claims 51-69, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier.

71. The method of any of claims 51 to 70, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation according to any of claims 1 to 20.

72. 71. The method of any of claims 51-70, wherein the superoxide dismutase mimetic is dissolved in a solution, the solution comprising about 0.25 mg / mL to 3.5 mg / mL of the superoxide dismutase mimetic, and is contained in an IV bag.

73. 73. The method of any one of claims 51 to 72, wherein X and Y are independently selected from monodentate ligands.

74. 74. The method of any of claims 51-73, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands.

75. 75. The method of any one of claims 51 to 74, wherein X and Y are independently selected from aquo ligands and halo ligands.

76. 76. The method of any one of claims 51 to 75, wherein X and Y are independently halo ligands.

77. 77. The method of any one of claims 51 to 76, wherein X and Y are chloro ligands.

78. The superoxide dismutase mimetic has the formula (GC4419): 【Chemistry 6】 78. The method according to any one of claims 51 to 77, wherein the compound is in the form of a dichloro complex of

79. 1. A method of treating a disease or condition in a human patient, comprising administering to the patient at least 25 mg of a superoxide dismutase mimetic at a rate of at least 100 mg / hour, wherein the superoxide dismutase mimetic has the formula (GC4419): 【Chemistry 7】 and X and Y are independently neutral or negatively charged ligands.

80. 80. The method of claim 79, wherein the superoxide dismutase mimetic is administered at a rate of at least 150 mg / hour.

81. 80. The method of claim 79, wherein the superoxide dismutase mimetic is administered at a rate of at least 300 mg / hour.

82. 80. The method of claim 79, wherein the superoxide dismutase mimetic is administered at a rate of at least 600 mg / hour.

83. 80. The method of claim 79, wherein at least 50 mg of the superoxide dismutase mimetic is administered to the patient.

84. 80. The method of claim 79, wherein at least 75 mg of the superoxide dismutase mimetic is administered to the patient.

85. 80. The method of claim 79, wherein at least 150 mg of the superoxide dismutase mimetic is administered to the patient.

86. 80. The method of claim 79, wherein at least 300 mg of the superoxide dismutase mimetic is administered to the patient.

87. 80. The method of claim 79, wherein at least 600 mg of the superoxide dismutase mimetic is administered to the patient.

88. 88. The method of any one of claims 79-87, wherein the administration occurs within a 15 minute time frame.

89. 88. The method of any one of claims 79-87, wherein the administration occurs within a 30 minute time frame.

90. 88. The method of any one of claims 79-87, wherein the administration occurs within a 60 minute time frame.

91. 91. The method of any of claims 79 to 90, wherein the superoxide dismutase mimetic is administered parenterally.

92. 91. The method of any of claims 79 to 90, wherein the superoxide dismutase mimetic is administered intravenously.

93. 93. The method of any of claims 79-92, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier.

94. 94. The method of any of claims 79 to 93, wherein the disease or condition is selected from cancer, a cardiovascular disorder, a cerebrovascular disorder, a skin disorder, a fibrotic disorder, a gastrointestinal disorder, an immune disorder, an inflammatory disorder, a metabolic disorder, a neurological disorder, an ophthalmological disorder, a pulmonary disorder, an infectious disease, and combinations thereof.

95. 95. The method of any of claims 79 to 94, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation according to any of claims 1 to 20.

96. 95. The method of any of claims 79-94, wherein the superoxide dismutase mimetic is dissolved in a solution comprising about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic and is contained in an IV bag.

97. 97. The method of any one of claims 79 to 96, wherein X and Y are independently selected from monodentate ligands.

98. 98. The method of any of claims 79-97, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands.

99. 99. The method of any one of claims 79 to 98, wherein X and Y are independently selected from aquo ligands and halo ligands.

100. 100. The method of any one of claims 79 to 99, wherein X and Y are independently halo ligands.

101. 101. The method of any one of claims 79 to 100, wherein X and Y are chloro ligands.

102. The superoxide dismutase mimetic has the formula (GC4419): 【Chemistry 8】 The method according to any one of claims 79 to 101, wherein the dichloro complex is

103. 1. A method of treating a disease or condition in a human patient, comprising administering to the patient a superoxide dismutase mimetic to achieve an exposure, as measured using area under the curve (AUC), of at least 4,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient, wherein the superoxide dismutase mimetic has the formula (GC4419): 【Chemistry 9】 and X and Y are independently neutral or negatively charged ligands.

104. 105. The method of claim 104, wherein the administration results in an exposure, as measured using area under the curve (AUC), of at least 5,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient.

105. 105. The method of claim 104, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 10,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient.

106. 105. The method of claim 104, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 20,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient.

