N-acetylcysteine amide (NACA) and (2r,2r')-3,3'-disulfanediyl bis (2-acetamidopropanamide) (dinaca) for prevention and treatment of radiation dermatitis and skin lightening, skin whitening and skin improvement

Abstract

To provide a method for preventing and treating radiation dermatitis and radiation-induced skin damage.SOLUTION: Provided is a method for use of N-acetylcysteine, N-acetylcysteine amide (NACA) or (2R,2R')-3,3'-disulfanediyl bis (2-acetamidopropanamide) (diNACA) for prevention and treatment of at least one of radiation dermatitis, skin lightening, and radiation-induced skin damage, whitening, or improving skin health in a human subject. The method comprises the steps of: identifying a human patient in need of radiation dermatitis prevention and treatment, or skin lightening, whitening, or improving skin health; and administering to the human patient a therapeutically effective amount of NACA or diNACA.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 791,422, filed January 11, 2019, the entire contents of which are incorporated herein by reference.

[0002] Federal Funding Statement none.

[0003] The present invention relates generally to the use of N-acetylcysteine ​​amide (NACA) or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropanamide) (diNACA) for the prevention and treatment of radiation dermatitis, radiation damage to the skin, skin lightening, skin whitening, or to improve skin health. [Background technology]

[0004] Radiation dermatitis is one of the most common adverse events in cancer radiotherapy, with 95% of patients undergoing radiation therapy exhibiting this symptom. Dermatitis not only reduces the quality of life, but also interferes with the implementation of necessary additional radiation therapy. Furthermore, there is no effective drug therapy other than topical steroids and emollient creams. Radiation is thought to damage the skin in two ways: by generating reactive oxygen species after reacting with water in the cell matrix, which in turn causes indirect inflammation. Considering the above facts, the mechanism of action of Nrf2 activators seems suitable to counter the progression of radiation dermatitis (Nakagami et al. Journal of Radiation Research, Vol. 57, No. 5, 2016, pp. 567-571).

[0005] Skin aging is a complex biological phenomenon that includes two independent processes that can be clearly distinguished clinically and biologically: intrinsic aging and extrinsic aging. Extrinsic aging (including photoaging) is the result of exposure to outdoor elements, mainly ultraviolet (UV) radiation. Photoaged skin exhibits various age-related clinical changes such as deep wrinkles, yellowish discoloration, and irregular pigmentation. In recent years, it has become clear that the process of skin aging caused by UV exposure involves excessive production of reactive oxygen species (ROS) in cells. ROS have a paradoxical effect on melanocytes, not only promoting depigmentation in the skin but also increasing pigmentation. UVB-induced H2O2 in keratinocytes causes melanocyte degeneration in the skin of vitiligo patients. In contrast, NO· induces melanogenesis by increasing the amount of tyrosinase and tyrosinase-related proteins. ROS-associated melanogenesis is suppressed by antioxidant treatment. The production of NO· through stabilization of NO synthase contributes in part to the inhibition of melanogenesis by ascorbic acid. N-acetylcysteine ​​(a precursor of glutathione) inhibits the induction of alpha-melanocyte-stimulating hormone by UVB irradiation (Watanabe F; Hashizume E; Chan GP; Kamimura A. Skin-whitening and skin-condition-improving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial. Clin Cosmetic Inv Dermatol. 2014;7:267-274).

[0006] Glutathione, a tripeptide of cysteine, glycine, and glutamic acid, is the body's major antioxidant and plays a key role in maintaining intracellular thiol status and detoxification. Glutathione exists in both reduced (GSH) and oxidized (GSSG) states. Although GSH is present in the body, most of the glutathione pool in the body is in the reduced form. GSH exerts its antioxidant activity by acting as a scavenger of free radicals during the reductive detoxification of hydrogen peroxide and lipid peroxides. In mammalian cells, GSH serves as an electron donor. During electron donation, it is converted to GSSG by glutathione peroxidase, but is reduced to GSH by glutathione reductase in the presence of nicotinamide adenine dinucleotide phosphate. GSH has a wide variety of physiological effects. Importantly, GSH inhibits melanogenesis by suppressing the activity of tyrosinase, and oral administration of GSH reduces melanin production in the skin in humans. GSH in aqueous solution is highly unstable and easily decomposed. For this reason, unlike oral formulations, no investigations have been reported on the skin whitening effect of GSH in topical formulations. In contrast, GSSG is less decomposed in aqueous solution, making it suitable for use in liquid form, but the skin whitening effect of topical GSSG is unknown. In a study of 30 healthy adult women aged 30 to 50 years, Watanabe et al. (2014) found that topical GSSG was safe and effective for whitening and reducing skin irritation. It has been shown to improve skin condition. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Nakagami et al. Journal of Radiation Research, Vol. 57, No. 5, 2016, pp. 567-571 [Non-Patent Document 2] Watanabe F; Hashizume E; Chan GP; Kamimura A. Skin-whitening and skin-condition-improving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial. Clin Cosmetic Inv Dermatol. 2014;7:267-274 Summary of the Invention [Means for solving the problem]

