Novel compositions for the treatment of inflammation-related disorders

Abstract

Deferoxamine (e.g., DFO B) and, for example, Zn 2+ Or Ga 3+ Disclosed herein are compositions comprising a hydrophilic nonionic surfactant comprising a complex with at least one metal, such as silver or gold or any combination thereof, and a nonionic triblock copolymer comprising polyethylene glycol (PEG) and poloxamer. The surfactant may further comprise a nonionic triblock copolymer consisting of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Also disclosed are procedures for preparing pharmaceutical compositions comprising the complex and said complex or any combination thereof, and methods for using the disclosed compositions and complexes in regulating cytokine levels in a subject, thereby treating inflammation-related disorders.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 468,018, filed on 22 May 2023. The entire disclosure of the application identified in this paragraph is incorporated herein by reference.

[0002] Field of Invention This specification discloses a novel composition comprising a complex of deferoxamine B with zinc or gallium and a hydrophilic nonionic surfactant formulation, wherein the complex can be administered orally, and its use in at least one of the following: modulation of inflammatory and anti-inflammatory cytokines, acting as an antibiotic, and chelation of unstable and redox-active iron both intracellularly and extracellularly. More specifically, the composition is useful for treating conditions associated with inflammation, infection, and iron overload.

[0003] Background reference The following is a list of references that are considered relevant to the background of the subject matter of this disclosure. 1. diabetesatlas.org / 2. Vijan S. Ann Intern Med 2015;163:322. 3. Wensink MJ, et al. Ann Intern Med. 2022 Mar 29;175(5):665-673. 4. Hirsch JD, et al., Am J Manag Care 2017;23:S231-S40. 5. King WMt, et al. Ther Adv Chronic Dis 2014;5:206-11. 6. Standards of Medical Care in Diabetes-2017 Abridged for Primary Care Providers. Clin Diabetes 2017;35:5-26. 7. Fernandez-Real JM, et al., Obesity (Silver Spring) 2016;24:352-8. 8. Fernandez-Real JM, et al., Diabetes Care 2015;38:2169-76. 9. Hansen JB, et al, Acta Physiol (Oxf) 2014;210:717-32. 30 10. Wang X, et al., Rev Endocr Metab Disord 2015;16:15-23. 11. Moreno-Navarrete JM, et al. Sci Rep 2017;7:5305. 12. Moreno-Navarrete JM, et al. Diabetologia 2017;60:915-26. 13. Chirumbolo S, et al. Nutrition 2015;31:1266-74. 14. Andrews M, et al. Nutrition 2015;31:51-7. 15. Lortz S, et al., J Mol Endocrinol 2014;52:301-10. 16. Ashourpour M, et al., Int J Food Sci Nutr 2010;61:316-23. 17. Iannantuoni F, et al., Antioxid Redox Signal 2018. 18. Hansen JB, et al. Cell Metab 2012;16:449-61. 19. MacDonald MJ, et al., FASEB J 1994;8:777-81. 20. Aigner E, et al., J Nutr Biochem 2013;24:112-7. 21. Kulaksiz H, et al., J Endocrinol 2008;197:241-9. 22. Niederau C, et al., Diabetologia 1984;26:441-4. 23. Davis RJ, et al., J Biol Chem 1986;261:8708-11. 24. Ferrannini E. Lancet 2000;355:2181-2. 25. Hiroyuki Tsuchiya, et al., Metabolism. 2013 Jan;62(1):62-9. 26. Szafranska K, et al., Front Physiol. 2021 Sep 13;12:735573. 27. The Tailor DG. et al., Lancet 2002 359, 1612-1615. 28. Petrillo S, et al., Antioxid Redox Signal. 2021 Aug 20;35(6):474-486. 29. Fernandez-Real JM, et al., Diabetes 2002;51:2348-54. 30. Nankivell BJ, et al., Kidney Int 1994;45:1006-13. 31. Redmon JB, et al., Diabetes 1993;42:544-9. 32. Cutler P. Diabetes 1989;38:1207-10. 33. Kaye TB, et al., J Diabetes Complications 1993;7:246-9. 34. Waalen J, et al., Curr Hematol Rep 2006;5:34-40. 35. De Sanctis V, et al., Curr Diabetes Rev 2013;9:332-41. 36. Chevion M. Free Radic Res Commun 1991;12-13 Pt 2:691-6. 37. Karck M, et al., J Thorac Cardiovasc Surg 2001;121:1169-78. 38. Keberle H. Ann N Y Acad Sci 1964;119:758-68. 39. Dumortier G, et al., Pharm Res. 2006 Dec;23(12):2709-28. 40. Wout ZG, et al., J Parenter Sci Technol. Nov-Dec 1992;46(6):192-200. 41 Korolenko TA, et al., Lipids Health Dis. 2016 Jan 22;15:16. 42. Johnston TP. J Pharm Pharmacol. 2010 Dec;62(12):1807-12. 43. Cheluvappa R, et al., Exp Gerontol. 2007 Oct;42(10):1012-9.

[0004] The approval of the above references in this specification should not be construed as meaning that they are in any way relevant to the patentability of the subject matter of this disclosure.

Background Art

[0005] Background of the Invention Diabetes is a very common disease, affecting 537 million adults worldwide (ages 20-79), or one in ten people. This number is projected to rise to 643 million by 2030 and 783 million by 2045. Currently, (according to the latest CDC report) an estimated 50% of people in the United States have either diabetes or prediabetes, with 37.3 million people having diabetes (11.3% of the US population) and 96 million people aged 18 and over having prediabetes (38.0% of the US adult population). The incidence of diabetes is increasing due to the aging of the population and the alarming rise in the prevalence of obesity among adults, children, and young adults. The prevalence of diabetes is projected to reach 783 million by 2045 (1). In 2012, the economic burden of diabetes was estimated at US$245 billion, which included US$176 billion in direct medical costs and US$69 billion in lost productivity (2). By 2021, diabetes had generated at least US$966 billion in medical costs, a 316% increase over the previous 15 years (3).

[0006] Medical care for type 2 diabetes (T2D) (primarily its symptoms) and its complications has clearly improved. Nevertheless, complications remain fairly common, and the disease usually worsens over time. Diabetes is one of the leading causes of death, vision loss, amputation, and end-stage renal failure in the United States. In addition, it is a substantial risk factor for atherosclerotic disease, which is a major cause of morbidity, mortality, and expenditure in diabetic patients. Generally, a classical risk factor for T2D is 30 kg / m². 2The above-mentioned symptoms include an increase in body mass index (BMI), an HbA1c level of 6% or higher, and metabolic syndrome (4). The current standard treatment for T2D includes, first, lifestyle and dietary management, followed by monotherapy with metformin to lower blood glucose in mild cases (HbA1c ≤ 9%), or dual therapy (metformin in combination with another drug). If the HbA1c reduction target is not reached after approximately 3 months of triple therapy, or if the disease had a more severe form in the early stages, treatment has advanced to include combinations with injectable therapy, such as rapid-acting insulin injections in various regimens with or without GLP-1 receptor agonists. Nevertheless, the use of drugs often remains severely limited, including the risk of adverse side effects, more importantly, life-threatening hypoglycemia (5). Recent studies on metformin, the first line of defense against T2D, have concluded that prenatal metformin treatment by fathers is associated with major birth defects, particularly genital defects in boys. Therefore, although this treatment was previously thought to have no adverse effects, it is now considered problematic (3).

[0007] A series of publications have revealed unfavorable evidence revealing a causal relationship between the accumulation of unstable redox-active iron in various tissues (e.g., pancreatic and hepatocytes) and T2D development (6-11). Iron affects glucose metabolism (12-14), which in turn affects the iron metabolic pathway. Briefly, the accumulation of unstable and redox-active iron in various tissues contributes to the formation of reactive oxygen-derived species (ROS) via the Fenton reaction, which promotes the initiation of inflammatory responses, and thus underlies insulin resistance (IR) and metabolic syndrome, playing a crucial role in the pathophysiology of T2D (15). Nevertheless, iron has been suggested to be functionally important for normal insulin secretion and pancreatic β-cell metabolism (9, 16, 17). Exposure to high glucose concentrations in pancreatic islets stimulates ferritin production (18), which serves as a mechanism for promoting and maintaining important iron stores during insulin secretion by β-cells (9). Therefore, hepcidin (an iron-regulating hormone) is produced by the liver and pancreas to promote intracellular iron accumulation by binding to the iron transporter ferroportin (Fpn) and mediating its internalization and degradation (17-20). It is located within insulin-secreting islets and secreted after stimulation by high glucose. Since Fpn is expressed by β-cells, hepcidin exerts an autocrine inhibitory effect on iron transport in β-cells (9, 20, 21).

[0008] Specifically, in the liver, excess iron accumulation interferes with glucose metabolism through both decreased insulin clearance and impaired insulin signaling, resulting in hyperinsulinemia (22). Hyperinsulinemia then promotes intrahepatic iron accumulation, acting as a reinforcing process (8, 22). Insulin has been reported to directly enhance extracellular iron uptake and induce redistribution of transferrin receptors on the cell surface (23). Thus, it has been shown that "iron and insulin are synergistic in the release of ROS and inflammatory cytokines in the subendothelial space and the promotion of oxidative stress" (24). These inflammatory cytokines then promote ferritin synthesis in Kupffer cells and macrophages (8). These processes lead to fatty liver and, most importantly, insulin resistance (25).

[0009] The porosity of liver sinusoidal endothelial cells (LSECs), a key characteristic of LSECs, ensures the bidirectional passive transport of lipoproteins, drugs, solutes, and insulin between hepatic capillaries and hepatic parenchyma. This porosity is realized through windows (transcellular pores with diameters ranging from 50 to 300 nm) that typically group together in sieve plates. Several liver disorders and, most importantly, aging significantly reduce LSEC porosity and impair their filtering properties (26). The loss of windows with aging manifests as changes in the hepatic microcirculation, particularly pronounced in LSECs, which contribute to dyslipidemia (26-27) and insulin resistance (26-27). At a morphological level, aged LSECs show a significant reduction in porosity (the percentage of cell surface area covered by windows) by approximately 50%, in other words, older LSECs become "de-fenestrated." This de-fenestration hinders the bidirectional transport of substrates between blood and hepatocytes. Biomolecules such as lipoproteins, hormones, or bioactive molecules (such as insulin) become less readily accessible through aging LSECs to reach the hepatocytes being processed and / or exert their effects. Consequently, older rats show a significant decrease in the hepatic volume of insulin distribution, indicating that windowing facilitates insulin transfer to hepatocytes, while "de-windowing" is associated with impaired insulin signaling and subsequent insulin resistance (26-28). Meanwhile, recent findings demonstrate a clear causal link between the accumulation of redox-active iron and LSEC de-windowing (26-28). In other words, a direct mechanism linking iron accumulation in a specific organ (liver) to a key feature of type 2 diabetes (insulin resistance) has been established.

[0010] For many years, increased iron storage was assumed to predict the onset of T2D, while iron deficiency was protective (29). Intracellularly unstable iron and redox-active iron often induce damage and modulate the development of various T2D complications (29). Attempts have been made in the past to treat diabetes with iron chelators, including Desferal® (whose active ingredient is deferoxamine B, DFO). These treatments have yielded controversial results that do not justify using Desferal® as an anti-T2D drug (31-33). Iron chelators have shown limited efficacy against diabetes caused by primary or secondary hemochromatosis (HFE hereditary hemochromatosis, β-thalassemia) (34, 35), but success has been even more limited in other subjects. The main drawback of Desferal® is that its active ingredient (DFO) does not penetrate membranes and therefore cannot remove intracellularly unstable iron from inside cells. DFO is a long, linear, polar molecule; this specific structure explains its lack of cellular infiltration.

[0011] When zinc ions bind to DFO, forming a newly developed zinc-DFO complex, the molecule becomes less polar and is characterized by a relatively rigid spherical structure. This spherical structure readily passes through the cell membrane. Intracellularly (and extracellularly), the zinc ions of the Zn-DFO complex readily exchange "complex" zinc ions with intracellularly unstable iron. This process was proposed by Chevion M in 1991, and the term "push-pull mechanism" was subsequently coined (36). Thus, the main obstacle to iron chelation by Desferal® (alone) is overcome by the use of the Zn-DFO complex (36, 37), resulting in the sequestering and removal of intracellularly toxic iron. This exchange reaction is explained by the affinity constant of DFO for trivalent iron (46) and the affinity constant of DFO for zinc (log stability constants are 10, respectively). 31 &10 11The levels are significantly higher than (38). When zinc-DFO enters the cell, rapid exchange of zinc ions by iron occurs in the presence of intracellularly unstable iron, forming an Fe-DFO complex. The zinc ions remain in the cell, while the Fe-DFO complex moves into the circulatory system and is subsequently removed from the body (36).

[0012] The antidiabetic effects of the Zn-DFO complex were tested in an animal model of the disease (T2D). In this model, the drug was administered by intraperitoneal injection. The drug showed high efficacy, normalizing blood glucose levels, improving the lipid profile, significantly reducing serum insulin, and improving insulin resistance (expressed as HOMA-IR, Homeostatic Model Assessment for Insulin Resistance) to near-normal levels (>93%). Since the effects on liver markers, such as ALT and AST, were limited, the need for a more potent effect, specifically targeting the liver, was now clear.

[0013] Furthermore, the Zn-DFO complex was tested in human subjects. In this study, the drug was administered subcutaneously using multiple dose escalations. The study was terminated early due to local pain at the injection site. This early termination meant that the participants did not reach the dose expected to be optimal (the dose reached using the dose escalation regimen was lower than planned). However, a significant decrease in blood glucose levels was observed in all three participants. In addition, two patients showed a decrease in serum insulin and HbA1c levels, and it also had some effect on insulin resistance, expressed as HOMA-IR. No systemic adverse effects were observed. These results highlight the need for an oral formulation of the Zn-DFO complex.

[0014] Poloxamers are a class of hydrophilic nonionic surfactants of copolymers, a more common class known as poloxamers. Poloxamer 407 is a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG). The two PEG blocks have an approximate length of 101 repeat units, while the propylene glycol block has an approximate length of 56 repeat units. Most of the common uses of poloxamer 407 are due to its surfactant properties. Nevertheless, pharmacological studies have revealed limitations in the use of poloxamer 407 in medicine, such as its effects on plasma levels of cholesterol and triglycerides (39, 40), alterations in the lipid composition of serum lipoproteins (41), and lipase inhibition, leading to the eventual formation of aortic atherosclerotic lesions (42). Poloxamer 407 was described in the LSEC as a compound with liver-specific effects acting as a "defenestration agent" (43). [Overview of the Initiative] [Means for solving the problem]

[0015] Summary of the Invention This specification discloses a hydrophilic nonionic surfactant formulation comprising (1) a complex of deferoxamine B (DFO B) with at least one metal such as zinc, gallium, silver, gold, molybdenum, vanadium, or any ionic form thereof, and (2) a nonionic triblock copolymer consisting of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) adjacent to two hydrophilic chains of polyethylene glycol (PEG) and polyoxyethylene (poly(ethylene oxide)), and a diluent. Zinc is Zn 2+ It can exist in the Zn-DFO complex as Ga 3+It can exist in the Ga-DFO complex as such. The hydrophilic nonionic surfactant may be a poloxamer such as poloxamer 407.

[0016] The hydrophilic formulation polyethylene glycol component concentration ranges from 17 to 23%, and the nonionic triblock copolymer, composed of two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)) and a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)), is present at 8 to 12% and acts as a diluent. The metal-DFO complex may be present in a pharmaceutical composition containing the metal-deferoxamine complex and a pharmaceutically acceptable inert component.

[0017] According to one embodiment, either the metal ion or deferoxamine B is in the form of an acid addition salt, and the complex contains the acid in addition to deferoxamine B and the metal ion. The acids are as follows: 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, alkanesulfonic acid, alkenesulfonic acid, alkynesulfonic acid with any substitution, adipic acid, ascorbic acid, aspartic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lact The following are selected from non-limiting examples, including bionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid or its derivatives, or substituted hydrocarbyl sulfonic acids, such as hydroxy-substituted, alkoxy-substituted, acyloxy-substituted, alkoxycarbonyl-substituted, halogen-substituted, aromatic-substituted, or amino-substituted alkyl sulfonic acids, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid, salicylic acid, sebacic acid, serenic acid, selenonic acid, or any selenine or selenone analog of the aforementioned sulfonate compounds, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, and undecylenic acid.

[0018] The pharmaceutical composition may be administered alone or in combination with other pharmaceutically acceptable drug products. The pharmaceutical composition may be adapted to any mode of administration to the target subject in need, including oral, gastric tube feeding, topical, ocular, nasal, ear administration, inhalation, eye drop administration, parenteral injection, parenteral suppository administration, parenteral patch administration, or any other clinically acceptable method and means of parenteral administration. The pharmaceutical composition may be administered topically and / or systemically by any pharmaceutically acceptable method, including tablets, minitablets, pills, lozenges, capsules, ingestible preparations, oral suspensions, soluble films, powders, ointments, creams, pastes, encapsulated gels, patches, liposomes containing the composition when applied in an acceptable carrier, or sprayable aerosols or vapors. Alternatively, any pulmonary delivery by oral inhalation may be used, such as by using a liquid nebulizer, aerosol-based metered dose inhaler (MDIs), or dry powder disperser. Alternatively, administration may be systemic, such as by oral administration, i / v, i / m, s / c, or any other mode of administration.

[0019] Metal-deferoxamine complexes can be applied as is or conjugated with sugars, starches, amino acids, polyethylene glycol, or polyglycerol compounds. Metal-deferoxamine complexes can be applied as is or conjugated with hydrazine, hydroxyamines, amines, halides, aliphatic, aromatic, heterocyclic compounds, or any other pharmaceutically acceptable group.

[0020] Clinical uses of the composition include type 2 diabetes, metabolic syndrome, any other diabetes-related conditions and complications, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis. Steatohepatitis (NASH), Wilson's disease; type 1 diabetes and its complications; neoplastic diseases with inflammatory elements in their pathophysiology; diseases of the blood and hematopoietic organs related to the immune system; metabolic disorders related to inflammatory elements; neurodegenerative and demyelinating disorders such as multiple sclerosis, amyotrophic lateral sclerosis, age-related macular degeneration, Parkinson's disease, and Alzheimer's disease; inflammatory diseases of the central nervous system; immune-related disorders of the circulatory and cardiovascular systems; inflammatory diseases of the respiratory system, especially asthma, cystic fibrosis, allergic rhinitis, nasal polyps, and COPD; inflammatory skin disorders, especially psoriasis, rheumatoid arthritis, psoriatic arthritis, wound healing, injury from exposure to chemicals, heat or cold; ischemia and re-opening injuries; stroke; immune-related diseases of the digestive system, especially inflammatory bowel disease; tetracholastic anemia; hemochromatosis; autoimmune disorders; inflammatory diseases of the oral cavity and salivary glands; infections, especially Escherichia coli. This includes the treatment, prevention, and / or prevention of infections caused by *C. coli*, *Staphylococcus aureus*, *Alcaligenes faecalis*, *Neisseria meningitidis*, *Prevotella intermedia*, *Porphyromonas gingivalis*, as well as the genera *Salmonella*, *Shigella*, *Proteus*, *Providencia*, *Enterobacter*, *Morganella*, and *Pseudomonas*.