107. 105. The method of claim 104, wherein the administration results in an exposure, as measured using area under the curve (AUC), of at least 40,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient.

108. 105. The method of claim 104, wherein the administration results in an exposure, as measured using the area under the curve (AUC), of at least 50,000 ng-hr / mL, as calculated from measured plasma concentrations of the superoxide dismutase mimetic in the patient.

109. 109. The method of any of claims 104-108, wherein the superoxide dismutase mimetic is administered parenterally.

110. 109. The method of any of claims 104 to 108, wherein the superoxide dismutase mimetic is administered intravenously.

111. The method of any of claims 104 to 110, wherein the superoxide dismutase mimetic is administered as a pharmaceutical composition comprising a superoxide dismutase mimetic corresponding to formula (GC4419) and a pharmaceutically acceptable carrier.

112. 112. The method of any of claims 104 to 111, wherein the disease or condition is selected from cancer, a cardiovascular disorder, a cerebrovascular disorder, a skin disorder, a fibrotic disorder, a gastrointestinal disorder, an immune disorder, an inflammatory disorder, a metabolic disorder, a neurological disorder, an ophthalmological disorder, a pulmonary disorder, an infectious disease, and combinations thereof.

113. The method of any of claims 104 to 112, wherein the superoxide dismutase mimetic is administered in the form of a unit dose formulation according to any of claims 1 to 20.

114. 113. The method of any of claims 104-112, wherein the superoxide dismutase mimetic is dissolved in a solution comprising about 0.25 mg / mL to about 3.5 mg / mL of the superoxide dismutase mimetic and is contained in an IV bag.

115. 115. The method of any of claims 104 to 114, wherein X and Y are independently selected from monodentate ligands.

116. 116. The method of any of claims 104-115, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands.

117. 117. The method of any of claims 104 to 116, wherein X and Y are independently selected from aquo ligands and halo ligands.

118. 118. The method of any one of claims 104 to 117, wherein X and Y are independently halo ligands.

119. 119. The method of any one of claims 104 to 118, wherein X and Y are chloro ligands.

120. The superoxide dismutase mimetic has the formula (GC4419): 【Chemistry 10】 The method according to any one of claims 104 to 119, wherein the compound is in the form of a dichloro complex of

121. 21. An article of manufacture comprising packaging material and within the packaging material containing a parenteral formulation for treating a disease or condition, or protecting tissue from damage resulting from exposure to a cancer therapy, in a patient in need thereof, wherein the parenteral formulation comprises a unit dose formulation of any of claims 1-20, and the packaging material comprises a label or package insert with instructions for parenterally administering the dose to the patient.

122. 122. The article of manufacture of claim 121, wherein the parenteral formulation is in the form of a solution and comprises about 20 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container.

123. 122. The article of manufacture of claim 121, wherein the parenteral formulation is in the form of a solution and comprises about 17.5 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container.

124. 122. The article of manufacture of claim 121, wherein the parenteral formulation is in the form of a solution and comprises about 15 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container.

125. 122. The article of manufacture of claim 121, wherein the parenteral formulation is in the form of a solution and comprises about 12.5 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container.

126. 122. The article of manufacture of claim 121, wherein the parenteral formulation is in the form of a solution and comprises about 10 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container.

127. 122. The article of manufacture of claim 121, wherein the parenteral formulation is in the form of a solution and comprises about 7.5 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container.

128. 122. The article of manufacture of claim 121, wherein the parenteral formulation is in the form of a solution and comprises about 5 mg / mL of the superoxide dismutase mimetic, and the formulation is a unit dose in a container.

129. 129. The article of manufacture of any of claims 121-128, wherein the disease or condition is selected from cancer, a cardiovascular disorder, a cerebrovascular disorder, a skin disorder, a fibrotic disorder, a gastrointestinal disorder, an immune disorder, an inflammatory disorder, a metabolic disorder, a neurological disorder, an ophthalmological disorder, a pulmonary disorder, an infectious disease, and combinations thereof.

130. 130. The article of manufacture of any of claims 121-129, wherein X and Y are independently selected from monodentate ligands.

131. 131. The article of manufacture of any of claims 121-130, wherein X and Y are independently selected from the group consisting of aquo ligands, halo ligands, carboxylato ligands, and bicarboxylato ligands.

132. 132. The article of manufacture of any of claims 121-131, wherein X and Y are independently selected from aquo ligands and halo ligands.

133. 133. The article of manufacture of any of claims 121-132, wherein X and Y are independently halo ligands.

134. 134. The article of manufacture of any of claims 121-133, wherein X and Y are chloro ligands.

135. The superoxide dismutase mimetic has the formula (GC4419): 【Chemistry 11】 The product according to any one of claims 121 to 134, which corresponds to the dichloro complex form of

Images