[0008] According to one embodiment, the present invention provides a method for the use of N-acetylcysteine ​​(NAC), N-acetylcysteine ​​amide (NACA), or diNACA for the prevention and / or treatment of at least one of radiation dermatitis, radiation damage to the skin, skin lightening, whitening, or for improving skin health in an animal or human, comprising administering to the animal or human a therapeutically effective amount of N-acetylcysteine ​​(NAC), N-acetylcysteine ​​amide (NACA), or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropanamide) (diNACA). In one aspect, the NAC, NACA, or diNACA is provided in or with a pharma- ceutically acceptable carrier. In another aspect, the NACA is administered intraocularly, subretinal, intravitreal, orally, intravenously, intramuscularly, topically, sublingually, by injection into the skin, or rectally. In another embodiment, the NAC, NACA, or diNACA is administered at a daily dose of about 0.5-150 mg / Kg. In another embodiment, the NAC, NACA, or diNACA is administered two or three times daily. In another embodiment, the NAC, NACA, or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. In another embodiment, the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In another embodiment, the dosage for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per administration. In another embodiment, the NACA is formulated as a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, In one embodiment, the NACA is administered prophylactically to prevent and / or treat radiation dermatitis, for skin lightening, whitening, or to improve skin health. In another embodiment, the animal is a human. In one embodiment, the method further comprises adding NACA or diNACA to the formulation to prevent damage to the skin from radiation from sun exposure. In one embodiment, the method further comprises adding NACA or diNACA to the formulation to prevent contact damage caused by exposure to biological weapons, chemical burns, thermal burns, and friction. In one embodiment, the method further comprises adding NACA or diNACA to the formulation to treat xeroderma pigmentosum. In one embodiment, the method further comprises adding NACA or diNACA to the formulation to treat other skin disorders caused by oxidative stress.

[0009] According to another embodiment, the present invention includes a method for preventing and / or treating radiation dermatitis, skin lightening, whitening, or improving skin health, comprising the steps of identifying a human in need of preventing and / or treating radiation dermatitis, skin lightening, whitening, or improving skin health, and administering to the human a therapeutically effective amount of NAC, NACA, or diNACA sufficient to prevent and / or treat radiation dermatitis, skin lightening, whitening, or improving skin health. In one aspect, the NAC, NACA, or diNACA is provided in or with a pharma- ceutically acceptable carrier. In another aspect, the NAC, NACA, or diNACA is administered intraocularly, subretinal, intravitreal, orally, intravenously, intramuscularly, topically, sublingually, cutaneously, subcutaneously, by injection into the skin, or rectally. In another aspect, the NAC, NACA, or diNACA is administered at a daily dose of about 0.5-150 mg / Kg. In another embodiment, NAC, NACA, or diNACA is administered two or three times a day. In another embodiment, NAC, NACA, or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. In another embodiment, the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In another embodiment, the dosage for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per administration. In another embodiment, the NAC, NACA, or diNACA is delivered orally via mini-tablets, capsules, tablets, effervescent, dual release, mixed release, sachets, powders, or liquids.In another aspect, NAC, NACA, or diNACA are used to prevent and / or treat radiation dermatitis. It is administered prophylactically for skin lightening, whitening, or to improve skin health. In one aspect, the method further comprises adding NACA or diNACA to the formulation to prevent damage to the skin due to radiation from sun exposure. In one aspect, the method further comprises adding NACA or diNACA to the formulation to prevent exposure to biological weapons, chemical burns, thermal burns, and contact injuries due to friction. In one aspect, the method further comprises adding NACA or diNACA to the formulation to treat xeroderma pigmentosum. In one aspect, the method further comprises adding NACA or diNACA to the formulation to treat other skin disorders caused by oxidative stress. [Brief description of the drawings]

[0010] For a more complete understanding of the features and advantages of the present invention, reference should now be made to the accompanying drawings, in which: See here for a detailed description. [Figure 1] FIG. 1 shows that GSSG, NPI-001 (NACA), and NPI2 (diNACA) treatment reduced RHE pigmentation. [Diagram 2] FIG. 1 shows that GSSG, NPI-001 (NACA), and NPI2 (diNACA) treatment reduced melanin extraction. [Diagram 3] FIG. 1 shows that NPI-001 (NACA) and (diNACA) increased the production levels of GSSG in human skin exposed to UVA-induced oxidative skin damage. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Although the making and using of various embodiments of the invention are discussed in detail below, it should be understood that the invention provides many applicable inventive concepts that can be implemented in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not limit the scope of the invention.

[0012] N-acetylcysteine, also known as 2-acetamido-3-sulfanylpropionic acid or NAC, has the structure:

[0013] [ka]

[0014] has.

[0015] N-acetyl-L-cysteine ​​amide (NACA), the amide form of N-acetyl-L-cysteine ​​(NAC), also known as (R)-2-(acetylamino)-3-mercapto-propanamide, N-acetyl-L-cysteine ​​amide, or acetylcysteine ​​amide, acts as a carrier for NAC and has the structure:

[0016] [ka]

[0017] has.

[0018] (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropanamide) (diNACA) is a dimeric form of N-acetyl-L-cysteine ​​amide that acts as a carrier for NAC or cysteine ​​and has the structure:

[0019] [ka]

[0020] has.

[0021] Glutathione (GSH) is a tripeptide, cL-glutamyl-L-cysteinyl-glycine, found in all mammalian tissues. It has several important functions, such as detoxifying electrophiles, scavenging ROS, maintaining the thiol status of proteins, and regenerating the reduced forms of vitamins C and E. As the major non-protein thiol in mammalian cells, GSH is essential for maintaining intracellular redox balance and the essential thiol status of proteins. It is also required for the function of several antioxidant enzymes, such as glutathione peroxidase.