[0021] Brief explanation of the drawing Embodiments are described only as non-limiting examples with reference to the accompanying drawings, in order to better understand the subject matter disclosed herein and to illustrate how it can be put into practice. [Brief explanation of the drawing]

[0022] [Figure 1] This shows a comparative dissolution profile of Zn-DFO release from capsules. [Figure 2A] This shows the AUC of DFO after intravenous administration. [Figure 2B] This shows the AUC of Fe-DFO after intravenous administration. [Figure 3] This shows the pharmacokinetics of Fe-DFO after oral administration of Zn-DFO diluted in water. [Figure 4A] This shows the pharmacokinetics of Fe-DFO formulated with poloxamer in serum after oral administration. [Figure 4B] This shows the kinetics of Fe-DFO formulated with gelucire in serum after oral administration. [Figure 4C] This shows the kinetics of Fe-DFO formulated with Labrasol / Labrafac in serum after oral administration. [Modes for carrying out the invention]

[0023] Detailed explanation Deferoxamine (DFO) is a siderophore (CAS #70-51-9) synthesized by several microorganisms, including the commonly recognized safe (GRAS) bacterium Streptomyces pilosus. As detailed herein, DFO is a chelating agent. It contains several hydroxamic acid groups that deprotonate to hydroxamates, which bind to metal ions to form complexes. In certain embodiments, DFO is DFO-B.

[0024] The term "chelation" refers to a specific method by which ions and molecules bond to metal ions. According to the International Union of Pure and Applied Chemistry (IUPAC), chelation involves the formation or presence of two or more distinct coordinate bonds between a polydentate (multiple bond) ligand and a single central atom. These ligands are usually organic compounds and are called chelants, chelators, or chelating agents, or metal ion sequestering agents. The chelating effect represents an increased affinity of a chelating ligand to a metal ion compared to the affinity of a group of similar non-chelating (monodentate) ligands to the same metal.

[0025] As used herein, the term “complex” (also known as a complex ion or coordination complex) refers to a chemical compound composed of a ligand having multiple binding sites (polydentate ligand) and a metal ion. A chelating ligand associates with at least one metal ion.

[0026] As used herein, the term “association” refers to a chemical or physical force that holds two entities (i.e., a ligand and a metal ion) together. Such a force may be any kind of chemical or physical bonding interaction known to those skilled in the art. Non-limiting examples of such association interactions include ionic bonds, covalent bonds, coordination bonds, complexes, hydrogen bonds, van der Waals bonds, and hydrophobic-hydrophilic interactions.

[0027] In some embodiments, the association may be via covalent bonding. In other specific embodiments, the association may be via coordinate bonding. As used herein, the term coordinate bonding refers to a type of covalent bond in which two shared electrons originate from the same atom (known as a coordinate bond). In the context of this disclosure, the association between a ligand and a metal includes the association to several sites on the metal via multiple atoms in the ligand. Thus, the association may be considered to involve two or more bonds, sometimes two covalent bonds, sometimes one covalent bond and one coordinate bond, and sometimes two coordinate bonds. The number of bonds is known as the coordination number of the complex. Bonds may include single bonds (sigma bonds) and / or double (pi) bonds and may be bipolar bonds.

[0028] Those skilled in the art will understand that, in some cases, associative interactions between two atoms or two chemical entities may be involved in two or more types of chemical and / or physical interactions.

[0029] When referring to metals, this should be understood as including any one or more elements commonly known as transition metals or post-transition metals. In some embodiments, metals may act as Lewis acids by accepting electron pairs from a donor Lewis base (i.e., a chelating agent), thereby forming complexes or complex ions. Note that the donated electrons can be considered as electron pairs donated to empty metallic orbitals. In the context of this disclosure, metals may be referred to as “central metals.”

[0030] In some embodiments, at least one metal is selected from the group consisting of zinc, gallium, silver, gold, molybdenum, or any ionic form thereof. In some embodiments, the metal may be a non-toxic metal that can be found in the human body, i.e., an endogenous one. According to this disclosure, at least one metal is a metal ion. In some embodiments, at least one metal ion is Zn 2+ , Ga 3+ Ag1+ 、 Au 3+ 、 Au 1+ 、 V 4+ 、 V 5+ 、 Mo 4+ and Mo 6+ may be selected from the group consisting of

[0031] As detailed herein, when the complex is administered to a tissue or organism, the association between the ligand and the metal is reversible, so the metal ion can be replaced by a different metal ion from an endogenous source and then can bind to another cellular component or be released into circulation in a ligand-free / unbound form. When referring to the ligand-free / unbound form, it should be noted that the metal ion does not contain the ligand (i.e., DFO) or is not bound to the ligand.

[0032] It has been suggested that the release of metal ions from the complex and the accompanying substitution by different metal ions are due to the difference in the dissociation constants of each of the two metal ions from the ligand (i.e., DFO). In other words, when the difference in the dissociation constants is such that the dissociation of the complex and the release of the metal ion are thermodynamically favorable, the association constant of the "new" metal with the ligand (i.e., DFO) is higher than that of the original metal ion, so the substitution is favorable. Without being bound by theory, the complex of deferoxamine B (DFO-B) and Zn 2+ has been suggested to release the metal ion (i.e., Zn 2+ ) and have a tendency to bind to Fe 3+ . In some embodiments, the free unbound form of the metal ion may have a physiological effect, such as an antioxidant effect.

[0033] In some other embodiments, the metal ion is a redox-inactive metal. In other words, the metal ion is not involved in redox reactions in the body.

[0034] In some embodiments, at least one metal ion is Zn 2+ . In some further embodiments, at least one metal ion is Ga 3+In some embodiments, the compositions described herein include DFO and Zn 2+ It may contain at least one complex of DFO and Ga. In some further embodiments, the compositions described herein include DFO and Ga 3+ It may contain at least one complex with .

[0035] It should be understood that the compositions described herein may contain at least one metal-DFO complex. In some further embodiments, the compositions may contain at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more complexes. Furthermore, it should be understood that these complexes or any combination thereof may be present in the composition in any ratio, for example, from 1:1 to 0.0001:100,000 or more.

[0036] In some further embodiments, the compositions described herein include DFO and Ga 3+ At least one complex with 10 and DFO and Zn 2+ It may contain at least one complex with . In certain embodiments, it should be noted that such combinations may be present in the composition in any ratio, for example, in the range of about 1:1 to 0.0001:100,000 to 100,000:0.0001. More specifically, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 and above.

[0037] According to one embodiment, either the metal ion or the DFO is in the form of an acid addition salt, and / or the complex contains an acid in addition to the siderophore and the metal ion. Acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, alkanesulfonic acid, alkenesulfonic acid, alkynesulfonic acid with any substitution, adipic acid, ascorbic acid, aspartic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobion The following are non-limiting examples that can be selected: acids, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid or its derivatives, or substituted hydrocarbyl sulfonic acids, such as hydroxy-substituted, alkoxy-substituted, acyloxy-substituted, alkoxycarbonyl-substituted, halogen-substituted, aromatic-substituted, or amino-substituted alkyl sulfonic acids, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid, salicylic acid, sebacic acid, serenic acid, selenonic acid, or any selenine or selenone analog of the aforementioned sulfonate compounds, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, and undecylenic acid.

[0038] Metal-DFO complexes can be applied as is or conjugated with sugars, starches, amino acids, polyethylene glycol, or polyglycerol compounds. Metal-DFO complexes can be applied as is or conjugated with hydrazine, hydroxyamines, amines, halides, aliphatic, aromatic, heterocyclic compounds, or any other pharmaceutically acceptable group.

[0039] In another embodiment, the compositions disclosed herein may be formulated into pharmaceutical compositions. More specifically, the compositions described herein include, as active ingredients, at least one of the metal-DFO complexes described above, or any combination thereof, and at least one pharmaceutically acceptable carrier, diluent and / or excipient.

[0040] As used herein, “pharmaceutically acceptable carrier” includes all solvents, dispersions, coatings, etc. The use of such media and agents for pharmaceutically active ingredients is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is intended. In some embodiments, the disclosed pharmaceutical compositions are suitable for systemic administration. The pharmaceutical compositions can be administered and dispensed in accordance with good medical practice by the methods described herein. More specifically, the compositions used in the methods and kits described herein can be adapted for systemic, parenteral, intraperitoneal, transdermal, oral (buccal or sublingual), rectal, topical (buccal or sublingual), vaginal, intranasal, and any other suitable route of administration. Such formulations can be prepared by any method known in the pharmaceutical field, for example, by associating the active ingredient with one or more carriers or excipients.

[0041] As used herein, the terms “systemic administration” and “administered systemically” mean the administration of a compound, drug, or other substance that is not administered directly into the central blood system but enters the patient’s system and is thereby susceptible to metabolism and other similar processes. As used herein, the terms “parenteral administration” and “administered parenterally” mean a mode of administration that is usually by injection, other than enteral and topical administration, and include, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0042] Systemic administration includes parenteral injection by intravenous bolus injection, intravenous infusion, subcutaneous, intramuscular, or intraperitoneal injection, or any other clinically acceptable method including suppositories, patches, tablets, pills, lozenges, capsules, ingestible preparations, ointments, creams, pastes, encapsulated gels, patches, boluses, or sprayable aerosols or vapors containing these complexes and combinations thereof when applied in an acceptable carrier. Alternatively, any pulmonary delivery by oral inhalation, such as using a liquid nebulizer, aerosol-based metered dose inhaler (MDI), or dry powder disperser.

[0043] In other embodiments, the pharmaceutical compositions described herein are adapted for topical administration. "Topical administration" means that the pharmaceutical compositions and carriers may be adapted for any form of topical administration, including on the skin, orally, bronchoalveolar lavage, ocular administration, enema, nasal administration, ocular administration, and inhalation.

[0044] Regardless of the route of administration selected, the compounds and / or pharmaceutical compositions described herein, which can be used in a preferred hydrated form, can be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0045] Pharmaceutical compositions used to treat subjects in need generally include buffers, agents for adjusting their osmolality, and optionally, one or more pharmaceutically acceptable carriers, excipients, and / or additives known in the art. Supplementary active ingredients may also be incorporated into the composition. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and the use of surfactants.

[0046] In some embodiments, pharmaceutical compositions containing DFO and a metal as active ingredients can be administered either alone or in combination with other metal-DFO complexes. Of particular interest are formulations of the complexes or any compositions described herein adapted for use as nanoparticles or microparticles. Nanoscale drug delivery systems using liposomes and nanoparticles are emerging technologies for rational drug delivery that offer improved pharmacokinetic properties, controlled and sustained release of drugs, and, more importantly, lower systemic toxicity. A particularly desirable solution is the ability to enable externally triggered release of encapsulated compounds. Externally controlled release can be achieved when the drug delivery vehicle, such as liposomes or polyelectrolyte multilayer capsules, incorporates nanoparticle (NP) actuators. More specifically, controlled drug delivery systems (DDS) have several advantages compared to conventional drug forms. Because the drug is delivered to the site of action, impact on vital tissues and undesirable side effects can be minimized. Accumulation of the therapeutic compound at the target site is increased, and as a result, a lower dose of the drug is required. This form of therapy is particularly important when there is a discrepancy between the dose or concentration of a drug and its therapeutic outcome or toxic effect. Cell-specific targeting can be achieved by conjugating drugs to specially designed carriers. Various nanostructures, including liposomes, polymers, dendrimers, silicon or carbon materials, and magnetic nanoparticles, have been tested as carriers in drug delivery systems. Therefore, it should be understood that complexes or any composition thereof can be formulated with any of the nanoparticles or microparticles disclosed herein.

[0047] Another embodiment relates to a method for regulating cytokine levels in cells. More specifically, the method disclosed herein may involve a contact step between the cells and an effective amount of at least one complex of DFO and at least one metal, or a derivative thereof, any composition containing the same, or any vehicle, matrix, nanoparticles, or microparticles. Thus, in some embodiments, the level of the metal-DFO complex in the cells. As will be shown later herein, the regulation used herein may involve increasing or decreasing cytokine levels in cells or subjects, as will be described later herein.

[0048] Furthermore, in some embodiments, the complexes described herein for regulating cytokine levels in cells may be brought into contact with cells. The term “contact” means bringing together, putting together, incubating together, or mixing. Thus, a first article is brought into contact with a second article when two articles are brought together, for example by bringing them into contact with each other or by combining them. The term “contact” includes all means or steps that enable interaction between the disclosed complex and the cells or subject to be regulated, as will be further specified herein.

[0049] In some embodiments, the metal of the complex used by the method described herein may be selected from the group consisting of lanthanides, actinides, transition metals and / or transition metals. In another embodiment, the metal of the complex used may be selected from the group consisting of zinc, gallium, silver, gold, molybdenum, vanadium or any ionic form thereof. In a further embodiment, the metal ion of the complex used by the method described herein is Zn 2+ , Ga 3+ Ag 1+ Au 3+ , can be selected from the group consisting of vanadium and molybdenum. Furthermore, in some specific embodiments, the metal ion of the complex used by the method described is Zn 2+It is possible. In some specific embodiments, the disclosed method involves DFO and Zn 2+ At least one complex with can be used. In alternative specific embodiments, the metal ion of the complex used by the method described is Ga 3+ It is possible. In some further embodiments, the method involves DFO and Ga 3+ At least one complex with can be used.

[0050] As shown above, the disclosed method can modulate cytokine levels in cells. The term "modulation" as used herein refers to a decrease or alternatively an increase in cytokine levels in the cells. In more specific embodiments, the metal-DFO complex can increase cytokine levels in cells in contact with the disclosed complex or in subjects administered with the disclosed complex by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 4% in cells in contact with the disclosed complex or in subjects administered with the disclosed complex, compared to cells or subjects not treated with the disclosed complex. This can result in a decrease, reduction, removal, attenuation, or suppression of cytokine levels by 4%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or approximately 100%.Alternatively, in some embodiments, the regulation is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 5% in cells or subjects that have come into contact with or been administered with the disclosed complex, compared to cells or subjects that have not been treated with the complex. 1%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85% This may be associated with an increase, rise, enhancement, or increase in cytokine levels of 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or approximately 1000%.

[0051] Specifically, the cytokine modulation methods described herein relate to the modulation of at least one inflammatory cytokine and at least one anti-inflammatory cytokine. "Cytokines" are a category of small proteins (approximately 5–20 kDa) released by cells that have specific effects on cell-cell interactions, cell-cell communication, or cell behavior. Cytokines may also be involved in autocrine signaling. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor, but generally do not include hormones or growth factors (despite some terminological overlap). Cytokines are produced by a wide range of cells, including immune cells such as macrophages, B lymphocytes, T lymphocytes, and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells, and a given cytokine may be produced by two or more types of cells. It should be noted that in some embodiments, the methods described may be applicable to modulating the levels of any of the cytokines described above.

[0052] Furthermore, in some other embodiments, the methods described may be used to modulate levels of inflammatory cytokines in cells. "Inflammatory cytokines" are cytokines that promote systemic inflammation. By their inflammatory action, they initiate or exacerbate pathological processes by causing fever, edema, inflammation, tissue destruction, and in some cases even shock and death. Non-limited examples of inflammatory cytokines include, but are not limited to, IL1-α, IL1-β, IL-6 and TNF-α, members of the IL-20 family, IL-33, LIF, IFN-γ, OSM, CNTF, TGF-β, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-8, and various other chemokines that chemically attract inflammatory cells.

[0053] In some embodiments, the modulation of inflammatory cytokines as used herein refers to the following cytokines: IL-1α, TNF-α, IL-6, and IL-17. In more specific embodiments, the methods described herein may result in a reduction in the levels of inflammatory cytokines, specifically a reduction in the levels of at least one of IL-1α, TNF-α, IL-6, and IL-17.

[0054] In some further embodiments, the methods described herein may be used to modulate levels of anti-inflammatory cytokines in cells. Anti-inflammatory cytokines are a group of immunomodulatory molecules that control the response of inflammatory cytokines and act in coordination with specific cytokine inhibitors and soluble cytokine receptors to downregulate the inflammatory immune response. Key anti-inflammatory cytokines include, but are not limited to, the interleukin IL-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13. Under various circumstances, leukemia inhibitors, interferon-α, and transforming growth factor TGF-β are classified as either anti-inflammatory cytokines or inflammatory cytokines. Specific cytokine receptors for IL-1, TNF-α, and IL-18 also function as inhibitors of inflammatory cytokines. In some specific embodiments, the methods described herein may result in the modulation of levels of at least one of IL-13, IL-10, and IL-4. In some other embodiments, the methods described herein may result in an increase in the level of at least one anti-inflammatory cytokine in the cells, more specifically, at least one of IL-13, IL-4, and IL-10.

[0055] Further embodiments describe methods for modulating cytokine levels in a subject. More specifically, in some embodiments, the methods disclosed herein may include administering to the subject an effective amount of a complex of DFO with at least one metal, any composition containing the same, or any vehicle, matrix, nanoparticles, or microparticles. It should be understood that in certain embodiments, the method may use any complex described herein, any combination thereof with other metal-DFO complexes, or any composition containing the same.

[0056] Therefore, in several more specific embodiments, the method described can modulate the levels of one or more inflammatory cytokines in a subject. In a further specific embodiment, the method can reduce the level of at least one inflammatory cytokine in a subject. In a more specific embodiment, such inflammatory cytokine may be at least one of IL-1α, IL-6, TNF-α, and IL-17.

[0057] Furthermore, in several specific embodiments, the described method can modulate the levels of one or more anti-inflammatory cytokines in a subject. In a more specific embodiment, the method can increase the level of at least one anti-inflammatory cytokine in a subject. In a more specific embodiment, such anti-inflammatory cytokine may be at least one of IL-13, IL-4, and IL-10.

[0058] The severity of attacks of inflammatory cytokine-mediated diseases can be reduced by decreasing the biological activity of inflammatory cytokines, or, alternatively or additionally, by increasing the levels or activity of anti-inflammatory cytokines. Therefore, reducing the biological activity of IL-1α and TNF-α can be achieved through several different but highly specific strategies, including neutralizing antibodies, soluble receptors, receptor antagonists, and protease inhibitors that convert inactive precursors into active mature molecules. Blockade of IL-1α or TNF-α has been highly successful in patients with psoriasis, rheumatoid arthritis, inflammatory bowel disease, or graft-versus-host disease.

[0059] Therefore, in certain embodiments, the methods described herein may be particularly applicable to subjects suffering from disorders associated with at least one of elevated levels of inflammatory cytokines and / or decreased levels of anti-inflammatory cytokines, or any other immune-mediated or immune-related disorders.

[0060] More specifically, metal-DFO complexes may be appropriate for subjects suffering from disorders such as inflammatory, infectious, proliferative, neurodegenerative, ischemic, metabolic, spinal cord injury, trauma, autoimmune disorders, and acute or chronic wounds or injuries. In some embodiments, a common factor among these groups of disorders may be their relationship to inflammatory cytokines. This refers to elevated IL-1α, IL-6, TNF-α, and IL-17, and / or anti-inflammatory cytokines, specifically one of IL-13, IL-10, or IL-4, which are reduced while the disorder is active and should be noted to return to baseline levels after certain treatments described below.

[0061] As used herein, the terms “reduction,” “attenuation,” and “elimination” relate to an action that causes a gradual decrease in size, quantity, number, or intensity. In particular, a reduction of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of expression compared to a preferred control. It should be further noted that the reduction or decrease may be a decrease of approximately 1 / 20 to 1 / 100. Furthermore, it should be understood that the decrease in the level or expression of the inflammatory cytokine may be due to a decrease in the transcription, translation, or stability of the cytokine. In relation to the above, it should be understood that, where provided, percentage values ​​such as 10%, 50%, 120%, and 500% are interchangeable with “multiplier change” values, i.e., values ​​such as 0.1, 0.5, 1.2, and 5, respectively.