[0022] Intracellular GSH levels are determined by the balance between production and loss. Production occurs through de novo synthesis and regeneration of GSH from GSSG by GSSG reductase. In general, the GSSG reductase system contains sufficient amounts of GSH to maintain all intracellular GSH in a reduced state. Since GSH has limited capacity, enhancing this pathway will hardly increase it. The main cause of intracellular GSH loss is transport out of the cell. While intracellular GSH levels range from 1 to 8 mM, extracellular levels are only a few μM, and this large concentration gradient essentially prevents GSH from being transported into the cell, where it is rapidly degraded by γ-glutamyltranspeptidase once transported out of the cell. Inhibition of GSH transporters could theoretically increase intracellular GSH levels, but this could be problematic because the transporters are not GSH specific and their inhibition could lead to imbalances of other amino acids and peptides. Thus, intracellular GSH levels are mainly regulated by changes in synthesis.

[0023] GSH is synthesized in the cytosol of almost all cells by two ATP-requiring enzymatic steps: L-glutamate + L-cysteine ​​+ ATP [→] γ-glutamyl-L-cysteine ​​+ ADP + Pi and γ-glutamyl-L-cysteine ​​+ L-glycine + ATP [→] GSH + ADP + Pi. The first reaction is rate-limiting and is catalyzed by glutamate cysteine ​​ligase (GCL, EC 6.3.2.2). GCL is composed of a 73 Kd heavy catalytic subunit (GCLC) and a 30 Kd modifier subunit (GCLM) that are encoded by different genes. GCCL is regulated by non-allosteric competitive inhibition of GSH (Ki=2.3 mM) and the availability of L-cysteine. The apparent Km of GLC for glutamate is 1.8 mM, which is approximately 10 times higher than the intracellular glutamate concentration and therefore not limiting for glutamate, whereas the Km for cysteine ​​is 0.1-0.3 mM, which is closer to the intracellular concentration. The second reaction is catalyzed by the 118 Kd GSH synthase (GS, EC 6.3.2.3), which is composed of two identical subunits. GS does not appear to be important in regulating GSH synthesis under normal conditions, but may play a role under stress conditions, since in response to surgical trauma, GSH levels and GS activity were reduced, whereas GCL activity was unchanged. Furthermore, increased expression of both GCLC and GS caused an increase in GSH levels, compared with increased expression of GCLC alone. To maximize the effect of increased synthase, it is necessary to achieve increased cysteine ​​levels. In cultured neurons, 90% of cysteine ​​uptake occurs via the sodium-dependent excitatory amino acid transporter (EAAT) system. There are five EAATs, and cysteine ​​uptake by neurons occurs primarily through EAAT3, more commonly known as excitatory amino acid carrier-1 (EAAC1). Under normal circumstances, most EAAC1 resides in the ER and translocates to the plasma membrane only when activated. This translocation is negatively regulated by glutamate transporter-associated protein 3-18 (GTRAP3-18), and inhibition of GTRAP3-18 increased GSH levels in neurons.Thus, cysteine ​​internalization represents an obstacle to GSH synthesis, but fortunately can be bypassed by N-acetylcysteine ​​(NAC), which readily enters cells even in the absence of activated EAAC1. Systemically administered NAC enters the CNS and increases GSH levels, providing benefit in neurodegenerative disorders where oxidative stress is an important part of the pathology.

[0024] All intracellular organelles, including cytoplasm, mitochondria, and nucleus, must be protected from oxidative damage. Previously, the present inventors performed gene transfer of enzymes that detoxify reactive oxygen species, but this approach requires the expression of two enzymes in the cytoplasm and two enzymes in the mitochondria. In contrast, in the present invention, the expression of only two enzymes in the cytosol results in the protection of all intracellular organelles, since GSH can diffuse everywhere throughout the cell.

[0025] NAC is used to treat acetaminophen overdose with a loading dose of 140 mg / kg, followed by 17 doses of 70 mg / kg every 4 hours starting 4 hours after the loading dose. In clinical studies, NAC has been administered orally at 400-1000 mg once daily and 200-600 mg three times daily. However, after a single oral dose of 600 mg in humans, NAC is rapidly absorbed and subsequently rapidly cleared. The plasma half-life of NAC has been reported to be 2.5 hours. and NAC is undetectable 10-12 hours after administration. During absorption, NAC is rapidly metabolized to cysteine, the direct precursor of glutathione. According to one embodiment, the present invention provides a method for preventing, ameliorating, or treating a disease or condition associated with oxidative stress in a subject, comprising administering a therapeutically effective amount of NACA to increase the amount of glutathione expressed in the subject's tissue.

[0026] As used herein, "active oxygen species" or "reactive oxygen species" refers to "Reactive oxygen species" refers to the oxygen species that is produced by the transfer of one or two electrons to superoxide. anion of the form O2" or of the formula O 2- " or compounds containing an O--O single bond, such as hydrogen peroxide and lipid peroxides. Such superoxides and peroxides are highly reactive and can cause damage to cellular components including proteins, nucleic acids, and lipids.

[0027] As used herein, the term "agent" refers to a compound that is therapeutically active or potentially therapeutically active, e.g., an antioxidant. An agent may be a previously known or unknown compound. As used herein, an agent is typically a compound that is not cell-based, but an agent can include biological therapeutics, e.g., peptide or nucleic acid therapeutics, e.g., siRNA, shRNA, cytokines, antibodies, and the like.

[0028] As used herein, the term "amelioration" or "treatment" is understood to mean alleviating or reducing at least one sign, symptom, indicator, or effect of a particular disease or condition. For example, preventing, ameliorating, or treating radiation dermatitis, skin lightening, whitening, or improving skin health means reducing, delaying, or eliminating one or more signs or symptoms of radiation dermatitis, skin lightening, whitening, or improving skin health, including, but not limited to, improved skin health, reduction in radiation-induced dermatitis, skin lightening, and / or whitening, or other clinically accepted indicators of a disease state or progression. Amelioration and treatment may require more than one administration of an agent, alone or in combination with other therapeutic agents and interventions. Amelioration or treatment does not necessarily cure the disease or condition.

[0029] As used herein, the term "antioxidant" refers to a molecule that slows down or prevents the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidant. Such reactions can be facilitated by the production of superoxide anions or peroxides. Oxidation reactions can generate free radicals, which initiate chain reactions that damage cells. Antioxidants terminate these chain reactions by scavenging free radical intermediates and inhibit other oxidative reactions by oxidizing themselves. As a result, antioxidants are often reducing agents, such as thiols, ascorbic acid, or polyphenols. Antioxidants include, but are not limited to, α-tocopherol, ascorbic acid, Mn(III) tetrakis(4-benzoic acid)porphyrin, α-lipoic acid, and n-acetylglucosamine. Contains lucisteine.

[0030] As used herein, the term "effective amount" or "effective dose" refers to an amount of an agent that produces an intended pharmacological, therapeutic, or prophylactic result. A pharmacologically effective amount results in the amelioration of one or more signs or symptoms of a disease or condition or the progression of a disease or condition, causing regression of a disease or condition. For example, a therapeutically effective amount preferably reduces visual acuity loss, total visual acuity loss, visual field loss by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 10 ... By "therapeutic agent" is meant an amount of therapeutic agent that reduces the level of inflammatory bowel disease by 80%, at least 85%, at least 90%, at least 95% or more over a defined period of time, e.g., 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years or more. Two or more administrations may be required to provide an effective dose.

[0031] As used herein, the terms "effective" and "effectiveness" include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a treatment to produce a desired biological effect in a patient. Physiological safety refers to the absence of toxicity or other adverse effects at the cellular, organ and / or organism level resulting from administration of the treatment. On the other hand, the term "ineffective" refers to a level of physiological effects (often called side effects) that are ineffective, at least in an unstratified population. The absence of adverse effects indicates that the treatment does not provide sufficient pharmacological efficacy to be therapeutically useful. (Such treatments may be ineffective in a subpopulation that can be identified by the expression profile(s).) "Low efficacy" means that the treatment produces a therapeutically significantly lower level of pharmacological efficacy and / or a therapeutically higher level of adverse physiological effects, e.g., high hepatotoxicity.

[0032] Thus, in the context of administration of a drug, a drug that is "effective against" a disease or condition indicates that administration in a clinically relevant form will produce a beneficial effect for at least a statistically significant percentage of patients, such as amelioration of symptoms, cure, reduction of disease signs or symptoms, extension of life span, improvement in quality of life, or other effect generally recognized as favorable by physicians skilled in the treatment of a particular type of disease or condition.

[0033] As used herein, the term "peroxidase" or "peroxide metabolizing enzyme" refers to a large family of enzymes that typically catalyze reactions of the following form:

[0034] ROOR1+electron donor(2e-)+2H+→ROH+R1OH For many of these enzymes, the substrate of choice is hydrogen peroxide, where each R is H, while others are more active with organic hydroperoxides such as lipid peroxides. Peroxidases can contain a heme cofactor or a redox-active cysteine ​​or selenocysteine ​​residue in the active site.

[0035] As used herein, the phrase "pharmaceutically acceptable carrier" is art-recognized and includes any pharma-ceutically acceptable substance, composition, or vehicle suitable for administering the compounds of the present invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating substances associated with carrying or transporting the subject agent from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. For example, pharma-ceutically acceptable carriers for administration of cells are typically carriers acceptable for delivery by injection and do not include agents such as surfactants or other compounds that may damage the cells being delivered. Some examples of substances which may serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, celluloses and derivatives thereof such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, buffers such as agar-agar, magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions and other non-toxic compatible substances used in pharmaceutical preparations, particularly ophthalmic solutions. Preferred for intravenous delivery include phosphate buffered saline solutions.

[0036] Wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0037] Examples of pharma- ceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0038] The formulations of the present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, intramuscular, intraperitoneal, intraocular, intravitreal, subretinal and / or other parenteral administration routes. The particular route of administration will depend, inter alia, on the particular cells to be targeted. The formulations may be conveniently presented in unit dosage form and may be prepared by any method well known in the pharmaceutical industry. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

[0039] As used herein, "plurality" is understood to mean two or more. For example, plurality means at least 2, 3, 4, 5, or more.

[0040] As used herein, the term "polypeptide" or "peptide" is understood to mean two or more independently selected natural or unnatural amino acids linked by a covalent bond (e.g., a peptide bond). A peptide can include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more natural or unnatural amino acids linked by peptide bonds. Polypeptides as described herein include full-length proteins (e.g., fully processed proteins) as well as shorter amino acid sequences (e.g., fragments of naturally occurring proteins or synthetic polypeptide fragments).

[0041] As used herein, the term "small molecule" refers to a compound, typically an organic compound, having a molecular weight of less than about 1500 Da, 1000 Da, 750 Da, or 500 Da. In one embodiment, small molecules do not include polypeptides or nucleic acids that contain only naturally occurring amino acids and / or nucleotides.

[0042] As used herein, the term "subject" refers to a living organism, particularly a human. In certain embodiments, the living organism is an animal, and in certain preferred embodiments, the subject is a mammal, and in certain embodiments, the subject is a domesticated mammal or a primate, including a non-human primate. Examples of subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, goats, and sheep. A human subject may also be referred to as a subject or a patient.