[0062] Interleukin-1α (IL-1α), as used herein and also known in some embodiments as hematopoietin-1, is a protein of the interleukin-1 family encoded by the IL1A gene in humans. Generally, interleukin-1 is responsible for the production of inflammation, as well as the promotion of fever and sepsis. IL-1α inhibitors have been developed to disrupt these processes and treat diseases.

[0063] IL-1α is primarily produced by activated macrophages, as well as neutrophils, epithelial cells, and endothelial cells. Upon stimulation, a wide variety of other cells can produce precursor forms of IL-1α. These forms include fibroblasts, macrophages, granulocytes, eosinophils, mast cells and basophils, endothelial cells, platelets, monocytes and myeloid cell lines, hematopoietic T lymphocytes and B lymphocytes, astrocytes, renal mesangial cells, Langerhans cells, cutaneous dendritic cells, natural killer cells, macrogranular lymphocytes, microglia, neutrophils, lymph node cells, maternal placental cells, and several other cell types. IL-1α possesses metabolic, physiological, and hematopoietic activity and plays a central role in regulating the immune response. It binds to the interleukin-1 receptor, thereby initiating a pathway that activates tumor necrosis factor-α.

[0064] Furthermore, the interleukin-6 (IL-6) used herein is an interleukin that acts as a classic inflammatory cytokine. It is a key mediator of the acute phase response. It can be secreted by macrophages, neutrophils, adipocytes and myocytes in response to several stress mediators, thus stimulating further neutrophil production and initiating several cellular stress-inducing mechanisms. IL-6 stimulates inflammatory and autoimmune processes in numerous diseases, including psoriasis, both types of diabetes, rheumatoid arthritis, atopic dermatitis, irritant contact dermatitis, and sepsis.

[0065] Tumor necrosis factor-α (TNF-α), also known as kakexin or kaketin, is a cytokine involved in systemic inflammation. TNF-α is a member of the cytokine group that stimulates acute-phase responses. It is primarily produced by activated macrophages, but can also be secreted by neutrophils, mast cells, eosinophils, myocytes, endothelial cells, fibroblasts, and natural killer cells. The primary, though not the only, function of this cytokine is to modulate immune cells. Following activation by different stress-related stimuli, it can induce fever, inflammation, and apoptosis (programmed cell death) using several different mechanisms in numerous cell types. Increased TNF-α levels are associated with a wide variety of inflammatory diseases. Localized increases in TNF-α levels have been demonstrated to induce typical signs of inflammation: fever, swelling, redness, pain, and loss of function. Multiple reports exist regarding crosstalk and mutual activation of cytokines such as the IL-1 superfamily, IL-6, and TNF-α.

[0066] Interleukin-17A (IL-17 or IL-17A), as used herein, was first identified as a transcript from rodent T cell hybridomas and is a primary member of a group of cytokines called the IL-17 family (30). Known as CTLA8 in rodents, IL-17 shows high homology to viral IL-17 encoded by the open reading frame of T lymphotropic razinovirus herpesvirus thymili. Interleukin-17, like interferon-gamma, is a cytokine that acts as a potent mediator in delayed-type responses by increasing chemokine production in various tissues and recruiting monocytes and neutrophils to inflammatory sites. IL-17 is produced by T helper cells and induced by IL-23, resulting in devastating tissue damage in delayed-type responses. Interleukin-17 functions as an inflammatory cytokine that responds to immune system invasion by extracellular pathogens, inducing the destruction of the pathogen's cellular matrix. Interleukin-17 acts synergistically with tumor necrosis factor and interleukin-1. To induce this function, IL-17 binds to a type 1 cell surface receptor called IL-17R, of which at least three variants exist: IL17RA, IL17RB, and IL17RC.

[0067] Numerous immunomodulatory functions have been reported for the IL-17 family of cytokines, likely due to the induction of many immune signaling molecules. The most notable role of IL-17 is its involvement in inducing and mediating inflammatory responses. IL-17 is commonly associated with allergic reactions. IL-17 induces the production of many other cytokines (e.g., IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α), chemokines (including IL-8, GRO-α, and MCP-1), and prostaglandins (e.g., PGE2) from many cell types (fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages). The release of cytokines triggers many functions, including airway remodeling, which is characteristic of the IL-17 response. Increased chemokine expression attracts other cells, including neutrophils rather than eosinophils. IL-17 function also involves T helper 17 (T h IL-17F is essential to a subset of CD4+ T cells known as 17). As a result of these roles, the IL-17 family is associated with many immune / autoimmune diseases, including rheumatoid arthritis, asthma, lupus, allograft rejection, antitumor immunity, and more recently, psoriasis and multiple sclerosis. Notably, within this family, IL-17F has been well-characterized both in vitro and in vivo and has been shown to have a pro-inflammatory role in asthma, with its expression level correlating with disease severity. Therefore, IL-17F may play an important role in allergic airway inflammation and may have significant therapeutic implications in asthma. Due to its involvement in immunomodulatory function, IL-17 inhibitors are being investigated as a possible treatment for autoimmune diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

[0068] In recent years, new treatments for inflammatory disorders have been developed based on at least one rationale: reducing levels of inflammatory cytokines. For example, since TNF-α is known to promote the inflammatory response, monoclonal antibodies that suppress this cytokine have been developed to treat inflammation-related diseases such as psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, and ankylosing spondylitis. Another TNF-α inhibitor, circulating receptor fusion protein, is used to treat psoriasis, rheumatoid arthritis, and ankylosing spondylitis.

[0069] Reducing the biological activity of IL-1 and TNF is achieved through several different but highly specific strategies, including neutralizing antibodies, soluble receptors, receptor antagonists, and protease inhibitors that convert inactive precursors into active mature molecules. Blocking IL-1 and TNF has proven highly successful in treating patients with rheumatoid arthritis, inflammatory bowel disease, or graft-versus-host disease. Similarly, the use of IL-17 inhibitors has also been a strategy for treating other inflammation-related disorders. Based on new evidence from animal models, IL-17 is suggested as a target for anti-inflammatory therapy to improve post-stroke recovery and reduce skin cancer formation. IL-17 is also involved in multiple sclerosis. IL-17A, IL-17F, and IL-17A / F receptor inhibitors: brodalumab, ixekizumab, and secukinumab have recently been approved for the treatment of psoriasis. Therefore, the disclosed metal-DFO E complexes, compositions, kits, and methods provide novel tools for treating and preventing any disorders associated with elevated inflammatory cytokine levels, specifically those described herein.

[0070] Furthermore, the methods described herein may result in an increase in the level of at least one anti-inflammatory cytokine, specifically IL-13, IL-10, and IL-4. For example, according to some embodiments demonstrating the “increase” or “enhancement” of the expression level of an anti-inflammatory cytokine, specifically one of IL-13, IL-10, and IL-4, it means that such increase or enhancement may be an increase or rise of approximately 10% to 100% of the expression of such cytokine. As used herein, the terms “increase,” “boost,” and “enhance” relate to an action that gradually increases in size, quantity, number, or intensity. In particular, an increase of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of expression compared to a preferred control. It should be further noted that the increase or rise may be approximately 30 to 100 times. Furthermore, it should be understood that the increase in the level or expression of the IL-13 cytokine may be due to the transcription, translation, or stability of the cytokine. In relation to the above, it should be understood that, where provided, percentage values ​​such as 10%, 50%, 120%, and 500% are interchangeable with “multiplier change” values, i.e., values ​​such as 0.1, 0.5, 1.2, and 5, respectively.

[0071] Interleukin-13 (IL-13) as used herein is an example of an anti-inflammatory cytokine. IL-13 is secreted by many cell types, but particularly by T helper type 2 (Th2) cells. While some publications describe it as a mediator of allergic "inflammation" and disease, it has also been described as a mediator that plays a potent anti-inflammatory role. Furthermore, IL-13 has been shown to induce several changes in the gut that create an environment hostile to parasites (helmins), ultimately leading to the separation and removal of parasites from the intestinal wall.

[0072] Interleukin-10 (IL-10) is a major anti-inflammatory cytokine found within the human immune response. It is a potent inhibitor of Th1 cytokines, including both IL-2 and IFN-γ. Due to this activity, it was initially named a cytokine synthesis inhibitor. In addition to its activity as a Th2 lymphocyte cytokine, IL-10 is also a potent inactivator of monocyte / macrophage inflammatory cytokine synthesis. After engaging with its high-affinity 110-kD cell receptor, IL-10 inhibits monocyte / macrophage-derived TNF-α, IL-1, IL-6, IL-8, IL-12, granulocyte colony-stimulating factor, MIP-1a, and MIP-2a.

[0073] The pharmaceutical compositions described herein may be particularly suitable for treating inflammation-related disorders. Given the limited availability of specific anti-inflammatory therapies and the recognition of the role of inflammatory cytokines in the pathogenesis of several disorder groups, the development of new anti-inflammatory therapies is anticipated. Therefore, the use of the metal-DFO complexes described herein in therapeutics is currently required.

[0074] Therefore, the disclosed metal-DFO complexes may be useful in methods for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of pathological conditions or disorders in subjects where such treatment is needed. In some specific embodiments, the method comprises administering a therapeutically effective amount of at least one complex of DFO with at least one metal or any combination thereof with other metal-DFO complexes, or any pharmaceutical composition, carrier, matrix, or vehicle containing these, to a subject to be treated. In some specific embodiments, these disorders and / or diseases may be characterized by having clinically beneficial effects when unstable iron or copper is chelated, more specifically when inflammatory cytokines associated with these disorders are reduced (downregulated) and / or anti-inflammatory cytokines associated with these disorders are increased (upregulated). In more specific embodiments, the disclosed metal-DFO complex provides a method for treating, preventing, reducing, attenuating, inhibiting and eliminating disorders associated with elevated inflammatory cytokines by administering a therapeutically effective amount of at least one complex of DFO and at least one metal, a carrier, matrix, or vehicle containing the same, to the subject in need.

[0075] In some embodiments, the metal of the complex used by the described method may be the post-transition metal and / or transition metal.

[0076] In another embodiment, the metal of the complex used by the method described herein may be selected from the group consisting of zinc, gallium, silver, gold, molybdenum, vanadium, or any ionic form thereof. In a further embodiment, the metal ion of the complex used by the method is Zn 2+ , Ga 3+ Ag 1+ and Au 3+ , which can be selected from the group consisting of vanadium and molybdenum. Furthermore, in certain embodiments, the metal ion of the complex used by the disclosed method is Zn 2+ It is possible. In some embodiments, the method involves DFO and Zn, as previously described herein. 2+It may include at least one complex with. In alternative specific embodiments, the metal ion of the complex used by the method is Ga 3+ It is possible. In some further embodiments, the method involves DFO and Ga 3+ At least one complex with can be used.

[0077] As previously disclosed herein, depending on the specific embodiments, the disclosed methods may be useful in treating, preventing, suppressing, reducing, eliminating, protecting against or delaying the onset of a disease, condition, or disorder, the disorder being associated with at least one of elevated inflammatory cytokine levels and / or decreased anti-inflammatory cytokine levels. Specifically, the inflammatory cytokine may be at least one of IL-1α, TNF-α, IL-6, and IL-17. In some further embodiments, the anti-inflammatory cytokine may be at least one of IL-13, IL-10, and IL-4.

[0078] As described above, some embodiments provide methods for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a disease or disorder associated with at least one of elevated inflammatory cytokine levels and / or decreased anti-inflammatory cytokine levels. In more specific embodiments, the disorder may be at least one of inflammatory, infectious, proliferative, neurodegenerative, ischemic, metabolic, spinal cord injury, trauma, autoimmune disorder, and acute or chronic wound or injury.

[0079] In specific embodiments, a method is provided for treating inflammatory disorders in subjects in need, comprising the steps of administering to the subject a therapeutically effective amount of at least one complex of DFO and at least one metal, a carrier, matrix or vehicle comprising the same, wherein the inflammatory disorder is type 2 diabetes, metabolic syndrome, any other diabetes-related conditions and complications, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NAFLD) Steatohepatitis (NASH), Wilson's disease; type 1 diabetes and its complications; neoplastic diseases with inflammatory elements in their pathophysiology; diseases of the blood and hematopoietic organs related to the immune system; metabolic disorders related to inflammatory elements; neurodegenerative and demyelinating disorders such as multiple sclerosis, amyotrophic lateral sclerosis, age-related macular degeneration, Parkinson's disease, and Alzheimer's disease; inflammatory diseases of the central nervous system; immune-related disorders of the circulatory and cardiovascular systems; inflammatory diseases of the respiratory system, especially asthma, cystic fibrosis, allergic rhinitis, nasal polyps, and COPD; inflammatory skin disorders, especially psoriasis, rheumatoid arthritis, psoriatic arthritis, wound healing, injury from exposure to chemicals, heat or cold; ischemia and re-opening injury; stroke; immune-related diseases of the digestive system, especially inflammatory bowel disease; tetracholastic anemia; hemochromatosis; autoimmune disorders; inflammatory diseases of the oral cavity and salivary glands; Escherichia coli This refers to any disorder / disease or condition selected from infections caused by *C. coli*, *Staphylococcus aureus*, *Alcaligenes faecalis*, *Neisseria meningitidis*, *Prevotella intermedia*, *Porphyromonas gingivalis*, and the genera *Salmonella*, *Shigella*, *Proteus*, *Providencia*, *Enterobacter*, *Morganella*, and *Pseudomonas*.

[0080] The general term "inflammatory disorder" refers to a disorder in which inflammation is the primary response to harmful stimuli such as pathogens, damaged cells, or irritants. Inflammation is a protective response involving immune cells, blood vessels, and molecular mediators, and is the ultimate consequence of long-term oxidative stress. "Inflammatory disorders" are a large group of disorders that underlie a wide variety of human diseases. The immune system can also be involved in inflammatory disorders resulting from an abnormal immune response of an organism to its own components, or from the initiation of an inflammatory process for unknown reasons, i.e., autoimmune and autoinflammatory disorders, respectively. Non-immune diseases with a pathogenic origin in the inflammatory process include cancer, atherosclerosis, and ischemic heart disease.

[0081] The purpose of inflammation is to eliminate the initial cause of cell damage, remove necrotic cells and tissue, and initiate tissue repair. Classical physiological signs of acute inflammation are pain, fever, redness, swelling, and loss of function. A series of biochemical events propagate and mature the inflammatory response, involving the local vascular system, immune system, and various cells within the damaged tissue. Persistent inflammation, known as "chronic inflammation," results in a progressive shift in the types of cells present at the site of inflammation and is characterized by simultaneous tissue destruction and healing from the inflammatory process. Inflammation also induces high systemic levels of specific cytokines designed as inflammatory cytokines, including IL-1α, IL-6, IL-8, IFN-γ, TNF-α, IL-17, and IL-18. The inflammatory response must be actively terminated when it is no longer necessary to prevent unnecessary "bystander" damage to the tissue. Failure to do so results in chronic inflammation and cell destruction. Resolution of inflammation occurs through different mechanisms in different tissues. Acute inflammation is usually resolved by mechanisms that have previously remained somewhat unclear. Newly emerging evidence suggests that an actively coordinated dissipation program is initiated within the first few hours after the onset of the inflammatory response. After entering the tissue, granulocytes facilitate the conversion of arachidonic acid-derived prostaglandins and leukotrienes to lipoxins, thereby initiating termination sequences. This leads to the cessation of neutrophil recruitment and the initiation of programmed cell death (programmed cell death) by apoptosis. These events are consistent with the biosynthesis of resolvins and protectins from omega-3 polyunsaturated fatty acids, which critically shorten the duration of neutrophil infiltration by initiating apoptosis. As a result, apoptotic neutrophils are phagocytosed by macrophages, leading to neutrophil clearance and the release of anti-inflammatory and reparative cytokines such as transforming growth factor-β1. The anti-inflammatory program terminates with the departure of macrophages through the lymphatic vessels.

[0082] As used herein, the term “inflammation-related pathological conditions” includes: type 2 diabetes, metabolic syndrome, any other diabetes-related conditions and complications, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NAFLD). Steatohepatitis (NASH), Wilson's disease; type 1 diabetes and its complications; neoplastic diseases with inflammatory elements in pathophysiology; diseases of the blood and hematopoietic organs related to the immune system; metabolic disorders related to inflammatory elements; neurodegenerative and demyelinating disorders such as multiple sclerosis, amyotrophic lateral sclerosis, age-related macular degeneration, Parkinson's disease, and Alzheimer's disease; inflammatory diseases of the central nervous system; immune-related disorders of the circulatory and cardiovascular systems; inflammatory diseases of the respiratory system, especially asthma, cystic fibrosis, allergic rhinitis, nasal polyps, and COPD; inflammatory disorders of the skin, especially psoriasis, rheumatoid arthritis, psoriatic arthritis, wound healing, injury from exposure to chemicals, heat or cold; ischemia and re-opening injuries; stroke; immune-related disorders of the digestive system, especially inflammatory bowel disease; tetracholastic anemia; hemochromatosis; autoimmune disorders; inflammatory diseases of the oral cavity and salivary glands; Escherichia coli This relates to at least one, but not limited to, infections caused by *C. coli*, *Staphylococcus aureus*, *Alcaligenes faecalis*, *Neisseria meningitidis*, *Prevotella intermedia*, *Porphyromonas gingivalis*, and the genera *Salmonella*, *Shigella*, *Proteus*, *Providencia*, *Enterobacter*, *Morganella*, and *Pseudomonas*.

[0083] Chronic or acute inflammatory skin conditions include dermatitis, inflammatory skin disorders, and inflammation-related skin pigmentation abnormalities such as vitiligo and eczema. More specifically, certain embodiments relate to the disclosed metal-DFO complex for treating dermatitis, as well as the use of the composition, method and kit thereof. The term “dermatitis” generally refers to inflammation of the skin. Various types usually have in common an allergic reaction to a particular allergen. The term may be used to refer to eczema, also known as dermatitis eczema or eczematous dermatitis. A diagnosis of eczema often implies atopic dermatitis (childhood eczema), but without the appropriate context, it means merely a “rash,” i.e., transient skin inflammation. In some languages, “dermatitis” and eczema are synonymous, but in other languages, “dermatitis” refers to an acute condition and “eczema” refers to a chronic condition. The two conditions are often classified together. In some specific embodiments, the methods, complexes, and compositions described herein may be applicable to any type of dermatitis, specifically, atopic dermatitis, contact dermatitis, seborrheic dermatitis, or seborrheic dermatitis and dry eczema. More specifically, as used herein, atopic dermatitis is an allergic disease thought to have a hereditary component and often occurs in families where members also have asthma. Itchy rashes are particularly prominent on the head and scalp, neck, inner elbows, behind the knees, and buttocks. It is very common and increasing in developed countries. Irritant contact dermatitis can be misdiagnosed as atopic dermatitis. Furthermore, as used herein, contact dermatitis is of two types: allergic (resulting from a delayed reaction to allergens such as poison ivy, nickel, or balsam of Peru) and irritant (resulting from a direct reaction to surfactants such as sodium lauryl sulfate). As used herein, xerosis (also known as asteatotic eczema, fissured eczema, winter pruritus, or winter skin itching) is dry skin that can become severe eczema. This is exacerbated by dry winter weather, and the limbs and trunk are most affected. The itchy and tender skin resembles a dry, cracked riverbed.Finally, this method may be used to treat seborrheic dermatitis ("cracking" in infants), a condition that, when used herein, may be classified as a form of eczema closely associated with dandruff. This causes dry or oily peeling of the scalp, eyebrows and face, and sometimes the trunk. This condition is harmless except in severe cases of cracking. In newborns, this causes a dark yellow, crusty scalp rash called cracking, which is considered to be associated with biotin deficiency and is often treatable. It should be understood that the method described herein may be applicable to any form of dermatitis disclosed herein.