[0043] As used herein, "superoxide dismutase" is understood to be an enzyme that dismutates superoxide into oxygen and hydrogen peroxide. Examples include, but are not limited to, SOD1, SOD2, and SOD3. Sod1 and SOD3 are two isoforms of Cu-Zn-containing superoxide dismutase enzymes present in mammals. Cu-Zn-SOD or SOD1 is found in the intracellular space, while extracellular SOD (ECSOD or SOD3) is found primarily in the extracellular matrix of most tissues.

[0044] As used herein, the term "therapeutically effective amount" means an amount of an agent that, upon single or multiple administration to a cell or subject, is effective to prolong survival in a patient with such disorder, to alleviate one or more signs or symptoms of the disorder, to prevent or delay beyond that expected in the absence of such treatment, and the like.

[0045] A drug or other therapeutic intervention can be administered to a subject alone or in combination with one or more additional therapeutic agents or therapeutic interventions as a pharmaceutical composition or therapeutic treatment mixed with conventional excipients, e.g., pharma- ceutically acceptable carriers.

[0046] The pharmaceutical agents may be conveniently administered in unit dosage form, e.g., as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1985), and may be prepared by any of the methods well known in the pharmaceutical art. Formulations for parenteral administration may contain common excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes, and the like. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyethylene-polyoxypropylene copolymers may be useful excipients for controlling the release of certain drugs.

[0047] The present invention relates to the use of NACA for skin lightening and / or whitening, to improve skin health and / or to prevent, reduce or treat radiation-induced dermatitis. In one embodiment, the present invention includes a method for the use of N-acetylcysteinamide (NACA) or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropanamide) (diNACA) for the prevention and treatment of radiation dermatitis in a human, comprising administering to the human a therapeutically effective amount of NACA. In some embodiments, NACA is provided in or with a pharma-ceutically acceptable carrier. In other embodiments, NACA is administered intraocularly, subretinaly, intravitreally, orally, intravenously, intramuscularly, topically, sublingually or rectally.

[0048] It is understood that the actual preferred amount of active compound to be used in a given therapy will vary, for example, with the particular compound employed, the particular composition formulated, the mode of administration, and the characteristics of the subject, such as the subject's species, sex, weight, general health, and age. Optimal administration rates for a given method of administration can be readily ascertained by one of ordinary skill in the art using conventional dosage determination tests performed in conjunction with the above guidelines.

[0049] Ranges specified herein are understood to be a shorthand for listing all values ​​within the range.

[0050] As used herein, embodiments of the present invention are defined to include pharma- ceutically acceptable derivatives thereof. "Pharmaceutically acceptable derivative" refers to any pharmaceutical salt, ester, salt of an ester, or other derivative of a compound of the present invention that can provide (directly or indirectly) a compound of the present invention upon administration to a recipient. Particularly preferred derivatives are those that increase the bioavailability of a compound of the present invention when such a compound is administered to a mammal (e.g., by allowing an orally administered compound to be more easily absorbed into the blood, increasing the serum stability of the compound, or decreasing the clearance rate of the compound), or enhance the delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) compared to the parent species. Derivatives include derivatives in which groups that enhance aqueous solubility or active transport across the intestinal membrane are added to the structures of the formulas described herein.

[0051] Embodiments of the present invention may be modified by adding appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may be used to enhance the functionality of a given biological category. These include those that increase biological penetration into the cellular compartment (e.g., blood, lymphatic system, central nervous system), those that increase oral availability, those that increase solubility to allow administration by injection, those that alter metabolism, and those that alter excretion rate. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharma- ceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecyl sulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, metasulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate, and undecanoate. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium, and N-(alkyl)4 + Salts are included. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[0052] Embodiments of the invention can be administered, for example, by injection, intraocularly, intravitreal, subretinal, intravenous, intraarterial, subdermal, intramuscular, or subcutaneously; or orally, buccal, nasal, transmucosal, by catheter directly to the diseased organ, topically, or in an ophthalmic preparation, in dosages ranging from about 0.001 to about 100 mg per kg of body weight, or more preferably 0.5 to 10 mg per kg of body weight according to the requirements of the particular drug. It is understood that when a compound is delivered directly to the eye, considerations such as body weight are less relevant to the dose.

[0053] The frequency of administration depends on the agent administered, the progression of the disease or condition in the subject, and other considerations known to those skilled in the art. For example, a composition delivered to the eye has different pharmacokinetic and pharmacodynamic considerations than a composition delivered to an intraocular compartment, for example, the clearance in the subretinal space is very low. Thus, administration may be monthly, once every three months, once every six months, once a year, once every five years, or less frequently. If systemic administration of an antioxidant is performed in combination with administration of an expression construct to the subretinal space, it is expected that the administration frequency of the antioxidant will be more frequent than that of the expression construct, for example, once or twice a day or more, once or twice a week or more.

[0054] Figure 1. GSSG, NPI-001, and diNACA treatment reduced RHE pigmentation.

[0055] Figure 2. GSSG, NPI-001 and diNACA treatments reduced melanin extraction. Melanin (mg / ml) was extracted from RHE after 0, 7 and 14 days of treatment. Error bars represent standard deviation. N-4 is the number of samples per treatment. Statistical analysis was performed by one-way ANOVA with Dunnett's multiple comparisons compared to untreated controls on the day of collection. (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001).

[0056] Figure 3. NPI-001 and diNACA increased thiol production levels in human skin exposed to UVA-induced oxidative skin damage.

[0057] Reconstituted Human Epithelium (RHE) model to evaluate the ability of NPI-001 and NPI2 to reduce pigmentation in skin:

[0058] Reconstructed human epithelium (RHE) containing melanocytes from African-American origin was obtained from MatTek (MelanoDerm™ Catalog No. MEL-300B). The medium was reapplied every other day and the basal treatment was applied and the cells were cultured for 14 days. RHEs at days 0, 7, and 14 were photographed and frozen for melanin extraction.