[0084] It should be understood that, based on their anti-inflammatory properties, the complexes and compositions described herein may be applicable to the treatment of other inflammatory skin disorders, specifically psoriasis.

[0085] Psoriasis is also an inflammatory disorder mediated by inflammatory and anti-inflammatory cytokines. While the exact cause and pathogenesis of psoriasis are unknown, overexpression of inflammatory type 1 (Th1) cytokines has been demonstrated in psoriasis and is considered pathophysiologically important. Importantly, a relative deficiency of cutaneous IL-10 mRNA expression has been demonstrated compared to other inflammatory skin diseases. In addition, previous publications have demonstrated that patients undergoing established anti-psoriasis therapy showed higher IL-10 mRNA expression in peripheral blood mononuclear cells than patients prior to therapy. This suggested that IL-10 may possess anti-psoriasis capabilities. In fact, subcutaneous administration of IL-10 produced immunosuppressive effects in patients (decreased monocytic HLA-DR expression, TNF-α and IL-12 secretion capacity, IL-12 plasma levels and responsiveness to recall antigens), and a shift to type 2 (Th2) cytokine patterns (increased percentage of IL-4, IL-5, and IL-10 producing T cells, selectively increased IgE serum levels). More specifically, psoriasis is a common skin condition characterized by plaque-like, raised, red areas of scaly skin inflammation. Psoriasis often affects the elbows and knees, scalp, navel, and areas surrounding the genitals or anus. This occurs when the immune system sends out incomplete signals that accelerate the growth cycle of skin cells. The scaly erythema commonly caused by psoriasis, called psoriasis vulgaris, is an area of ​​inflammation and excessive skin production. Skin rapidly accumulates in these areas, giving it a silvery-white appearance. Localized psoriasis frequently occurs on the skin of the elbows and knees, but can affect any area, including the scalp, palms and soles of the feet, and genitals. In contrast to eczema, psoriasis is more likely to be found outside the joints. This disorder is a chronic, recurrent condition with varying severity from mild localized patches to complete body coverage. Fingernails and toenails are frequently affected (psoriatic onychomycosis) and can be seen as a separate symptom. Psoriasis can also cause inflammation of the joints, known as psoriatic arthritis. 10–15% of people with psoriasis develop psoriatic arthritis, which is of a chronic, recurrent nature. The symptoms of psoriasis can manifest in various forms. Variants include localized psoriasis, pustular psoriasis, guttate psoriasis, and flexural psoriasis.Psoriasis can be classified into non-pustular and pustular types.

[0086] Non-pustular psoriasis includes psoriasis vulgaris and erythrodermic psoriasis. Psoriasis vulgaris (chronic psoriasis vulgaris or plaque-like psoriasis) is the most common form of psoriasis. It affects 80-90% of people with psoriasis. Focal psoriasis typically presents as raised areas of inflamed skin covered with silvery-white, scaly skin. These areas are called plaques.

[0087] Psoriatic erythroderma (Erythrodermic psoriasis) is characterized by widespread inflammation and peeling of the skin over large areas of the body surface. This can be accompanied by severe itching, swelling, and pain. It often results from an exacerbation of unstable focal psoriasis, particularly after the abrupt discontinuation of systemic treatment. This form of psoriasis can be fatal because the extreme inflammation and peeling disrupt the body's ability to regulate temperature and the skin's ability to perform barrier functions.

[0088] In yet another specific embodiment, the methods described herein may be used to treat pustular psoriasis. Pustular psoriasis manifests as raised bumps (pustules) filled with non-infectious pus. The skin beneath and around the pustules is red and tender to the touch. Pustular psoriasis can generally be localized to the hands and feet (palmoplantar pustulosis) or can spread throughout the body as widespread patches occurring randomly on any part of the body. Subtypes of pustular psoriasis include generalized pustular psoriasis (von Tsunbusch type pustular psoriasis), palmoplantar pustulosis (persistent palmoplantar pustulosis, Barber's type pustular psoriasis, limb pustular psoriasis), annular pustular psoriasis, acrodermatitis continuum, and impetigo herpetiformis.

[0089] It should be understood that the methods described herein may also be applicable to the treatment of any additional types of psoriasis, such as drug-induced psoriasis, psoriasis reversal, or psoriasis flexureus. The latter manifests as smooth inflammatory plaques on the skin folds, particularly around the genitals (between the thighs and groin), underarms, the overweight abdomen (pannus), and under the breasts (submammary folds). These are aggravated by friction and sweat and are vulnerable to fungal infections.

[0090] Furthermore, the methods reported herein may be used to treat guttate psoriasis. This type of psoriasis is characterized by numerous small, scaly, red or pink teardrop-shaped lesions. These numerous spots of psoriasis appear over a wide area of ​​the body, mainly the trunk, but also on the limbs and scalp. Guttate psoriasis is often preceded by a streptococcal infection, typically streptococcal pharyngitis.

[0091] Nail psoriasis can be treated by the disclosed methods and may result in various changes in the appearance of the fingernails and toenails. These changes include discoloration of the nail plate, nail depressions, lines across the nail, thickening of the skin beneath the nail, and nail laxity (onycholysis) and breakdown.

[0092] In yet another embodiment, metal-DFO complexes may be used to treat psoriatic arthritis. Psoriatic arthritis involves inflammation of the joints and connective tissue. While psoriatic arthritis can affect any joint, it is most common in the joints of the fingers and toes. This can result in sausage-shaped swelling of the fingers and toes, known as dactyly. Psoriatic arthritis can also affect the hips, knees, and spine (spondylitis). Approximately 10-15% of people with psoriasis also have psoriatic arthritis.

[0093] In some embodiments, treatment of a subject suffering from psoriasis may improve the subject's physiological condition, for example, by smoothing the skin that has been roughened due to the disease. In preferred embodiments, such psychological improvement can be achieved by topical application of metal complexes described herein that do not irritate the skin and do not promote inflammation.

[0094] It should be understood that the complexes, compositions, and methods described herein may be applicable to the treatment of psoriasis and extracutaneous features of psoriasis, including psoriatic arthritis.

[0095] Acne is another non-limiting example of a skin inflammatory disorder that can be treated by the disclosed methods. Acne is a general term used for exacerbating skin diseases. It is sometimes used as a synonym for acne vulgaris. However, there are several different types of acne. These include acne vulgaris, acne clusters, miliary necrotizing acne, tropical acne, infantile / neonatal acne, exfoliative acne, fulminant acne, drug-induced / drug-induced acne (steroid acne), halogenated acne (iodine dermatitis, bromine dermatitis, chloracin), oily acne, tar acne, cosmetic acne, occupational acne, summer acne, nape keloid acne, mechanical acne, acne with facial edema, pomade acne, necrotizing acne, blackheads, and facial disseminated miliary lupus.

[0096] Inflammation-related skin disorders can be treated by the methods described herein, and may also include insect bites and stings. While stinging, insects inject formic acid and / or toxins. These can cause immediate skin reactions, often resulting in redness and swelling in the area of ​​injury. Stings from Hymenoptera are usually painful and, in at-risk patients, can trigger a life-threatening systemic allergic reaction called anaphylaxis. Systemic allergic sting reactions often result in symptoms and signs of the skin, blood vessels, or respiratory system, either alone or in any combination with the possible involvement of other less common target tissues. Cardiac anaphylaxis can also cause bradycardia, arrhythmia, angina, or myocardial infarction. Bites from mosquitoes, fleas, and ticks are more likely to cause itching than pain. Skin reactions to insect bites and stings usually last up to a few days. However, in some cases, local reactions can last up to two years. There are three types of reactions to stings. A normal reaction involves redness, itching, and pain in the area surrounding the bite. A major localized reaction occurs when the diameter of the swollen area exceeds 5 cm. A systemic reaction occurs when symptoms develop in areas other than the bite site.

[0097] In yet another embodiment, the methods described herein may be applicable to the treatment of vitiligo. Vitiligo as used herein is a chronic disorder that causes depigmentation of skin patches. This occurs when melanocytes die or become unable to function. The cause of vitiligo is unknown, but research suggests that it may result from autoimmune, genetic, oxidative stress, neurological, or viral causes. The incidence worldwide is less than 1%, and the most common form is non-segmental vitiligo. Symptoms usually begin between the ages of 10 and 30 and include whitening or graying of the hair, loss of skin color in the mouth, and loss of eye color. The most notable symptom of vitiligo is depigmentation of skin patches that occur on the limbs. In non-segmental vitiligo (NSV), there is usually some form of symmetry in the location of the depigmented patches. New patches also appear over time and may generalize over a large part of the body or be localized to specific areas. Vitiligo, characterized by little or no remaining pigmented skin, is called generalized vitiligo. Unlike segmental vitiligo, which is very common in teenagers, non-segmental vitiligo (NSV) can occur at any age. Classes of non-segmental vitiligo include generalized vitiligo, generalized vitiligo, localized vitiligo, acrofacial vitiligo, and mucosal vitiligo. Segmental vitiligo (SV) has varying prevalence due to its appearance, etiology, and associated diseases. Its treatment differs from that of NSV. It tends to affect areas of skin associated with the posterior roots of the spine. It spreads much more rapidly than NSV, and if left untreated, its course is much more stable / static, it is not associated with autoimmune diseases, and it is a treatable condition that responds to topical treatment.

[0098] It should be understood that the metal-DFO complexes, compositions, complexes, kits, and methods described herein may be applicable to any form of inflammatory skin disorder, specifically any form of dermatitis or psoriasis disclosed herein.

[0099] Furthermore, it should be understood that in certain embodiments, the methods described herein may be applicable to the treatment of acute or chronic wounds. In some further embodiments, the methods may be applicable to the treatment of chemical or thermal burns and acute or chronic injuries caused by mechanical impact / blows. Thus, the disclosed methods may be useful for wound healing.

[0100] As used herein, the term wound refers to a relatively rapid type of injury in which the skin is torn, cut, or punctured (open wound), or blunt trauma causes a contusion (closed wound). In pathology, this specifically refers to a sharp injury that damages the dermis of the skin. Wounds can be further classified as penetrating and non-penetrating. Penetrating wounds result from trauma that penetrates the entire thickness of the skin and reaches the underlying tissues and organs. Non-penetrating wounds are usually the result of blunt trauma or friction with another surface, and this type of wound does not penetrate the skin. Various types of wounds include thermal injuries: Thermal injuries (burns, sunburns, frostbite, etc.) can be caused by extreme temperatures, which are either very high or very low. Burns are a type of burn resulting from contact with heated objects such as boiling water, steam, hot cooking oil, fire, and hot objects. Burns from boiling water and steam are the most common type of burn affecting children, but in adults, burns are most commonly caused by fire. Burns are generally classified by severity from first to fourth degree, although the American Burn Association (ABA) simply classifies burns as mild, moderate, and severe based on the depth and size of the burn. Chemical wounds: These result from contact with or inhalation of chemicals that cause damage to the skin or lungs. Chemical burns occur when living tissue is exposed to corrosive substances such as strong acids or strong bases. Chemical burns can cause extensive tissue damage according to standard burn classifications. The main types of irritating and / or corrosive products are acids, bases, oxidizing / reducing agents, solvents, and alkylating agents. In addition, chemical burns can be caused by several types of chemical weapons, such as blistering agents like mustard gas and lewisite, or whealing agents like phosgene oxime. Bites and stings: Bites can originate from humans, dogs, bats, rodents, snakes, scorpions, spiders, and ticks. Electrical wounds: These typically present as superficial burn-like or puncture-like wounds resulting from the passage of high-voltage currents through the body, and may include more serious internal injuries.

[0101] Wounds can be classified as acute or chronic depending on the healing time. Acute wounds heal without complications within the expected timeframe. Chronic wounds take longer to heal and may have several complications. Factors contributing to non-healing chronic wounds include diabetes, venous or arterial disease, infections, and metabolic deficiencies in older adults.

[0102] Diabetic foot non-healing wounds are considered one of the most important complications of diabetes and represent a significant global medical, social, and economic burden that greatly impacts the quality of life of patients. Associated with inadequate circulation, venous dysfunction, and immobility, non-healing wounds occur most frequently in the elderly and in diabetic patients (a population rapidly increasing with the aging population and rising chronic disease rate in the country).

[0103] While diabetes can damage the body in many ways, unhealed ulcers of the feet and lower legs are a common and outward manifestation of the disease. Diabetic patients also frequently suffer from nerve damage in the feet and legs, and may develop minor wounds or irritations unconsciously. Given the abnormalities of the microvascular system and other complications of diabetes, these wounds take a long time to heal and require specialized treatment approaches for proper healing.

[0104] Pressure ulcers, also known as pressure sores, bedsores, and decubitus ulcers, are localized injuries to the skin and / or underlying tissues, usually occurring on bony prominences as a result of pressure, or pressure combined with shear and / or friction. The most common sites are the skin above the sacrum, coccyx, heels, or buttocks, but other areas such as the elbows, knees, ankles, or posterior cranial region can also be affected.

[0105] Pressure ulcers develop when pressure applied to soft tissue completely or partially obstructs blood flow to that tissue. Shearing is also a contributing factor, as it can pull on the blood vessels supplying the skin. Pressure ulcers most commonly develop in individuals who are immobile, such as those who are bedridden or confined to a wheelchair. It is widely believed that other factors can affect the skin's tolerance to pressure and shear, thereby increasing the risk of developing pressure ulcers. These factors include protein-calorie malnutrition, microclimate (skin wetting caused by sweating or incontinence), diseases that reduce blood flow to the skin, such as arteriosclerosis, or diseases that reduce skin sensation, such as paralysis or neuropathy. Healing of pressure ulcers can be delayed by a person's age, condition (such as arteriosclerosis, diabetes, or infection), smoking, or medications such as anti-inflammatory drugs.

[0106] As shown above, in some embodiments, the disclosed method may be for wound healing. Wound healing is a complex process in which skin or other body tissues repair themselves or are repaired after injury. In normal skin, the epidermis (surface layer) and dermis (deep layer) form a protective barrier against the external environment. When this barrier is breached, a coordinated cascade of biochemical events is rapidly activated to repair the damage. This process can be divided into predictable stages: blood clotting (hemostasis), inflammation, new tissue growth (proliferation), and tissue remodeling (maturation).

[0107] It should not be overlooked that the compositions described herein may be acceptable as topical application compositions, particularly when used to treat inflammatory skin disorders. Specific embodiments are intended for the treatment of psoriasis by topical administration to affected skin areas, specifically by ointments, creams, suspensions, pastes, lotions, powders, solutions, oils, encapsulated gels, liposomes containing complexes, any nanoparticles containing complexes, or combinations thereof, using sprayable aerosols or vapors. Conventional pharmaceutical carriers, aqueous, powdered, or oily bases, thickeners, etc., may be required or desirable. The terms “topical application” or “topical administration” mean that an ointment, cream, emollient, balm, lotion, solution, plaster, ointment, or any other pharmaceutical form is applied to part or all of the skin of a patient who has, had, is affected by, exhibits, or exhibits one or more symptoms of psoriasis or other skin lesions.

[0108] Similarly, the metal-DFO complexes or any pharmaceutical compositions thereof described herein, as well as the methods, may be applicable to prevent, treat, improve or suppress other inflammatory / immune-mediated disorders, such as inflammatory bowel disease (IBD), specifically ulcerative colitis and Crohn's disease.

[0109] Inflammatory bowel disease (IBD) is a common gastrointestinal disorder that can be recognized as a result of an imbalance between the Th1 pro-inflammatory and Th2 anti-inflammatory subtypes of the immune response. IBD is a group of inflammatory conditions of the colon and small intestine. The main types of IBD are Crohn's disease and ulcerative colitis (UC). Other forms of IBD account for far fewer cases. These include collagenous colitis, lymphocytic colitis, ischemic colitis, vasocolitis, and undifferentiated colitis when a definitive diagnosis cannot be made to distinguish Crohn's disease from ulcerative colitis.

[0110] The main difference between Crohn's disease and ulcerative colitis (UC) lies in the location and nature of the inflammatory changes. Crohn's disease can affect any part of the digestive tract from mouth to anus (skip lesions), although the majority of cases begin in the terminal ileum. In contrast, ulcerative colitis is limited to the colon and rectum. Microscopically, ulcerative colitis is limited to the mucosa (inner epithelium of the intestine), while Crohn's disease affects the entire intestinal wall. Finally, Crohn's disease and ulcerative colitis present with different rates of extraintestinal symptoms (such as liver problems, arthritis, skin symptoms, and eye problems). Crohn's disease and ulcerative colitis share the same symptoms, including diarrhea, vomiting, weight loss, fever, and abdominal pain.

[0111] Since inflammatory processes are central to immune-mediated disorders, the anti-inflammatory effects of the compositions described herein make them suitable for the treatment of subjects suffering from immune-mediated disorders, such as various forms of arthritis. It should be understood that various forms of arthritis can generally be classified into two main categories, inflammatory arthritis and degenerative arthritis, each with different causes. Accordingly, according to one specific embodiment, metal-DFO complexes or any pharmaceutical compositions thereof may be particularly intended for the treatment and / or alleviation of inflammatory disorders, such as inflammatory arthritis.

[0112] Inflammatory arthritis is characterized by synovitis, bone erosion, osteopenia, soft tissue swelling, and uniform narrowing of the joint cavity. More specifically, the features of arthritis are synovitis and bone erosion. The latter initially appears as a focal discontinuity in a thin white subchondral plate. Usually, this subchondral plate can be seen even in cases of severe osteopenia, but its discontinuity indicates bone erosion. While it is true that periarticular and focal subchondral plateonia can precede true bone erosion, the presence of bone erosion also indicates clear arthritis. As bone erosion expands, bone destruction spreads into the trabeculae within the medullary cavity. One of the important features of inflammatory arthritis concerns the concept of marginal bone erosion. This term is given to bone erosion located at the margin of the inflamed synovial joint. This particular location represents the part of the joint that is intra-articular but not covered by hyaline cartilage. Therefore, early arthritis causes marginal erosion before erosion of the subchondral plate beneath the joint surface. When searching for bone erosion, it is essential to take images of the joint from multiple angles to profile various bone surfaces. A second important feature of the inflammatory joint process is uniform narrowing of the joint cavity. This occurs because the destruction of the articular cartilage is uniform throughout the intra-articular space. A third finding of inflammatory joint disease is soft tissue swelling.

[0113] Inflammatory arthritis can be further divided into several subgroups, and therefore, it should be understood that the metal-DFO complexes, compositions, and methods described herein may be applicable to the treatment of all inflammatory arthritis, including different subgroups of arthritis. Systemic arthritis is characterized by the involvement of multiple joints and includes two main categories: rheumatoid arthritis and seronegative spondyloarthritis.

[0114] According to one embodiment, the metal-DFO complexes, compositions, and methods described herein may be used for the treatment and / or alleviation of rheumatoid arthritis. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder that most commonly causes inflammation and tissue damage of the joints (arthritis) and tendons, along with anemia. It can also cause diffuse inflammation of the lungs, pericardium, pleura, and sclera of the eye, and can also cause nodular lesions, which are the most common in the subcutaneous tissue. This can result in a state of physical disability and pain, which can lead to substantial loss of function and mobility. Serological markers such as rheumatoid factor and antibodies against cyclic citrullinated peptides are important indicators of rheumatoid arthritis. The radiographic features of rheumatoid arthritis are characteristic of arthritis, including specific osteopenia, uniform joint cavity loss, bone erosion, and soft tissue swelling. Due to the chronic nature of the inflammation, further findings such as joint subluxation and subchondral cysts may also be apparent.

[0115] The category of seronegative spondyloarthritis includes psoriatic arthritis, reactive arthritis, and ankylosing spondylitis, characterized by distal lesions of the hands and feet with additional features of inflammation, multiple joint lesions, and bone proliferation. Therefore, according to one embodiment, the disclosed metal-DFO complex, composition, and method may be used to treat and / or alleviate any condition in the category of seronegative spondyloarthritis.

[0116] More specifically, according to one non-limiting embodiment, the metal-DFO complexes, compositions, and methods described herein may be used to prevent, treat, alleviate, or suppress any type of arthritis, including psoriatic arthritis. Psoriatic arthritis is a chronic disease characterized by inflammation of the skin (psoriasis) and joints (arthritis).

[0117] Men and women are equally likely to develop psoriasis. In the case of psoriatic arthritis, men are more likely to have the spondylitis type (involving the spine), while women are more likely to have the rheumatoid type (potentially involving many joints). Psoriatic arthritis typically develops in people between the ages of 35 and 55, however, it can develop in people of any age. Psoriatic arthritis shares many characteristics with several other arthritis conditions, including ankylosing spondylitis, reactive arthritis, and arthritis associated with Crohn's disease and ulcerative colitis. All of these conditions can cause inflammation of the spine and joints, eyes, skin, mouth, and various other organs.

[0118] In yet another embodiment, the metal-DFO complexes, compositions, and methods described herein may be used to prevent, treat, alleviate, or suppress reactive arthritis (ReA). Reactive arthritis, another type of seronegative spondyloarthropathy, is an autoimmune condition that develops in response to an infection in another part of the body. Contact with bacteria and the development of an infection can trigger reactive arthritis. It has symptoms similar to various other conditions collectively known as “arthritis,” such as rheumatoid arthritis. It is triggered by another infection and is therefore “reactive,” i.e., dependent on the other condition. The “trigger” infection is often cured or in remission in chronic cases, thus making it difficult to determine the initial cause.

[0119] The symptoms of reactive arthritis very often include a combination of three seemingly unrelated symptoms: inflammatory arthritis of the large joints, inflammation of the eyes (conjunctivitis and uveitis), and urethritis. ReA is also known as Reiter's syndrome, named after the German physician Hans Reiter, and it should be noted that it is also known as arthritis urethritis, venereal arthritis, and polyarteritis enteroarteriosis.

[0120] It should be understood that there are many other forms of inflammatory arthritis, including juvenile idiopathic arthritis, gout and pseudogout, and arthritis associated with colitis or psoriasis. Therefore, it should be understood that metal-DFO complexes, compositions, and methods are also applicable to these conditions.

[0121] Accordingly, the metal-DFO complexes, compositions, and methods described herein may be used to prevent, treat, reverse, or suppress juvenile idiopathic arthritis (JIA). JIA is the most common form of persistent arthritis in children (in this context, juvenile refers to onset before the age of 16, idiopathic refers to a condition without a defined cause, and arthritis is inflammation of the synovial membrane of the joints). JIA is a subset of arthritis seen in childhood and can be transient and self-limiting or chronic. It differs significantly from other types of arthritis that can be present in childhood (e.g., psoriatic arthritis and ankylosing spondylitis), which are commonly seen in adults and are chronic conditions.

[0122] Furthermore, in some specific embodiments for inflammatory disorders, any inflammatory respiratory disease, such as asthma, may benefit from treatment with the metal-DFO complex, composition described herein, where a therapeutically effective amount of the composition is administered to a subject suffering from the disease. Thus, in specific embodiments, the method may be used for the prevention, treatment, and / or reduction of respiratory disorders, specifically asthma.

[0123] Asthma is a common chronic inflammatory disease of the airways characterized by variable and recurrent symptoms, reversible airflow obstruction, and bronchospasm. Common symptoms include wheezing, cough, chest tightness, and shortness of breath. Asthma is thought to be caused by a combination of genetic and environmental factors. Its diagnosis is usually based on the pattern of symptoms, response to treatment over time, and vital capacity measurements. It is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate. Asthma can also be classified as atopic (exogenous) or non-atopic (endogenous), where atopic refers to a predisposition to developing type 1 hypersensitivity reactions.

[0124] Treatment for acute asthma symptoms typically involves inhaled short-acting beta-2 agonists (such as salbutamol) and oral corticosteroids. In very severe cases, intravenous corticosteroids, magnesium sulfate, and hospitalization may be necessary. Symptoms can be prevented by avoiding triggers such as allergens and irritants, as well as by the use of inhaled corticosteroids. If asthma symptoms remain uncontrolled, long-acting beta agonists (LABAs) or anti-leukotriene agents may be used in addition to inhaled corticosteroids.

[0125] Asthma is the result of chronic inflammation of the airways, which subsequently leads to increased contractility of the surrounding smooth muscle. This, among other factors, results in the classic symptoms of airway narrowing attacks and wheezing. The narrowing is typically reversible, with or without treatment. Occasionally, the airways themselves change. Typical changes in the airways include an increase in eosinophils and thickening of the reticular layer. Chronically, the smooth muscle of the airways may increase in size, along with an increase in the number of mucous glands. Other cell types involved include T lymphocytes, macrophages, and neutrophils. Involvement of other components of the immune system, including cytokines, chemokines, histamine, and leukotrienes, may also be present.

[0126] While there is no cure for asthma, symptoms can typically be managed. A specific, customized plan must be developed to actively monitor and manage symptoms. This plan should include reducing allergen exposure, conducting tests to assess symptom severity, and using medications. A treatment plan should be written out, and adjustments to treatment as symptoms change should be advised.

[0127] Importantly, the metal-siderophores disclosed herein, specifically metal-DFO complexes, not only serve as preventive measures against the development of the described respiratory disorder conditions but also reduce subsequent tissue damage, thus providing an additional therapeutic aspect to currently available drugs.

[0128] It should be noted that drugs for asthma and other respiratory disorders are typically provided as metered-dose inhalers (MDIs) combined with an asthma spacer, or as dry powder inhalers. The spacer is a plastic cylinder that mixes the drug with air, making it easier to receive the entire amount of medication. Nebulizers may also be used. Thus, the metal-DFO B complexes described herein can be administered using such MDIs and further combined with any other asthma medications, specifically those listed above.

[0129] As shown above, this disclosure intends to provide methods for treating various immune-related respiratory diseases. In addition to asthma, such respiratory diseases may include any other acute allergic symptoms of the airways, chronic rhinosinusitis (CRS), allergic rhinitis, COPD, nasal polyposis (NP), vasomotor rhinitis, airway hyperresponsiveness, cystic fibrosis and pulmonary fibrosis, or allergic sinusitis. Accordingly, this disclosure provides methods, combination compositions and kits for preventing, treating, reversing or suppressing any of the above respiratory diseases.

[0130] Therefore, in certain embodiments, the metal-DFOs described herein may be used to treat sinusitis. Sinusitis is an inflammation of the sinuses, which can result from infection, allergies, or autoimmune problems. In most cases, it is caused by a viral infection and resolves within 10 days. It is a common condition, with more than 24 million cases reported annually in the United States.

[0131] Chronic sinusitis, by definition, lasts for more than three months and can be caused by many different conditions that share chronic inflammation of the sinuses as a common symptom. Cases of chronic sinusitis are subdivided into those with and without polyps. When polyps are present, the condition is called chronic hyperplastic sinusitis. However, its causes are not well understood and may include environmental factors such as allergies, dust or pollution, bacterial infections, or fungal infections (allergic, infectious, or reactive). Non-allergic factors such as vasomotor rhinitis can also cause chronic sinus problems.

[0132] Allergic rhinitis, hay fever, or seasonal rhinitis, which can be treated by the methods described herein, is an allergic inflammation of the nasal cavity. This occurs when an individual with a sensitized immune system inhales allergens such as pollen or dust, which triggers antibody production. Most of these antibodies bind to mast cells containing histamine. When mast cells are stimulated by pollen and dust, histamine (and other chemicals) are released. This causes itching, swelling, and mucus production. Symptoms vary in severity from person to person. Highly sensitive individuals may experience urticaria or other rashes.

[0133] Chronic obstructive pulmonary disease (COPD), also known as chronic obstructive lung disease (COLD), chronic obstructive airway disease (COAD), chronic airflow limitation (CAL), and chronic obstructive respiratory disease (CORD), refers to a pair of commonly co-occurring lung diseases: chronic bronchitis and emphysema, which narrow the airways. This leads to restricted airflow into and out of the lungs, causing shortness of breath. In contrast to asthma, airflow limitation is rarely reversible and usually worsens gradually over time. COPD is most commonly caused by harmful particles or gases from smoking, which trigger an abnormal inflammatory response in the lungs. The inflammatory response in the larger airways is known as chronic bronchitis and is clinically diagnosed when people regularly cough up sputum. In the alveoli, the inflammatory response leads to the destruction of lung tissue, a process known as emphysema. The natural course of COPD is characterized by occasional, sudden exacerbations of symptoms called acute exacerbations, most of which are caused by infections or air pollution. This method, combination composition, and kit are applicable to the treatment of COAD and COPD.

[0134] Furthermore, the metal-DFOs described herein may be used to treat nasal polyps. Nasal polyps are polyp-like lumps that arise primarily from the mucous membranes of the nose and sinuses. They are often mucous overgrowths accompanied by allergic rhinitis. They are freely mobile and not tender to the touch. Nasal polyps are usually classified into posterior nasal polyps and ethmoid polyps. Posterior nasal polyps originate from the maxillary sinus, while ethmoid polyps, though far less common, originate from the ethmoid sinus. Posterior nasal polyps are usually solitary and unilateral, while ethmoid polyps are multiple and bilateral.

[0135] Non-allergic rhinitis refers to a runny nose that is not caused by allergies. Non-allergic rhinitis can be classified as either non-inflammatory or inflammatory rhinitis. One very common type of non-inflammatory non-allergic rhinitis, which is sometimes confused with allergies, is called vasomotor rhinitis, in which certain non-allergic triggers such as odors, fumes, smoke, dust, and temperature changes cause rhinitis. These non-allergic triggers are thought to cause dilation of blood vessels inside the nose, which leads to swelling and drainage. Vasomotor rhinitis can coexist with allergic rhinitis, which is called "mixed rhinitis." Vasomotor rhinitis appears to be significantly more common in women than in men, and some researchers believe that hormones play a role. Generally, the age of onset is after the age of 20, in contrast to allergic rhinitis, which can develop at any age. Individuals with vasomotor rhinitis typically experience symptoms year-round, but symptoms may worsen in spring and fall when rapid weather changes are more common. An estimated 17 million Americans suffer from vasomotor rhinitis. The antihistamine azelastine has been shown to be effective for allergic rhinitis, mixed rhinitis, and vasomotor rhinitis.

[0136] Airway hyperresponsiveness (or other combinations of bronchospasm and hyperresponsiveness) is a condition characterized by easily induced bronchospasm (constriction of the bronchioles or small airways). Airway hyperresponsiveness can be assessed with a bronchial loading test, most often using products such as methacholine or histamine. While these chemicals can induce bronchospasm in normal individuals, the threshold is lower for those with bronchial hyperresponsiveness. Although bronchial hyperresponsiveness is a prominent feature of asthma, it also frequently occurs in people with chronic obstructive pulmonary disease (COPD).

[0137] Another example of a condition treatable with the disclosed metal-DFO is cystic fibrosis (also known as CF), a common disease that affects the entire body, causing progressive disability and often premature death. The name cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation within the pancreas. Dyspnea is the most severe symptom, resulting from a high incidence of persistent lung infections that are treated with antibiotics and other drugs. Numerous other symptoms, including sinus infections, stunted growth, diarrhea, and infertility, arise from the effects of CF on other parts of the body. CF is caused by mutations in the protein cystic fibrosis transmembrane conductance regulator (CFTR) gene and is considered an autosomal recessive disorder.

[0138] Pulmonary fibrosis is the formation or development of excessive fibrous connective tissue (fibrosis) in the lungs. It can be described as "scarring of the lungs." Pulmonary fibrosis involves the gradual replacement of normal lung parenchyma with fibrous tissue. The thickening of scar tissue leads to an irreversible decrease in oxygen diffusion capacity. In addition, reduced compliance makes pulmonary fibrosis a restrictive lung disease. This is the main cause of restrictive lung diseases specific to the lung parenchyma.

[0139] Some embodiments relate, in particular, to methods for treating respiratory diseases with the disclosed metal-DFOs. According to one embodiment, such compositions may be particularly adapted for pulmonary delivery by oral or nasal inhalation. More specifically, pulmonary delivery may require the use of a liquid nebulizer, an aerosol-based metered-dose inhaler (MDI), or a dry powder dispersion device.

[0140] In further embodiments, the metal-DFO provides a method for treating or preventing an infection or condition in a mammalian subject caused by any pathogen, specifically at least one of bacterial pathogens, viral pathogens, and parasites. More specifically, the method comprises the step of administering an effective amount of the metal-DFO complex or any composition thereof to a subject in need.

[0141] As used herein, “infection” refers to the invasion of living tissue by disease-causing agents, their proliferation, and the host tissue’s response to these organisms and the toxins they produce. Infections, also known as contagious diseases or infectious illnesses, are diseases caused by infection. It should be understood that as used herein, infection also includes any infection caused by a pathogen. Pathogens include bacteria, viruses, prokaryotes, lower eukaryotes, complex eukaryotes, prions, parasites, yeasts, nematodes such as parasitic roundworms and pinworms, arthropods such as ticks, mites, fleas and lice, fungi such as ringworms, and other macroparasites such as tapeworms and other helminths.

[0142] Examples of prokaryotic microorganisms include, but are not limited to, Gram-positive bacteria, Gram-negative bacteria, Gram-variable bacteria, acid-fast microorganisms, and intracellular bacteria, as described in detail below in this specification. Examples of lower eukaryotes include yeasts and fungi such as Pneumocystis carinii, Candida albicans, Aspergillus, Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcus neoformans, Trichophyton, and Microsporum.

[0143] Complex eukaryotes include helminths, insects, spiders, nematodes, amoebas, Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis, Trypanosoma brucei gambiense, Trypanosoma cruzi, Balantidium coli, Toxoplasma gondii, Cryptosporidium, or Leishmania.

[0144] The term "virus" is used in its broadest sense and includes viruses of the adenoviridae, papovaviridae, herpesviridae (herpes simplex, varicella-zoster, Epstein-Barr virus, CMV), hepatitis A, hepatitis B, hepatitis C, influenza viruses A and B, poxviruses (smallpox, vaccinia), rhinovirus, poliovirus, rubella virus, arbovirus, rabies virus, flavivirus, measles virus, mumps virus, HIV, and HTLV I and II.

[0145] The term "fungus" includes fungi that cause diseases such as tinea, histoplasmosis, blastomycosis, aspergillosis, cryptococcosis, sporotrichosis, coccidioidomycosis, paracoccidioidomycosis, and candidiasis.

[0146] The term “parasite” includes, but is not limited to, somatic tapeworms, schistosomiasis, tissue roundworms, amoebas, and infections caused by various genera of Plasmodium, Trypanosoma, Leishmania, and Toxoplasma.

[0147] It should be noted that complexes of DFO with at least one metal can chelate unstable iron and / or copper, reducing the availability of unstable iron for microbial synthesis and growth purposes, thereby inhibiting the growth of pathogenic microorganisms and reducing the degree of infection / inflammation. Therefore, in some embodiments, metallic DFO may be useful in methods for treating infections caused by bacterial pathogens. In some specific embodiments, the bacterial pathogen may be at least one of enteropathogenic Escherichia coli (EPEC), Pseudomonas aeruginosa, and Staphylococcus aureus.

[0148] Bacterial infections are an example of inflammation-related disorders. The metal-DFOs described herein, including complexes or any combination thereof, and their pharmaceutical compositions may be used to prevent, treat, mitigate, or suppress bacterial infections. More specifically, the term “bacterial infection” refers to an infection caused by bacteria. In this context, the term “bacteria” (in the singular, “bacterium”) refers to any type of single-celled microorganism. The term, as used herein, includes a general classification according to its basic shape, namely spherical (cocci), rod-shaped (bacilli), spiral (spiral bacteria), comma-shaped (vibrio) or corkscrew-shaped (spirochetes), as well as bacteria existing as single cells, in pairs, in chains or in clusters.

[0149] In more specific embodiments, the term “bacteria” specifically refers to Gram-positive, Gram-negative, or acid-fast microorganisms. Gram-positive bacteria appear purple under a microscope because they retain the crystal violet stain used in Gram staining for bacterial differentiation. Gram-negative bacteria do not retain crystal violet, allowing for positive identification. In other words, the term “bacteria” as used herein applies to bacteria with a thicker peptidoglycan layer in the cell wall outside the cell membrane (Gram-positive) and bacteria with a thinner peptidoglycan layer in the cell wall sandwiched between the intracytoplasmic cell membrane and the bacterial outer membrane (Gram-negative).

[0150] The disclosed metal-DFO may act as an anti-inflammatory agent, a bacteriostatic agent and / or a disinfectant, and a potent chelating agent for unstable, redox-active iron. In some embodiments, examples of bacteria intended herein include the genera Treponema sp., Borrelia sp., Neisseria sp., Legionella sp., Bordetella sp., Escherichia sp., Salmonella sp., Shigella sp., Klebsiella sp., Yersinia sp., Vibrio sp., Hemophilus sp., Rickettsia sp., Chlamydia sp., Mycoplasma sp., Staphylococcus sp., and Streptococcus. Examples include the genera Bacillus sp., Clostridium sp., Corynebacterium sp., Proprionibacterium sp., Mycobacterium sp., Ureaplasma sp., and Listeria sp.In more specific embodiments, bacterial pathogens include enteropathogenic Escherichia coli (EPEC), Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pyogenes, Clostidium difficile, Enterococcus faecium, Klebsiella pneumonia, Acinetobacter baumanni, Enterobacter spp., Mycobacterium tuberculosis, Alcaligenes faecalis, Neisseria meningitis, and Prevotella intermedia. Examples include, but are not limited to, species of the genera Salmonella, Sigella, Proteus, Providencia, Enterobacter, and Morganella.

[0151] Therefore, the disclosed metal-DFO-containing compositions exhibit substantial antimicrobial effects applicable to the treatment of infection-borne disorders. It should also be understood that the beneficial antimicrobial effects of metal-DFO complexes or any of these compositions may be enhanced by combination with other known antimicrobial agents.

[0152] Furthermore, in some embodiments, the disclosed method may be applicable to the treatment of proliferative disorders in subjects requiring treatment. In some specific embodiments, the method includes administering a therapeutically effective amount of at least one complex of DFO and at least one metal, or any disclosed pharmaceutical composition, carrier, or vehicle containing the same, to a subject to be treated. It should be further understood that the method may be particularly relevant to proliferative disorders, which are malignancies associated with at least one of elevated pro-inflammatory cytokine levels and decreased anti-inflammatory cytokine levels.