[0059] After harvesting RHE on day 14, cultures were soaked in 1% sodium bicarbonate for 30 min, transferred to Eppendorf tubes containing 500 μl of Solvable™ reagent, and incubated overnight at 60°C. A synthetic melanin standard curve was generated with two-fold dilutions of Solvable™ reagent from 0.5 to 0.0039 mg / ml. 200 μl of extracted melanin was transferred to a 96-well plate and quantified by reading at 490 nm. In summary:

[0060] By both visual scoring and melanin extraction, NPI-001 (NACA 10 mM) was significantly more successful in inhibiting pigmentation in MelanoDerm™ RHE cultures over 14 days than a regimen of 2% GSSG and diNACA 10 mM treatment.

[0061] Treatment with GSSG, NPI-001 (NACA 10 mM), and diNACA (10 mM) significantly inhibited pigmentation compared to untreated control samples on the corresponding days.

[0062] Effects of NPI-001 (NACA 10 mM) and diNACA (10 mM) on human skin explants exposed to radiation (UVA).

[0063] Thinly melanized human skin grafts (single donor, n=6) in transwells were exposed to UVA radiation (24 J / cm2) with or without topical application of NPI-001 and diNACA (NPI-001 16.2 mg / ml; diNACA 32.2 mg / ml) at a final concentration of 100 mM, dissolved or suspended in 10% DMSO / water, at approximately 18 μl / cm2 (approximately 6 μl / 0.33 cm2) 30 min prior to UVA exposure (24 J / cm2 exposure). Tissues were harvested 24 h after UVA exposure, cut in half, heat separated into epidermal and dermal layers, weighed, and the dermal and epidermal layers were immediately immersed in derivatization solution and analyzed by LCMS. Both NPI-001 and diNACA treatment 30 min prior to UVA caused a statistically significant increase in dermal GSSG.

[0064] Dosages can be determined in relation to radiation dermatitis, radiation damage to the skin, skin lightening, whitening, or improving skin health. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. A typical preparation contains about 1% to about 95% active compound (w / w). Alternatively, such preparations contain about 20% to about 80% active compound. Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptom, the patient's disposition to the disease, condition or symptom, and the judgment of the attending physician.

[0065] In another aspect, NACA or diNACA can be useful agents in topical products, such as sunscreen products, thereby acting to protect skin cells from radiation damage. NACA or diNACA could be used alone or in combination with each other or other agents in sunscreen products.

[0066] In another aspect, NACA or diNACA may be useful agents for treating xeroderma pigmentosum or protecting patients with xeroderma pigmentosum from skin damage caused by exposure to sunlight or other radiation.

[0067] In another aspect, NACA or diNACA may be useful in preventing or treating the effects on the skin of agents that cause skin damage due to oxidative stress in the skin, including but not limited to biological warfare agents, chemical burns, thermal burns, contact injuries caused by friction, contact dermatitis, hypersensitivity reactions, and skin wrinkling and dehydration.

[0068] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. The suspension may contain suitable dispersing or wetting agents, such as TWEEN ( The sterile injectable preparations may also be formulated according to techniques known in the art using a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils have been used for some time as solvents or suspending media. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially their polyoxyethylated varieties, are useful in injectable preparations, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants or carboxymethylcellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. Other commonly used surfactants such as TWEEN® or SPAN® and / or other similar emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharma- ceutically acceptable solid, liquid or other dosage forms may also be used for the formulation.

[0069] In one or more embodiments, the NAC, NACA, or diNACA is administered at a daily dose of about 0.5-150 mg / Kg. In other embodiments, the NACA is administered two or three times daily. In another aspect, the NAC, NACA, or diNACA is administered with a second active agent selected from ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, and the like; an oil-soluble antioxidant, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; a metal chelator, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0070] In some embodiments, the dose of NAC, NACA, or diNACA for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In other aspects, the dose for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 102, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per administration. In other aspects, the NAC, NACA, or diNACA is delivered orally via mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid. In another embodiment, NACA is administered prophylactically to improve skin health and / or to prevent, reduce, or treat radiation-induced dermatitis, for skin lightening, and / or whitening.

[0071] In another embodiment, the present invention provides a method for treating radiation-induced dermatitis, skin lightening and / or whitening, and improving skin health, comprising the steps of identifying a human in need of treatment for age-related macular degeneration, and administering to the human a therapeutically effective amount of NAC, NACA, or diNACA sufficient to improve skin health and / or prevent, reduce, or treat radiation-induced dermatitis, skin lightening, and / or whitening. It will be appreciated that, as with the other embodiments defined above, the NAC, NACA, or diNACA is administered in a daily dose of about 0.5-150 mg / Kg. In another embodiment, the NAC, NACA, or diNACA is administered two or three times daily. In another embodiment, the NACA is administered with a second active agent as disclosed above.

[0072] In another embodiment, the dose of NAC, NACA, or diNACA for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In another embodiment, the dose for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 102, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per administration. In another embodiment, the NAC, NACA, or diNACA is delivered orally via mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid. In another embodiment, NACA is administered prophylactically to improve skin health and / or to prevent, reduce, or treat radiation-induced dermatitis, for skin lightening, and / or whitening.

[0073] As used herein, "susceptible to" or "prone to" or "predisposed to" a particular disease or condition, etc., means an individual who is more likely to develop the disease or condition than the general population based on genetic, environmental, health and / or other risk factors. The increased likelihood of developing the disease may be about a 10%, 20%, 50%, 100%, 150%, 200% or greater increase.