[0153] The term “proliferative disorder” refers to cell division and growth that are not part of the normal cellular turnover, metabolism, growth, or proliferation of the entire organism. Unwanted cell proliferation is observed in tumors and other pathological proliferations of cells that do not perform normal function and, for the most part, continue uninhibited at a rate exceeding the normal growth rate of cells in normal tissue in the absence of external intervention. Pathological conditions resulting from unwanted cell proliferation are called “hyperproliferative disorders” or “hyperproliferative disorders.” It should be noted that the terms “proliferative disorder,” “cancer,” “tumor,” and “malignant tumor” are all equally related to the hyperplasia of tissue or organ. In general, the compositions and methods described herein may be used in the treatment of non-solid and solid tumors.

[0154] Furthermore, the malignant tumors envisioned herein may be any one of carcinoma, melanoma, lymphoma, leukemia, myeloma, and sarcoma. As used herein, carcinoma refers to an invasive malignant tumor consisting of transformed epithelial cells. Alternatively, this refers to a malignant tumor composed of transformed cells of unknown histogenesis but possessing certain molecular or histological features associated with epithelial cells, such as the production of cytokeratin or intercellular crosslinks.

[0155] As used herein, melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce melanin, the dark pigment responsible for skin color. They are primarily found in the skin, but can also be found in other parts of the body, including the intestines and eyes. Melanoma can occur in any part of the body that contains melanocytes.

[0156] Leukemia refers to a progressive malignant disease of the hematopoietic organs, generally characterized by abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally classified clinically based on (1) the duration and characteristics of the acute or chronic disease, (2) the type of cells involved; myeloid, lymphoid, or monocytic, and (3) an increase or absence of the number of abnormal cells, whether hematological leukemic or non-leukemic (subleukemic).

[0157] Sarcomas are cancers that arise from transformed connective tissue cells. These cells originate from the embryonic mesoderm or intermediate layer that forms bone, cartilage, and adipose tissue. This is in contrast to carcinomas that originate in the epithelium, which covers the surface of structures throughout the body and is the origin of cancers of the breast, colon, and pancreas.

[0158] Myeloma, as referred to herein, is a cancer of plasma cells, a type of white blood cell typically responsible for antibody production. The abnormal cell aggregates accumulate in the bone, causing bone lesions, and in the bone marrow, these aggregates interfere with the production of normal blood cells. Most cases of myeloma are also characterized by the production of paraproteins, abnormal antibodies that interfere with the production of normal antibodies, potentially leading to kidney problems and immunodeficiency. Hypercalcemia (high calcium levels) is frequently encountered.

[0159] Lymphoma is a cancer of the lymphoid cells of the immune system. Typically, lymphomas exist as solid tumors of lymphoid cells. These malignant cells often originate from lymph nodes and manifest as enlargement (tumor) of the lymph nodes. This can also affect other organs, in which case it is called extranodal lymphoma. Non-specific examples of lymphoma include Hodgkin's disease, non-Hodgkin lymphoma, and Burkitt's lymphoma.

[0160] Further malignancies that can be treated and / or prevented by the metal-DFO complexes described herein include, but are not limited to, hematological malignancies (including lymphoma, leukemia and myeloproliferative disorders as described above), dysplasia and aplastic anemia (both viral and idiopathic), myelodysplastic syndromes, all kinds of paraneoplastic syndromes (both immune-mediated and idiopathic), and solid tumors (including gastrointestinal, colon, lung, liver, breast, prostate, pancreatic and Kaposi's sarcoma). Metal-DFO complexes may also be applicable to the treatment or suppression of solid tumors such as those of the lips and oral cavity, pharynx, larynx, paranasal sinuses, major salivary glands, thyroid gland, esophagus, stomach, small intestine, colon, colon, anal canal, liver, gallbladder, extrahepatic bile duct, ampulla of Vater (hepatopancreatic duct), exocrine pancreas, lung, pleural mesothelioma, bone, soft tissue sarcoma, skin carcinomas and malignant melanoma, breast, vulva, vagina, cervix, uterine body, ovaries, fallopian tubes, gestational trophoblastic tumor, penis, prostate, testes, kidney, renal pelvis, ureter, bladder, urethra, eyelid cancer, conjunctival cancer, conjunctival malignant melanoma, uveal malignant melanoma, retinoblastoma, lacrimal gland cancer, orbital sarcoma, brain, spinal cord, vascular system, angiosarcoma, and Kaposi's sarcoma.

[0161] In some further embodiments, the disclosed metal-DFO may be useful for treating neurodegenerative disorders in subjects requiring such treatment, comprising the step of administering to the subject a therapeutically effective amount of at least one complex of DFO with at least one metal, or any combination thereof, or any pharmaceutical composition, carrier, matrix, or vehicle containing the same. In some embodiments, the neurodegenerative disorder is at least one of the group of “neurodegenerative diseases” characterized by neurodegenerative processes, including at least one of amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. Such diseases are incurable and result in progressive degeneration and / or death of neuronal cells.

[0162] The term "neurodegeneration" is a general term referring to the progressive loss of structure or function of neurons, ultimately leading to their death. The greatest risk factor for neurodegenerative diseases is aging. Mitochondrial DNA mutations and oxidative stress both contribute to aging. Many of these diseases are late-onset, meaning that for each disease there are factors that change as a person ages. One constant factor is that in each disease, neurons gradually lose function as the disease progresses with age.

[0163] In some further embodiments, metal-DFO complexes and their compositions may be applicable to the treatment of spinal cord injury and trauma. Spinal cord injury (SCI) is damage to the spinal cord that causes changes in its function. The injury can occur at any level of the spinal cord and can be classified as complete injury, complete loss of sensation and muscle function, or incomplete, meaning that some nerve signals can pass through the injured area of ​​the spinal cord. Depending on the location and severity of the injury along the spinal cord, symptoms can vary widely, from mild, such as pain or numbness, to severe, such as paralysis and incontinence.

[0164] Spinal cord injuries can be traumatic or non-traumatic and can be classified into three types based on their cause: mechanical force, toxicity, and ischemia (due to insufficient blood supply). Injuries can also be divided into primary and secondary injuries: primary injuries involve immediate cell death at the site of the initial injury, while secondary injuries involve a biochemical cascade initiated by the initial injury, which can lead to further tissue damage including activation of the ischemic cascade, inflammation, swelling, apoptosis, and neurotransmitter imbalance. These can occur over minutes or weeks following the injury.

[0165] Typically, spinal cord injury (SCI) results from physical trauma such as traffic accidents, gunshot wounds, falls, and sports injuries, but it can also be caused by other factors such as infection, insufficient blood flow, or pressure from tumors. Non-traumatic SCIs account for 30% to 80% of all SCIs. SCIs can occur due to infections, disc diseases, and spinal vascular diseases. Spontaneous bleeding can occur inside or outside the protective membrane lining the spinal cord, and a disc can herniate. Injuries can occur due to vascular dysfunction such as arteriovenous malformations, or when blood clots block blood vessels, cutting off the blood supply to the spinal cord. A decrease in systemic blood pressure can reduce blood flow to the spinal cord, potentially causing loss of sensation and voluntary movement in the areas supplied by the affected level of the spinal cord. Congenital conditions and tumors compressing the spinal cord can also cause SCIs, as can spondylosis and ischemia. Multiple sclerosis is a disease that can damage the spinal cord, as can infectious and inflammatory conditions such as tuberculosis, herpes zoster or herpes simplex, meningitis, myelitis, and syphilis. In developed countries, the most common cause of non-traumatic SCI is degenerative diseases, followed by tumors, while in many developing countries, the main causes are infectious diseases such as HIV and tuberculosis.

[0166] SCI is also classified according to the degree of impairment. The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), published by the American Spinal Injury Association (ASIA), is widely used to record sensory and motor impairments after SCI. This is based on neurological responses, tactile and pricking sensations tested in each dermatome, and the strength of the muscles that control important movements on both sides of the body.

[0167] The prognosis ranges from complete recovery to permanent paralysis of the limbs, known as tetraplegia (also called quadriplegia), in cases of cervical-level injuries, and paraplegia (paralysis of two limbs) in cases of lower-level injuries. Short-term and long-term complications that can occur after injury include muscle atrophy, pressure ulcers, infections, and respiratory problems. Swelling can cause further damage to the spinal cord by reducing blood supply and causing ischemia, which can trigger an ischemic cascade involving the release of toxins that damage neurons.

[0168] It should be further understood that the disclosed metal-DFO complexes may be applicable to any of the spinal cord injuries described herein and associated conditions or complications. In further embodiments, the disclosed metal-DFO complexes may be useful in treating ischemic injury in a subject in need, comprising the step of administering to the subject a therapeutically effective amount of at least one complex of DFO and at least one metal, or any combination thereof, or any pharmaceutical composition, carrier, matrix or vehicle containing the same, wherein the ischemic injury is at least one of atherosclerosis of the arteries of the heart, brain, arms, legs, pelvis and kidneys.

[0169] The term "ischemia" means "a reduction in blood supply." As used herein, the term "ischemic disorder" refers to a group of disorders characterized by ischemic vascular disease, that is, disorders characterized by the accumulation of a waxy substance called plaque inside blood vessels, which thereby restricts normal blood flow. When plaque accumulates in arteries, this condition is called "atherosclerosis." Atherosclerosis can affect any artery in the body, including the arteries of the heart, brain, arms, legs, pelvis, and kidneys. As a result, different diseases may develop depending on which arteries are affected.

[0170] Ischemic vascular disease (IVD) is a term that encompasses a group of diseases resulting from plaque buildup. In some embodiments, the metal-DFO complexes described herein may be applicable to coronary heart disease (CHD). Coronary heart disease occurs when atherosclerosis affects the coronary arteries of the heart. When oxygen-rich blood flow to the myocardium is reduced or blocked, angina (pain) or a heart attack may occur, respectively.

[0171] In some embodiments, the metal-DFO complexes described herein may be applicable to the treatment of heart attacks. A heart attack occurs when oxygen-rich blood flow to a portion of the heart muscle is blocked. If blood flow is not rapidly restored, the portion of the heart muscle begins to die. Without prompt treatment, a heart attack can lead to serious problems, and even death. Furthermore, in some embodiments, the method may be applicable to carotid artery disease (CAD). Carotid artery disease occurs when plaque accumulates in the arteries on either side of the carotid arteries. These arteries supply oxygen-rich blood to the brain. Therefore, if blood flow to the brain is reduced or blocked, even for a few minutes, oxygen deprivation can cause damage or death of brain cells, known as a stroke. When brain cells die or are damaged due to a stroke, symptoms occur in the parts of the body controlled by these brain cells. Examples of symptoms of a stroke include sudden weakness; paralysis or numbness of the face, arms, or legs; difficulty speaking or understanding speech; and visual impairment.

[0172] In some further embodiments, the metal-DFO complexes described herein may be applicable to the treatment of peripheral arterial disease (PAD). PAD is a disease in which plaque accumulates in the arteries of the legs or arms. Blockage of blood flow to the legs can cause pain and numbness. It can also increase the risk of infection in the affected limb. In severe cases, blockage of blood flow can cause gangrene (tissue death).

[0173] As mentioned above, all types of ischemic vascular disease are caused by atherosclerosis. Atherosclerosis can begin when certain factors damage the inner lining of the arteries. These factors include smoking, certain high levels of fat and cholesterol in the blood, high blood pressure, and high levels of sugar in the blood due to insulin resistance or diabetes.

[0174] In some further embodiments, the metal-DFO complexes described herein may be useful for treating metabolic disorders in subjects requiring such treatment, comprising the step of administering to the subject a therapeutically effective amount of at least one complex of DFO and at least one metal, any combination thereof, or any pharmaceutical composition, carrier, matrix or vehicle containing the same. In some embodiments, the method may be particularly relevant to metabolic disorders, specifically at least one of type 1 diabetes, type 2 diabetes and any diabetes-related conditions.

[0175] Metabolism is the process by which the body uses food to obtain or produce energy. Food consists of proteins, carbohydrates, and fats. Chemicals in the digestive system break down food into sugars and acids, which the body can then use immediately, or they can be used to store energy in body tissues such as the liver, muscles, and body fat.

[0176] A "metabolic disorder" occurs when abnormal chemical reactions disrupt this process. Individuals can develop metabolic disorders if certain organs, such as the liver or pancreas, are affected or not functioning properly. Diabetes mellitus (DM), commonly known as type 5 diabetes, is a group of metabolic disorders characterized by persistently high blood glucose levels. If left untreated, diabetes can lead to many complications. Acute complications include diabetic ketoacidosis and nonketotic hyperosmolar coma. Serious long-term complications include cardiovascular disease, stroke, chronic renal failure, foot ulcers, and eye damage. Diabetes is caused by either insufficient insulin production by the pancreas (type 1 diabetes) or a lack of adequate response by the body's cells to the insulin produced (type 2 diabetes).

[0177] There is growing evidence linking inflammation to the development of type 2 diabetes. This evolving concept, which suggests that insulin resistance and type 2 diabetes may have immune components, offers new avenues for anti-inflammatory therapies for type 2 diabetes. Therefore, based on their anti-inflammatory effects, compositions and methods described herein can be used to treat and / or alleviate autoimmune disorders such as diabetes.

[0178] Diabetes mellitus is a syndrome characterized by metabolic disorders and inappropriately high blood sugar levels (hyperglycemia), resulting from low levels of the hormone insulin or compensating for insufficient insulin secretion and abnormal resistance to insulin action. Characteristic symptoms include excessive urine production (polyuria), excessive thirst and increased fluid intake (polydipsia), and blurred vision; however, if blood sugar levels are only slightly elevated, these symptoms are unlikely to be present.

[0179] Diabetes has three main forms: type 1 diabetes, type 2 diabetes, and gestational diabetes (which occurs during pregnancy). Type 1 diabetes is characterized by the loss of insulin-producing beta cells in the islets of Langerhans in the pancreas, resulting in insulin deficiency. The main cause of this beta cell loss is T-cell-mediated autoimmune attack. No preventive measures are known for type 1 diabetes. Most affected individuals are otherwise healthy and have a healthy weight at the time of onset. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Type 1 diabetes can develop in children or adults and has traditionally been called "juvenile diabetes" because it represents the majority of cases of diabetes that develop in children.

[0180] In yet another specific embodiment, the metal-DFO compositions described herein may be used to prevent, treat, reverse, or suppress type 2 diabetes. Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, is a metabolic disorder characterized by hyperglycemia in a state of insulin resistance and relative insulin deficiency. As the condition progresses, medication may be required. Long-term complications due to hyperglycemia include an increased risk of heart attack, stroke, amputation, and renal failure. There are many factors that can potentially cause or worsen type 2 diabetes. These include obesity, hypertension, elevated cholesterol (combined hyperlipidemia), and a condition often called metabolic syndrome (also known as syndrome X, Levan syndrome, or CHAOS). Other causes include acromegaly, Cushing's syndrome, hyperthyroidism, pheochromocytoma, chronic pancreatitis, cancer, and medications. Further factors found to increase the risk of type 2 diabetes include aging, a high-fat diet, and a sedentary lifestyle.

[0181] Insulin resistance means that somatic cells do not respond properly when insulin is present. Unlike type 1 diabetes, insulin resistance is generally "post-receptor," meaning it is a problem with the cells that respond to insulin, not with the production of insulin. Severe complications can arise from poorly managed type 2 diabetes, including renal failure, erectile dysfunction, blindness, slow-healing wounds (including surgical incisions), and arterial diseases, including coronary artery disease. While type 2 diabetes most commonly develops in middle age and beyond, it is becoming more frequent in adolescents and young adults due to increased childhood obesity and lack of physical activity.

[0182] It should be further understood that the metal-DFO complex methods, kits, and complexes described herein may be applicable to the treatment of diabetes-related conditions. The terms “associated” and “related” as used interchangeably herein should be understood to mean, when referring to medical conditions, diseases, disorders, conditions, or any medical conditions that share a causal relationship, coexist more frequently than by chance, or in which at least one disease, disorder, condition, or medical condition causes a second disease, disorder, condition, or medical condition. Such conditions may include, for example, eye-related complications (cataracts, glaucoma, retinopathy), neuropathy, nephropathy, cardiomyopathy, stroke, hypertension, peripheral artery disease, and pressure ulcers and any ulcers, chronic ulcers, or slow-healing ulcers, or injuries of the skin or organs associated with diabetic conditions. According to this disclosure, undesirable side effects to be treated or prevented are preferably eye and / or vision-related side effects such as cataracts.

[0183] The therapeutic methods and uses described herein may also be used for the benefit of persons suffering from diabetes-related or diabetes-associated diseases or disorders, including hyperinsulinemia, dyslipidemia, hypercholesterolemia, impaired glucose tolerance, hypertension, cardiovascular disease, diabetic cardiomyopathy, diabetic arrhythmias, atherosclerosis, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease, microalbuminuria, and albuminuria.

[0184] Hyperinsulinemia is a condition characterized by excessive levels of circulating insulin in the blood. Also known as prediabetes, insulin resistance, and syndrome X, it is commonly associated with PCOS (polycystic ovary syndrome) in women. Hyperinsulinemia is often mistaken for diabetes or hypoglycemia, as these are both distinct conditions. If left unmonitored and untreated, hyperinsulinemia can develop into diabetes, and if diabetes develops, it may remain present. It is not caused by diabetes, as is commonly believed. Hyperinsulinemia can cause hypoglycemia in some patients.

[0185] As used herein, dyslipidemia refers to a disturbance in the amount of lipids in the blood. In developed societies, most cases of dyslipidemia are hyperlipidemia, that is, elevated blood lipid levels, often caused by diet and lifestyle. Long-term elevated insulin levels can lead to dyslipidemia. Increased O-GlcNAc transferase (OGT) levels are known to cause dyslipidemia. Impaired glucose tolerance (IGT) is a prediabetic state characterized by abnormal blood glucose levels associated with insulin resistance and an increased risk of cardiovascular disease. IGT can precede type II diabetes for many years.

[0186] As used herein, hypertension (HTN) or hypertension is a chronic condition characterized by elevated blood pressure in the arteries. This is the opposite of hypotension. It is classified as either primary (systemic) or secondary. Approximately 90–95% of cases are called "primary hypertension," which refers to hypertension for which no medical cause can be found. In the remaining 5–10% of cases (secondary hypertension), it is caused by other conditions affecting the kidneys, arteries, heart, or endocrine system. Persistent hypertension is a risk factor for stroke, heart attack, heart failure, and aneurysm, and is a major cause of chronic renal failure.

[0187] As used herein, cardiomyopathy is a clinical or subclinical condition diagnosed when ventricular dysfunction develops in diabetic patients in the absence of impaired myocardial function, such as coronary atherosclerosis and hypertension. Functionally, it is characterized by impaired or preserved systolic function in the presence of ventricular dilation, myocyte hypertrophy, interstitial fibrosis, and diastolic dysfunction.

[0188] Atherosclerosis (also known as arteriosclerotic vascular disease or ASVD) is a condition in which the walls of arteries thicken as a result of the accumulation of fatty substances such as cholesterol. It is a syndrome that affects arterial blood vessels and is a chronic inflammatory response in the arterial walls, largely caused by the accumulation of macrophages (leukocytes) and promoted by low-density lipoproteins (plasma proteins that transport cholesterol and triglycerides), and occurs when there is insufficient removal of fats and cholesterol from macrophages by functional high-density lipoproteins (HDL). This is commonly referred to as arterial hardening or narrowing. This is caused by the formation of multiple plaques within the arteries.

[0189] Diabetic nephropathy, also known as Kimmel-Steel-Wilson syndrome, or tuberous diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive renal disease caused by vascular damage to the capillaries in the renal glomeruli. It is characterized by renal syndrome and diffuse glomerulosclerosis. It is a result of diabetes over many years and is a major indication for dialysis in many Western countries.

[0190] Glomerulonephritis, also known as glomerulonephritis (GN), is a kidney disease characterized by inflammation of the glomeruli or small blood vessels of the kidney. It may present with isolated hematuria and / or proteinuria (the presence of blood and / or protein in the urine) or can be treated as renal syndrome, acute renal failure, or chronic renal failure. These are classified into several different pathological patterns, which are broadly classified into non-proliferative and proliferative types. The primary cause is specific to the kidney, while secondary causes are associated with certain infections (bacterial, viral, or parasitic pathogens), drugs, systemic disorders (systemic disorders, SLE, vasculitis), or diabetes.

[0191] Glomerulosclerosis refers to the hardening of the glomeruli in the kidneys. It is a common term used to describe the scarring of the renal glomeruli. Proteinuria (large amounts of protein in the urine) is one of the signs of glomerulosclerosis. Diabetes mellitus is a frequent cause of glomerulosclerosis.

[0192] Renal syndrome is a condition in which the kidneys are damaged and large amounts of protein (1.73 mg) are released. 2 It is a nonspecific disorder that causes the leakage of at least 3.5 grams of protein per day per body surface area from the blood into the urine.

[0193] In kidneys affected by renal syndrome, the podocytes have small pores that are large enough to tolerate proteinuria (resulting in hypoalbuminemia as some of the proteinalbumin moves from the blood to the urine), but not large enough to allow cells to pass through (hence, no hematuria). In contrast, in nephritis syndrome, RBCs pass through the pores, causing hematuria. Diabetes is often an underlying cause of renal syndrome.

[0194] Hypertensive nephropathy, or hypertensive nephrosclerosis, or hypertensive kidney disease, is a medical condition referring to kidney damage due to chronic hypertension. In the kidneys, as a result of benign arterial hypertension, hyaline (a pink, amorphous, homogeneous substance) accumulates in the walls of arterioles and arterioles, leading to thickening of these walls and narrowing of the tubules (hyaline arteriosclerosis). The resulting ischemia leads to tubular atrophy, interstitial fibrosis, glomerular changes (smaller glomeruli with varying degrees of hyaline formation, from mild to sclerotic glomeruli), and periglomerular fibrosis. In advanced stages, renal failure occurs. Functional nephrons have dilated tubules and often have hyaline columns in the lumen. Further complications often associated with hypertensive nephropathy include glomerular damage, which leads to proteinuria and hematuria.

[0195] End-stage renal failure is an advanced stage of chronic kidney disease (CKD), also known as chronic kidney disease. CKD manifests as a progressive loss of kidney function over months or years. Symptoms of kidney function deterioration are nonspecific and may include general malaise and loss of appetite. Recent expert guidelines classify the severity of chronic kidney disease into five stages, with stage 1 being the mildest and usually causing few or no symptoms, and stage 5 being a severe disease with a short life expectancy if left untreated. Stage 5 CKD is also called advanced chronic kidney disease and is synonymous with the now-outdated terms end-stage renal disease (ESRD), chronic kidney failure (CKF), or chronic renal failure (CRF).

[0196] As shown above, the metal-DFOs disclosed herein may be used to treat any immune-related disorder. It should be noted that “immune-related disorder” is a condition that can be treated, prevented, or diagnosed by targeting specific components of the immune response in a subject, such as an adaptive or innate immune response, either through activation or suppression of the immune system. Such disorders may be either inflammatory diseases or autoimmune diseases.

[0197] According to one specific embodiment, the metal-DFOs disclosed herein may be particularly suitable for treating inflammatory diseases or inflammation-related conditions. The terms “inflammatory disease” or “inflammation-related condition” refer to any disease or pathological condition that may benefit from a reduction in at least one inflammatory parameter, such as the induction of inflammatory cytokines, e.g., IFN-γ and IL-2. The condition may be caused (primarily) by inflammation, or inflammation may be one of the symptoms of a disease caused by another physiological cause.

[0198] Other immune-related disorders that can be treated by the methods and kits described herein include ulcerative colitis, Crohn's disease, irritable bowel disease (IBD), alopecia areata, lupus, ankylosing spondylitis, Meniere's disease, antiphospholipid syndrome, mixed connective tissue disease, autoimmune Addison's disease, multiple sclerosis, autoimmune hemolytic anemia, myasthenia gravis, autoimmune hepatitis, pemphigus vulgaris, Behçet's disease, pernicious anemia, bullous pemphigoid, polyarteritis nodosa, cardiomyopathy, polychondritis, herpetiform dermatitis, polyglandular syndrome, and chronic fatigue syndrome. Syndrome (CFIDS), polymyalgia rheumatica, chronic inflammatory demyelination, polymyositis and dermatomyositis, chronic inflammatory polyneuropathy, primary agammaglobulinemia, Churg-Strauss syndrome, primary biliary cirrhosis, pemphigoid scarring, psoriasis, CREST syndrome, Raynaud's phenomenon, cold agglutinin disease, Reiter's syndrome, rheumatic fever, lupus discoid, rheumatoid arthritis, essential mixed cryoglobulinemia, sarcoidosis, fibromyalgia, scleroderma, Graves' disease, Sjögren's syndrome, Guillain-Barré syndrome, stiff person syndrome, Hashimoto's disease, Takayasu's arteritis, idiopathic pulmonary fibrosis, temporal arteritis / giant cell arteritis, idiopathic thrombocytopenic purpura Examples include, but are not limited to, purpura (ITP), IgA nephropathy, uveitis, vasculitis, lichen planus, and vitiligo. The metal-DFO complexes described herein may be administered to subjects to treat or prevent disorders associated with abnormal or undesirable immune responses related to the above diseases.

[0199] Compositions comprising the disclosed metal-DFO may be useful in treating any condition associated with the disorders described above. The terms “associated” and “related” as used interchangeably herein are understood to mean, when referring to medical conditions, diseases, disorders, conditions or any medical conditions that share a causal relationship, coexist more frequently than by chance, or in which at least one disease, disorder, condition or medical condition causes a second disease, disorder, condition or medical condition.

[0200] Furthermore, it should be understood that there are numerous possible clinical applications for these complexes, including but not limited to the treatment of amyotrophic lateral sclerosis, age-related macular degeneration, cataracts, sepsis, wound healing, injury from exposure to chemical agents, heat or cold, ischemia and reperfusion injury, stroke, injury from ionizing radiation, injury associated with pulmonary anemia, and hemochromatosis and Wilson's disease.

[0201] Furthermore, it should be noted that in certain embodiments, the metal-DFO complexes disclosed herein may be applicable to the treatment of any disorder associated with elevated IL-1α levels. Examples of these disorders include sepsis, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, myocardial infarction, coronary artery disease, atherosclerosis, inflammatory cardiomyopathy, cardiac hypertrophy, osteoarthritis, CAPS, Schnitzler syndrome, ankylosing spondylitis, systemic lupus erythematosus, familial Mediterranean fever, systemic juvenile idiopathic arthritis, Mackle-Wells syndrome, gout, pseudogout, type 2 diabetes, psoriatic arthritis, psoriasis, antisynthetic enzyme syndrome, anterior cruciate ligament rupture, relapsing polychondritis, hemochromatosis-associated wrist arthritis, chronic relapsing polymyelitis, erosive osteoarthritis of the hand, heart failure, diabetic cardiomyopathy, asymptomatic multiple myeloma, giant cell arteritis, dry eye disease, metabolic syndrome, hidradenitis suppurativa, acne, Behçet's disease, and more. This includes, but is not limited to, one of the following: Lau syndrome / granulomatous arthritis, mevalonate kinase deficiency, Magid syndrome, Henoch-Schönlein purpura, idiopathic recurrent pericarditis, macrophage activation syndrome, Sweet's syndrome / neutrophilic dermatosis, neutrophilic panniculitis, Erdheim-Chester disease / histiocytosis, multicentric Castleman disease, Jessner-Kanov disease, Kawasaki disease, colitis associated with chronic granulomatous disease, PAPA syndrome, SAPHO syndrome, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, fibrosarcoma, type 1 diabetes, stroke, acute brain injury, Alzheimer's disease, colorectal cancer, breast cancer, malignant melanoma, glioma, prostate cancer, cervical cancer, lung cancer, bladder cancer, Paget's disease, or tumor necrosis factor receptor-associated periodic syndromes.

[0202] In other embodiments, the metal-DFOs disclosed herein may be applicable to the treatment of any disorder associated with elevated TNF-α levels. Non-limiting examples include septic shock, inflammatory bowel disease, ulcerative colitis, juvenile idiopathic arthritis, Takayasu's arteritis, pathological corneal neovascularization and lymphangiogenesis, sarcoidosis, amyloidosis, postoperative cognitive impairment, ovarian cancer, stroke, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, psoriasis, psoriatic arthritis, pediatric Crohn's disease, pediatric ulcerative colitis, colorectal cancer, idiopathic pulmonary fibrosis, cystic fibrosis, retinitis pigmentosa, pancreatic cancer, Paget's disease, and tumor necrosis factor receptor-associated periodic syndromes.

[0203] Furthermore, it should be noted that in certain embodiments, the metal-DFO complexes disclosed herein may be applicable to the treatment of any disorder associated with elevated IL-6 levels. These disorders include rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, periodontitis, pneumonitis, idiopathic pulmonary fibrosis, depression, colorectal cancer, uveitis, Castleman disease, systemic juvenile idiopathic arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, vasculitis syndrome, spondyloarthritis, relapsing polychondritis, acquired hemophilia A, autoimmune hemolytic anemia, adult-onset Still's disease, amyloid A amyloidosis, polymyalgia rheumatica, edematous remitting seronegative symmetric synovitis, Behçet's disease, graft-versus-host disease, tumor necrosis factor receptor-associated periodic syndromes, pulmonary arterial hypertension, atopic dermatitis, sciatica, relapsing polychondritis, type 2 diabetes, obesity, Graves' ophthalmopathy, and rheumatoid arthritis. Cardiovascular diseases in urban areas include giant cell arteritis, non-ST-elevation myocardial infarction, schizophrenia, ovarian cancer, fibrous dysplasia of bone, primary Sjögren's syndrome, ankylosing spondylitis, Ertheim-Chester disease, ANCA-associated vasculitis, neuromyelitis optica, chronic glomerulonephritis, Takayasu's arteritis, prostate cancer, renal cell carcinoma, multiple myeloma, lymphoma, cytokine release syndrome, listeriosis, asthma, COPD, psoriasis, multiple sclerosis, osteoarthritis, sepsis, interstitial lung disease, intraocular inflammation, endometriosis, Alzheimer's disease, traumatic brain injury, breast cancer, pancreatic cancer, AIDS-related conditions, cutaneous and systemic plasmacytosis, gastric cancer, cervical cancer, malignant melanoma, hepatocellular carcinoma, leukemia, glioblastoma, uterine cancer, cystic fibrosis, oral cancer, and Paget's disease.

[0204] In certain embodiments, the metal-DFO complexes disclosed herein may be applicable to the treatment of any disorder associated with elevated IL-17 levels. Examples of such disorders include inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondyloarthritis, multiple sclerosis, asthma, colorectal cancer, lung cancer, hepatocellular carcinoma, hepatic fibrosis, esophageal squamous cell carcinoma, glioblastoma, ovarian cancer, breast cancer, malignant melanoma, gastric cancer, head and neck cancer, nasopharyngeal cancer, COPD, SAPHO syndrome, pulmonary fibrosis, cardiac fibrosis, renal fibrosis, Paget's disease, osteosarcoma, gastric ulcer, bladder cancer, systemic juvenile idiopathic arthritis, systemic lupus erythematosus, airway neutrophilia, cystic fibrosis, allergic rhinitis, alopecia areata, atopic dermatitis, cutaneous T-cell lymphoma, and mastocytosis.

[0205] As used herein, the term “method” means a style, means, technique and procedure for accomplishing a given task, for example, but not limited to, those that are publicly known to those skilled in the art in the fields of chemistry, pharmacology, biology, biochemistry and medicine, or that can be readily developed from styles, means, techniques and procedures known to those skilled in the art.

[0206] As used herein, “disease,” “disorder,” “condition,” etc., are interchangeable because they relate to the health of the subject, and each and all of such terms have meaning.

[0207] As used herein, “treatment” means the administration of a therapeutic dose of the metal-DFO complex described herein that is effective in improving undesirable symptoms associated with the disease, preventing the onset of such symptoms before they occur, slowing the progression of the disease, slowing the worsening of symptoms, enhancing the onset of remission, delaying irreversible damage caused in the progressive chronic phase of the disease, delaying the onset of the progression phase, reducing the severity or curing the disease, improving survival or faster recovery, preventing the onset of the disease, or a combination of two or more of the above.

[0208] The “effective dose” for the purposes disclosed herein is determined by considerations known in the art. The dose must be effective in achieving the desired therapeutic effect described above, in particular, depending on the type and severity of the disease being treated and the treatment regimen. The effective dose is typically determined in a well-designed clinical trial (dose-range study), and those skilled in the art know how to appropriately conduct such a trial to determine the effective dose. As is generally known, the effective dose depends on a variety of factors, including various pharmacological parameters such as the distribution profile in the body and the half-life in the body, undesirable side effects (if any), age, and sex.

[0209] More specifically, compositions containing the disclosed metal-DFO complex or any combination, mixture, or cocktail thereof may be administered for prophylactic and / or therapeutic purposes. In therapeutic applications, the composition is administered to patients already suffering from inflammation or immune-related disorders, or specifically, disorders associated with at least one of elevated levels of pro-inflammatory cytokines and / or decreased levels of anti-inflammatory cytokines, in an amount sufficient to cure or at least partially cessate the condition and its complications. The amount sufficient to achieve this is defined as the “therapeutic effective dose.” The amount effective for this use depends on the severity of the condition and the general state of the patient’s own immune system, but is generally in the range of about 0.01 to about 10,000 mg / kg, specifically about 0.01 to about 1000, 500, 250, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, and 0.1 mg / kg. It should be noted that in certain embodiments, effective doses may be approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg / kg or more. In some further embodiments, the effective dose may be 2.5 mg / kg of the metal-DFO complex or any combination thereof. Single or multiple doses on a daily, weekly, or monthly schedule can be administered at dose levels and patterns selected by the treating physician. More specific embodiments relate to the use of doses typically two to three times per week.

[0210] The term "prevention" refers to preventing or mitigating the occurrence or recurrence of a biological or medical event, specifically the occurrence or recurrence of a disorder associated with at least one of elevated levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines, which are required to be prevented by researchers, veterinarians, physicians, or other clinicians in tissues, systems, animals, or humans. The term "preventive effective dose" is intended to mean the amount of the pharmaceutical composition that achieves this objective. Therefore, in certain embodiments, the disclosed method is particularly effective for prevention, i.e., prevention of conditions associated with infection. Thus, subjects administered with the composition are less likely to experience symptoms associated with the infection, and less likely to experience recurrence in subjects who have previously experienced it.

[0211] As used herein, the term “relief” refers to a reduction in symptoms and improvement of the condition of the subject, which may manifest as inhibition of pathological processes related to immune-related disorders as described herein, a significant reduction in their magnitude, or an improvement in the physiological condition of the disease subject.

[0212] The term "inhibit" and all variations thereof are intended to include limiting or prohibiting the progression and worsening of pathological symptoms or processes, the symptoms or processes of such pathological processes being relevant.

[0213] The term “elimination” optionally refers to the substantial eradication or removal of pathological symptoms and, if applicable, pathological etiologies by the following methods:

[0214] The terms “delay,” “delay onset,” and “shorten,” and all variations thereof, are intended to encompass delaying the progression and / or worsening of a pathological disorder or infection, as well as delaying the progression, further worsening, or onset of their symptoms, so that they appear later than in the absence of treatment.

[0215] More specifically, treatment or prevention includes preventing or delaying the onset of the disease, preventing or delaying the onset of symptoms, and / or reducing the severity of such symptoms that have developed or are expected to develop. These further include improving existing symptoms, preventing further symptoms, and improving or preventing the underlying metabolic causes of the symptoms. The terms “suppression,” “mitigation,” “reduction,” or “attenuation” as used herein should be understood to refer to a delay, suppression, or reduction of a process by approximately 1% to 99.9%, specifically by approximately 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 99%, or 99% to 99.9%.

[0216] The disclosed methods relate to the treatment of subjects or patients in need of them. “Patient” or “subject in need” means any organism that may be infected with the aforementioned pathogens and for which the prevention and control kits, systems and methods described herein are desired, including humans, dogs and cats, livestock and non-livestock mammals such as cattle, monkeys, horses and mice, rodents, poultry, aquaculture, fish and exotic ornamental fish. It should be understood that the subject to be treated may also be any reptile or zoo animal. More specifically, the disclosed kits and methods are intended to prevent pathological conditions in mammals. “Mammalian subject” means any mammal for which the proposed treatment is desired, including humans, horses, dogs and cats, most specifically humans. Specifically, it should be noted that in the case of non-human subjects, the methods may be carried out using injection, administration via drinking water, feed, spray, oral lavage and direct administration into the gastrointestinal tract of the subject in need.

[0217] Another embodiment relates to a complex of DFO with at least one metal. In some embodiments, the complex is of DFO with at least one metal, where the at least one metal may be a post-transition metal or a transition metal. In another embodiment, the complex is of DFO with at least one metal, where the metal may be selected from the group consisting of zinc, gallium, silver, gold, molybdenum, and vanadium. In a further embodiment, the complex is of DFO with at least one metal, where the metal is Zn 2+ , Ga 3+ Ag 1+ and Au 3+ It is selected from the group consisting of the following. In a specific embodiment, the complex is made of DFO and Zn 2+ It is a complex with Ga. In some other embodiments, the complex is Ga 3+ It may be a DFO that has this property.

[0218] In some specific embodiments, the DFOs described herein relate to compositions of DFO and at least one metal for use in methods of treating, preventing, suppressing, reducing, eliminating, protecting against or delaying the onset of pathological conditions or disorders in subjects where such treatment is needed.

[0219] Combinations of separate pharmaceutical compositions in kit form are also described. The kit comprises at least two separate pharmaceutical compositions: (i) lanthanides, actinides, post-transition metals or transition metals, or any combination thereof, which are at least one form of salts, esters and amides thereof, and a pharmaceutically acceptable carrier or diluent; and (ii) DFO or a pharmaceutically acceptable derivative thereof, further combined with a hydrophilic nonionic surfactant comprising polyethylene glycol (PEG) and a nonionic triblock copolymer, optionally further comprising a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) adjacent to two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). In some embodiments, the hydrophilic nonionic surfactant is a poloxamer. In particular, the hydrophilic nonionic surfactant may be poloxamer 407.

[0220] In some specific embodiments, the metal contained in the kit may be at least one of zinc, gallium, silver, gold, molybdenum, and vanadium. In some specific embodiments, the kit may contain zinc. In some further embodiments, the kit may contain gallium. Furthermore, in some embodiments, the kit may contain zinc and gallium.