[0074] According to one embodiment, the present invention provides a method for the use of N-acetylcysteine ​​(NAC), N-acetylcysteinamide (NACA), or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropanamide) (diNACA) for the prevention and / or treatment of at least one of radiation dermatitis, radiation-induced skin damage, skin lightening, whitening, or improving skin health in an animal or human, comprising, consisting essentially of, or consisting of administering to an animal or human a therapeutically effective amount of N-acetylcysteinamide NAC, NACA, or diNACA. In one aspect, the NAC, NACA, or diNACA is provided in or with a pharma- ceutically acceptable carrier. In another aspect, the NACA is administered intraocularly, subretinal, intravitreal, orally, intravenously, intramuscularly, topically, sublingually, by injection into the skin, or rectally. In another embodiment, the NAC, NACA, or diNACA is administered at a daily dose of about 0.5-150 mg / Kg. In another embodiment, the NAC, NACA, or diNACA is administered two or three times daily. In another embodiment, the NAC, NACA, or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. In another embodiment, the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In another embodiment, the dosage for administration is 0.1 to 0.25, 0.1 to 0.4, 0.35 to 0.5, 0.5 to 1, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 2.5, 2.5 to 3.5, 4 to 6, 5 to 8, 6 to 9, or 7 to 10 grams per administration.In another embodiment, the NACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid formulation. In another embodiment, the NACA prevents and / or treats radiation dermatitis. The composition is administered prophylactically to improve skin health, for skin lightening, whitening, or to improve skin health. In another aspect, the animal is a human. In one aspect, the method further comprises adding an external agent to protect skin cells from damage caused by radiation. In one aspect, the method further comprises adding an active agent for the treatment of xeroderma pigmentosum, or an active agent for protection to protect the skin of a patient with xeroderma pigmentosum from skin damage caused by exposure to sunlight or other radiation. In one aspect, the method further comprises adding an active agent for the treatment of biological warfare agents, chemical burns, thermal burns, contact injuries caused by friction, contact dermatitis, hypersensitivity reactions, and skin wrinkles, and dehydration.

[0075] According to another embodiment, the present invention includes a method for preventing and / or treating radiation dermatitis, skin lightening, whitening, or improving skin health, comprising, consisting essentially of, or consisting of the steps of identifying a human in need of preventing and / or treating radiation dermatitis, skin lightening, whitening, or improving skin health, and administering to the human a therapeutically effective amount of NAC, NACA, or diNACA sufficient to prevent and / or treat radiation dermatitis, skin lightening, whitening, or improving skin health. In one aspect, the NAC, NACA, or diNACA is provided in or with a pharma- ceutically acceptable carrier. In another aspect, the NAC, NACA, or diNACA is administered intraocularly, subretinal, intravitreal, orally, intravenously, intramuscularly, topically, sublingually, cutaneously, subcutaneously, by injection into the skin, or rectally. In another aspect, the NAC, NACA, or diNACA is administered at a daily dose of about 0.5-150 mg / Kg. In another embodiment, NAC, NACA, or diNACA is administered two or three times a day. In another embodiment, NAC, NACA, or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. In another embodiment, the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In another embodiment, the dosage for administration is 0.1 to 0.25, 0.1 to 0.4, 0.35 to 0.5, 0.5 to 1, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 2.5, 2.5 to 3.5, 4 to 6, 5 to 8, 6 to 9, or 7 to 10 grams per administration.In another embodiment, the NAC, NACA, or diNACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid formulation. In another embodiment, the NAC, NACA, or diNACA is administered orally as a skin lightening agent to prevent and / or treat radiation dermatitis. The composition is administered prophylactically to whiten, whiten, or improve skin health. In one aspect, the method further comprises adding an external agent to protect skin cells from damage caused by radiation. In one aspect, the method further comprises adding an active agent for the treatment of xeroderma pigmentosum or an active agent for protection to protect the skin of a patient with xeroderma pigmentosum from skin damage caused by exposure to sunlight or other radiation. In one aspect, the method further comprises adding an active agent for the treatment of biological warfare agents, chemical burns, thermal burns, contact injuries caused by friction, contact dermatitis, hypersensitivity reactions, and skin wrinkling, and dehydration.

[0076] It is contemplated that any embodiment discussed herein can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Further, a composition of the invention can be used to practice a method of the invention.

[0077] It will be understood that the specific embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the invention and are covered by the claims.

[0078] All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0079] When used in conjunction with the term "comprising" in the claims and / or specification, the use of the words "a" or "an" may mean "one," but it should not be construed as meaning "one or more," "at least one," or "any." and "one or more than one." Use of the term "or" in the claims is used to mean "and / or," even if the disclosure supports a definition that means only alternatives and "and / or," unless expressly stated to mean only alternatives or that the alternatives are mutually exclusive. Throughout this specification, the term "about" is used to indicate that a value includes the inherent variation of error for the device, method being employed to determine the value, or the variation that exists among the study subjects.

[0080] As used in this specification and the claims, "comprising" (and any form of "comprising", such as "comprise" and "comprises") "having" (and "have" and "has") any form of "having"); "including" (and "includes" and "including" or "containing" (as well as "contains" and "contain") The term "containing" or "containing any form thereof is inclusive or open ended and does not exclude additional, unrecited elements or method steps. In any of the embodiments of the compositions and methods defined herein, "comprising" can be substituted with "consisting essentially of" or "consisting of." As used herein, "consisting essentially of" is used interchangeably with "comprising" or "consisting of." The phrase "consisting of" requires the specified integers or steps as well as those that do not materially affect the nature or function of the claimed invention. As used herein, the term "consisting of" is used to indicate the presence of only a recited integer (e.g., a feature, element, characteristic, property, method / method step, or limitation) or group of integers (e.g., a feature, element, characteristic, property, method / method step, or limitation).

[0081] As used herein, the term "or combinations thereof" means A term such as "A, B, C, or a combination thereof" refers to all sequences and combinations of the items listed before the term. For example, "A, B, C, or a combination thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, if order is important in the particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Following this example, combinations containing repeats of one or more items or terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are expressly included. One of skill in the art will understand that there is typically no limit to the number of items or terms in any combination, unless otherwise clear from the context.

[0082] As used herein, without limitation, approximation terms such as "about," "substantial," or "substantially" are intended to be modified as such. The conditions described herein are not necessarily absolute or complete, but generally refer to conditions that would be justified for a person skilled in the art to specify the conditions as presented. The range of variation described depends on the magnitude of the change that can occur, and is within the range that a person skilled in the art can still recognize that the modified feature still has the necessary characteristics and capabilities of the unmodified feature. Generally, but depending on the above considerations, the terms may be modified by approximation words such as "about". The numerical values ​​given herein may vary from the stated value by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12, or 15%.

[0083] Furthermore, the headings of the sections of this specification are provided for consistency with the suggestions of 37 CFR 1.77 or to provide other organizational clues. These headings are not intended to limit or characterize the invention described in any claim that may arise from this disclosure. Specifically, by way of example, even if a heading refers to a "technical field," such claims should not be limited by language intended to describe the so-called technical field under that heading. Furthermore, the description of a technology in a "Background" section should not be construed as an admission that the technology is prior art to any invention in this disclosure. The "Summary" should also not be considered to characterize the invention described in the claims presented. Furthermore, any reference to the singular "invention" in this disclosure should not be used to assert that there is only one novel point in this disclosure. Multiple inventions may be described according to the limitations of multiple claims according to this disclosure, and such claims thus define the invention and equivalents thereof that are protected thereby. In any event, the scope of such claims should be considered on their merits in light of this disclosure, but should not be constrained by the headings set forth herein.

[0084] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. Although the compositions and methods of the present invention have been described with reference to preferred embodiments, those skilled in the art will recognize that changes can be made in the compositions and / or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Claims

1. Identifying a human patient in need of prevention and treatment of radiation dermatitis, or skin lightening, whitening, or skin improvement; and administering to said human patient a therapeutically effective amount of N-acetylcysteine ​​amide (NACA) or diNACA.

1. A method for use of N-acetylcysteine ​​(NAC), N-acetylcysteine ​​amide (NACA), or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropanamide) (diNACA) for the prevention and treatment of at least one of radiation dermatitis, skin lightening, radiation damage to the skin, whitening, or improving skin health in a human subject, comprising:

2. 10. The method of claim 1, wherein NAC, NACA, or diNACA is provided in or with a pharma- ceutically acceptable carrier.

3. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered orally, intravenously, intramuscularly, enterally, intraocularly, subretinal, intravitreal, topically, ophthalmically, sublingually, cutaneously, subcutaneously, or rectally.

4. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered in a daily dose of about 0.5 to 150 mg / Kg.

5. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered two or three times daily.

6. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered with a second active agent.

7. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.

8. 10. The method of claim 1, wherein the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose.

9. 10. The method of claim 1, wherein NAC, NACA, or diNACA is delivered orally via minitablets, capsules, tablets, effervescent, dual release, mixed release, sachets, powder, or liquid.

10. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered prophylactically to prevent and treat radiation dermatitis.

11. A therapeutically effective amount preferably reduces at least one of night vision loss, total vision loss, and visual field loss by at least 10%, at least 15%, at least 20%, at least 25%, or more than 10% relative to untreated control subjects over a defined period selected from at least one of 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years.

2. The method of claim 1, wherein the amount of therapeutic agent reduces the expression level of a vasopressin-releasing hormone (vasopressin) by at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more.

12. 10. The method of claim 1, wherein NAC, NACA, or diNACA is provided in or with a pharma- ceutically acceptable carrier.

13. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered orally, intravenously, intramuscularly, intranasally, enterally, intraocularly, subretinal, intravitreal, topically, sublingually, or rectally.

14. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered in a daily dose of about 0.5 to 150 mg / Kg.

15. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered two or three times daily.

16. 10. The method of claim 1, wherein NAC, NACA, or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.

17. 10. The method of claim 1, wherein the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose.

18. 10. The method of claim 1, wherein NAC, NACA, or diNACA is delivered orally via minitablets, capsules, tablets, effervescent, dual release, mixed release, sachets, powder, or liquid.

19. 2. The method of claim 1, wherein a therapeutically effective amount preferably refers to an amount of a therapeutic agent that reduces total visual acuity loss, visual field loss by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more compared to untreated control subjects over a defined period selected from at least one of 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years.

20. 10. The method of claim 1, further comprising the step of adding NACA or diNACA to the formulation to prevent damage to the skin by radiation from sun exposure.

21. 10. The method of claim 1, further comprising adding NACA or diNACA to the formulation to prevent exposure to biological warfare agents, chemical burns, thermal burns, and contact injuries caused by friction.

22. 10. The method of claim 1, further comprising adding NACA or diNACA to the formulation to treat xeroderma pigmentosum.

23. 10. The method of claim 1, further comprising adding NACA or diNACA to the formulation to treat other skin disorders caused by oxidative stress.

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