[0221] More specifically, the kit includes container means for housing both distinct compositions, such as divided bottles or divided foil packets. However, the distinct compositions may also be housed in a single, undivided container. Typically, the kit includes instructions for administering the distinct components. The kit form is particularly advantageous when the distinct components are preferably administered in different dosage forms (e.g., parenteral versus topical), at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0222] The kit may further contain acids in a separated container. In some embodiments, the acids are 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, alkanesulfonic acid, alkenesulfonic acid, alkynesulfonic acid with any substitution, adipic acid, ascorbic acid, aspartic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, The following are selected from the list: lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid or its derivatives, or substituted hydrocarbyl sulfonic acids, such as hydroxy-substituted, alkoxy-substituted, acyloxy-substituted, alkoxycarbonyl-substituted, halogen-substituted, aromatic-substituted, or amino-substituted alkyl sulfonic acids, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid, salicylic acid, sebacic acid, serenic acid, selenonic acid, or any selenine or selenone analog of the aforementioned sulfonate compounds, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, and undecylenic acid.

[0223] In some embodiments, the kit enables the use of an active ingredient in a method for treating, preventing, suppressing, reducing, eliminating, protecting against, or delaying the onset of a pathological condition or disorder in a subject where such treatment is needed.

[0224] In some other specific, non-limiting embodiments, metal-DFOs may be administered to subjects suffering from disorders involving elevated levels of IL-1α, TNF-α, IL-6, and IL-17 to reduce those IL-1α, TNF-α, IL-6, and IL-17 levels, comprising the step of administering a therapeutically effective dose of the kit to subjects suffering from the pathological disorders or diseases outlined above, in combination with at least one additional therapeutic compound of the choice. It should be further noted that the application of the kit or any of its components may form a complementary therapeutic regimen for subjects suffering from the pathological disorders or diseases outlined above.

[0225] Furthermore, the kits and complexes described herein, and any of their components, may be applied as a single daily dose or as multiple daily doses, preferably every 1 to 7 days. Such application may be once, twice, three, four, five, or six times per day, or may be applied once per day, every two days, every three days, every four days, every five days, every six days, every week, every two weeks, every three weeks, every four weeks, or even once a month. The application of the kit or any of its components may last for a maximum of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, one month, two months, three months, or longer. Specifically, the application may last from one day to one month. Most specifically, the application may last from one day to seven days.

[0226] The metal-DFO complex may contain either zinc or gallium. Under the conditions described below, the method involves mixing DFO (e.g., deferoxamine B) with zinc or gallium, where the metal is contained in a molar ratio of 1:0.01 to 1:100, usually 1:1, relative to the DFO.

[0227] One option is to mix the acids in a molar ratio of 1:0.01 to 1:100, usually 1:1 to DFO, for example: 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, alkanesulfonic acid, alkenesulfonic acid, alkynesulfonic acid with any substitution, adipic acid, ascorbic acid, aspartic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonate, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid This is in the presence of any of the following acids, which are not limited to hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid or its derivatives, or substituted hydrocarbyl sulfonic acids, such as hydroxy-substituted, alkoxy-substituted, acyloxy-substituted, alkoxycarbonyl-substituted, halogen-substituted, aromatic-substituted or amino-substituted alkyl sulfonic acids, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid, salicylic acid, sebacic acid, serenic acid, selenonic acid, or any selenine or selenone analog of the aforementioned sulfonate compounds, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, and undecylenic acid.

[0228] Another embodiment involves a process for preparing a complex of DFO with a metal ion, the process of contacting DFO with a metal ion such as zinc or gallium, in which the metal is present in a molar ratio of 1:0.01 to 1:100 relative to the DFO. In some selective embodiments, the stoichiometric ratio of metal to DFO is 1:1.

[0229] In some embodiments, the process for producing a complex of a metal ion with DFO involves contacting DFO (e.g., deferoxamine B) with a metal ion such as zinc or gallium, in the presence of an acid, where the metal is present in a molar ratio of 1:0.01 to 1:100 relative to DFO, with either the DFO or / or the metal ion in the form of a salt, and the acid in a molar ratio of 1:0.01 to 1:100, usually 1:1 relative to DFO. 1-Hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, alkanesulfonic acid, alkenesulfonic acid, alkynesulfonic acid with any substitution, adipic acid, ascorbic acid, aspartic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate Formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid or its derivatives, or substituted hydrocarbyl sulfonic acid, for example, hydroxy substitution, alkoxy substitution, acyloxy substitution, Selected from the group consisting of alkoxycarbonyl-substituted, halogen-substituted, aromatic-substituted, or amino-substituted alkyl sulfonic acids, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid, salicylic acid, sebacic acid, serenic acid, selenonic acid, or any selenine or selenone analog of the aforementioned sulfonate compounds, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, and undecylenic acid. [Examples]

[0230] simulated gastric juice In the first step of the study, the stability of the Zn-DFO complex in simulated gastric juice was tested. It is important to note that the stability of metal-ligand complexes is known to be pH-dependent. Previous studies have shown that the zinc-deferoxamine complex exists as a single entity within the pH range of 3 to 9, and beyond these conditions, it separates into two distinct entities, zinc and deferoxamine. Of these entities, only deferoxamine may be affected by the harsh conditions of gastric juice.

[0231] For this purpose, immediate-release gelatin capsules containing a Zn-DFO complex were placed in a dissolution chamber, and simulated gastric medium stirring experiments were performed at 37°C with and without pepsin (medium I) (USP-NF General Chapter Monograph). <711> The release and stability of deferoxamine were monitored. The dissolved and released Zn-DFO contents were monitored and measured by HPLC. The results are shown in Figure 1.

[0232] Over 90% of the Zn-DFO complex was released from the capsule within 30 minutes in medium II (with pepsin) and within 60 minutes in medium I (without pepsin). These results can be explained by the ability of pepsin to cleave cross-linked gelatin, thereby promoting dissolution. However, the results for medium II meet the acceptable criteria for immediate-release oral capsules. The decrease in Zn-DFO contents in both mediums after more than 1 hour under simulated gastric juice conditions was less than 4%. Therefore, Zn-DFO can be considered stable under the harsh gastric conditions of pH 1.2 and pepsin.

[0233] first pass metabolism In the next step, the effects of first-pass metabolism (liver transit) on Zn-DFO were investigated. Liver microsome stability assays were performed using liver vesicles obtained from six species: miniature pigs, male SD rats, humans, male beagle dogs, male cynomolgus monkeys, and male CD-1 mice. The drugs were incubated for 1 hour, and samples were taken at six time points (0, 5, 15, 30, 45, and 60 minutes) for analysis. Assays of Zn-DFO exposure to human liver microsomes for 1 hour resulted in 78.2% degradation. The resulting T1 / 2 value was 22.4 minutes. Similar results were obtained on rat, dog, mouse, and monkey microsomes. However, degradation by porcine microsomes was less than 25%. These values ​​were considered during the development of therapeutic regimens and formulations. The need to protect the complex from the effects of first-pass metabolism was concluded.

[0234] Formulation development Furthermore, the pharmacokinetics of Zn-DFO were evaluated in rats using intravenous, intraperitoneal, and oral administration. For this purpose, an LC-MS / MS method was developed. Due to the technical characteristics of the LC-MS / MS instrument, separation of zinc ions from Zn-DFO occurred during sample processing in the instrument, making it impossible to directly measure Zn-DFO. Therefore, the method aimed to detect free ligands (DFO alone) or Fe-DFO in rat serum.

[0235] In the first study, rats were administered 6 mg / kg via the IV, PO, and IP routes. This dose proved to be too low to allow for the detection of free DFO (with a few exceptions in the IV route). Fe-DFO levels were detected in both the PO and IV routes, but only sporadically in the IP route. Subsequently, another study was conducted using 30 mg / kg. In this study, the IV and PO routes were tested with several formulations based on different permeability enhancers for oral administration.

[0236] Table 1 shows the formulations that were tested.

[0237] [Table 1]

[0238] In this study, higher levels of free DFO were detected in the serum of rats administered the drug intravenously, but not at any experimental time point. No minimum or significant levels of free DFO exceeding the LOQ were observed in any of the other groups. However, high and significant levels were observed in all groups in which Fe-DFO was evaluated.

[0239] The results are summarized in Table 2.

[0240] [Table 2]

[0241] These comparative results of free DFO and Fe-DFO complex levels in rat blood after a single oral administration indicate that Zn-DFO is rapidly absorbed and rapidly metabolized to Fe-DFO (ultimately via cell exchange between Zn and Fe). The AUC of Fe-DFO formed using the PO route was approximately 50% compared to the value obtained after intravenous administration, i.e., defined as 100%. Interesting data were obtained while investigating the kinetics of DFO and Fe-DFO in rat blood using various administration routes. The concentration of DFO using IV injection began to decrease immediately after its initial detection (Figure 2A), while a second peak was observed for Fe-DFO (Figure 2B).

[0242] This finding may suggest that Fe-DFO is transiently compartmentalized in the liver. Furthermore, it can be confirmed that Fe-DFO represents only a small portion of free DFO, with a relative AUC of 12.41%. On the other hand, when administered orally (diluted with water), free DFO was not detected. However, the level of Fe-DFO was significant, as shown in the figure below (Figure 3).

[0243] After evaluating various oral formulations, formulation #2, based on poloxamer 407: 30% PEG, 10% poloxamer 407, and 70% water, demonstrated superior bioavailability and a reasonable washout time (Figure 4A). This formulation exhibited an extended half-life of Fe-DFO compared to all other formulations, representing 100% relative bioavailability. Therefore, this formulation will be used in future research. Figure 4A shows the dynamics of Fe-DFO in rat blood when Zn-DFO is administered using this formulation, allowing for comparison with two other formulations (Figure 4B - based on Gelucire®, and Figure 4C - based on Labrasol® / Labrafac®).

[0244] Evaluation of the efficacy of a zebrafish (Danio rerio) model for diet-induced type 2 diabetes. In this study, the test compound Zygosid-50 was administered orally via two routes of administration (as an aqueous solution by oral and intraperitoneal injection), and also as a formulation containing a permeability enhancer to understand the activity of Zygosid-50 across treatment groups. Zygosid-50 was administered three times a week. Blood samples were collected to measure fasting blood glucose, oral glucose tolerance, fasting insulin, and HOMA-IR (Hostasis Model Assessment of Insulin Resistance).

[0245] The zebrafish (Danio rerio) model strain used was a acclimatized wild-type individual. All fish were acclimated to constant laboratory conditions (14-hour light:10-hour dark photoperiod, diet, water, 28°C) in a rearing tank for at least one week prior to the experiment. The fish were fed a high-calorie flake diet for six weeks before the start of the experiment. Adult fish (body weight 0.8g ± 0.2g, age 1.5 years) showing no signs of infection were selected and examined using a target selection method and used for experimental analysis.

[0246] A 14 / 10 hour light-dark cycle was maintained throughout the experiment at a water temperature of 27±1℃ and a pH between 7.2±0.4. While adhering to established protocols, the experiment followed the proper animal practices established by the Institutional Animal Ethics Committee (IAEC) of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) in India. A washout process was performed every 48 hours to keep the fish in a clean environment and eliminate the risk of infection.

[0247] Diet-induced obesity and type II diabetes in zebrafish follow metabolic pathways similar to those in mammals. Therefore, a diet-induced obesity model was employed to increase the body weight of the fish. Test fish were fed a high-calorie, high-fat diet (15 mg of dry body weight / day / fish) for 6 weeks to induce adipose tissue deposition around the abdomen. The zebrafish test groups were classified into vehicle, diabetes model, Zygosid-50 IP, Zygosid-50 oral, and Zygosid-50 with a permeability enhancer (20% PEG, 10% poloxamer 407, 70% water), also referred to herein as PE. Treatment groups received up to 11 doses of known dilutions of the test compound. Test groups were screened for fasting glucose after 7 doses, with an additional 4 doses extended before primary drug screening. Test fish were monitored twice daily for phenotypic changes related to visible clinical signs such as motility and redness (indicating inflammation) around the limbs, including the pelvis, chest, and tail. After 11 doses, screening was performed on all test groups to evaluate the therapeutic efficacy of Zygosid-50.

[0248] fasting blood sugar Fasting blood glucose levels of the treated fish were evaluated using a glucometer. The fish were sedated in ice-cold water at 14-16°C for 30 seconds, and then placed laterally on a dissection tray with a minimal amount of water. Approximately 5 μL of blood sample was collected along the body axis and posterior to the anus in the dorsal aorta region. The blood was filled into a glucometer strip, and the reading was recorded.

[0249] Fasting serum insulin assay Fasting serum insulin concentration was measured using an ELISA kit (Invitrogen, Cat#KAQ1251) according to the manufacturer's instructions. Sandwich ELISA (enzyme-linked immunosorbent assay) is designed to measure the amount of target bound between matched antibody pairs. Target-specific antibodies were pre-coated into the wells of a supplied microplate. Samples, standards, or controls were then added to these wells and bound to the immobilized (capture) antibody. A sandwich was formed by the addition of a second (detection) antibody, followed by the addition of a substrate solution that reacts with the enzyme-antibody-target complex to produce a measurable signal. The intensity of this signal is directly proportional to the concentration of the target present in the original sample.

[0250] A standard curve was fitted before sample analysis. Optical density (OD) readings were measured spectrophotometrically at a wavelength of 450 nm ± 2 nm. OD values ​​provide a direct correlation with serum insulin concentration, and the values ​​were calculated by comparing the OD values ​​of the samples with the standard curve.

[0251] HOMA-IR We measured fasting insulin resistance using a previously validated homeostasis model of insulin resistance (HOMA-IR). The resulting IR was statistically significant for fasting insulin (IF) and fasting glucose (GF) (reference) according to the following formula: HOMA-IR (Fasting serum insulin * Fasting blood glucose) / 12.36

[0252] The denominator of 12.36 is the normalization factor, which is the product of the normal fasting plasma insulin of 3 μIU / mL and the normal fasting plasma glucose of 4.12 mmol / L obtained from the vehicle. The HOMA-IR range of 2.22 - 3.16 is considered normal.

[0253] Glucose homeostasis by oral glucose tolerance test Glucose homeostasis was evaluated using an oral glucose tolerance test. The time it takes for the fish to return to the normal blood glucose range determines glucose homeostasis. Glucose D was dissolved in water and administered orally (gastric sonde). The fish were fed 1.25 mg / g body weight. Blood glucose was measured using a glucometer at 0.5 h, 1 h, 1.5 h, 2 h, and 2.5 h after glucose administration.

[0254]

Table 3

[0255] In both the intraperitoneal administration group and the oral Zygosid-50 (30 ng) treatment group combined with a permeation enhancer, a significant decrease in fasting blood glucose levels occurred. However, in the oral Zygosid-50 (30 ng) treatment group, the lowest significance (p ≤ 0.05) of the decrease was observed. When comparing the results by dosage administration route, a significant difference was observed between the intraperitoneal (I.P.) administration and oral administration of Zygosid-50 (30 ng). However, no significance was observed between I.P. and the oral dosage administration combined with a permeation enhancer.

[0256]

Table 4

[0257] When comparing the results by dosage administration route, a significant difference (≤ p0.01) was observed between the intraperitoneal (I.P.) administration and oral administration of Zygosid-50 (30 ng). However, no significance was observed between I.P. and the oral dosage administration combined with a permeation enhancer.

[0258] [Table 5]

[0259] Serum insulin levels in the test groups were examined using an ELISA assay, and the data were expressed as mean and standard deviation. A 7-fold increase in serum insulin levels was observed among diabetic fish treated with Zygosid-50, and a relative decrease in elevated insulin levels was observed among Zygosid-50 IP administered with a permeability enhancer and among Zygosid-50 oral administered with a permeability enhancer, decreasing by 2.3 times and 2 times, respectively. Oral doses of Zygosid-50 also reduced insulin levels, but the permeability enhancer was more effective than oral doses alone.

[0260] [Table 6]

[0261] Treatment with Zygosid-50 significantly restored insulin homeostasis in the test group, although this varied depending on the dose-administration method. Comparing oral Zygosid-50 with Zygosid-50 plus a permeability enhancer, the group treated with Zygosid-50 plus the permeability enhancer showed a significant reduction in insulin resistance compared to the group receiving oral Zygosid-50 alone.

[0262] [Table 7]

[0263] Significant differences were observed among the diabetic fish groups with elevated blood glucose levels up to 2 hours after glucose administration, and these levels did not return to the normal range until 2.5 hours. In the Zygosid-50 treatment group, blood glucose levels were observed to return to the normal range from 1.5 hours after glucose administration. Zygosid-50 was observed to restore glucose homeostasis across both intravenous and oral administration routes. However, blood glucose levels returned to the normal range faster with oral Zygosid-50 and oral Zygosid-50 + permeability enhancer than with the intravenous administration group, and oral Zygosid-50 + permeability enhancer showed slightly higher efficacy.

[0264] This study evaluated the efficacy of the test compound Zygosid-50 in a zebrafish model of type 2 diabetes using various dose-administration routes. Screening parameters included fasting blood glucose levels, fasting serum insulin levels, blood glucose homeostasis as assessed by oral glucose tolerance tests, and HOMA-IR.

[0265] The results showed that Zygosid-50 was effective in reducing elevated fasting glucose and elevated fasting insulin, and in restoring glycemic homeostasis, regardless of the route of administration. However, statistical analysis was performed to determine the precise efficacy of Zygosid-50 via different routes of administration. The results showed that oral administration of Zygosid-50 with a permeability enhancer significantly reduced serum insulin levels, improved glycemic homeostasis, and lowered HOMA-IR.

Claims

1. A composition, A therapeutically effective amount of a complex comprising deferoxamine (DFO-B) or a pharmaceutically acceptable salt thereof and a metal, A hydrophilic nonionic surfactant comprising polyethylene glycol (PEG) and a nonionic triblock copolymer, A composition in which the metal is selected from the group consisting of Zn, Ga, Ag, Au, V, and Mo.

2. The aforementioned metal is Zn ２＋ or Ga ３＋ The composition according to claim 1.

3. The composition according to claim 1, wherein the pharmaceutically acceptable salt is an acid addition salt.

4. The aforementioned acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, alkanesulfonic acid, alkenesulfonic acid, alkynesulfonic acid with any substitution, adipic acid, ascorbic acid, aspartic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, and glutamic acid. The composition according to claim 3, selected from the group consisting of nic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid or its derivatives, substituted hydrocarbylsulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid, salicylic acid, sebacic acid, serenic acid, serenonic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, and undecylenic acid.

5. The composition according to claim 2, wherein the nonionic triblock copolymer is composed of two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)) and a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) adjacent to them.

6. The composition according to claim 5, wherein the hydrophilic nonionic surfactant is poloxamer.

7. The composition according to claim 5, wherein the concentration of polyethylene glycol is in the range of 17 to 23%, and the concentration of the nonionic triblock copolymer, which consists of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) adjacent to two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), is in the range of 8 to 12%.

8. The aforementioned metal is Zn ２＋ The composition according to claim 1, wherein the hydrophilic nonionic surfactant is poloxamer.

9. The aforementioned metal is Ga ３＋ The composition according to claim 1, wherein the hydrophilic nonionic surfactant is poloxamer.

10. The composition according to claim 1, further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, carriers, and excipients.

11. The composition according to claim 1, wherein the composition is formulated for systemic administration, such as by oral, gastric tube feeding, topical, ocular, nasal, or ocular administration, inhalation, ophthalmic administration, parenteral administration by injection, parenteral administration by suppository, parenteral administration by patch, or any other clinically acceptable method and means.

12. The composition according to claim 1, wherein the composition is selected from the group consisting of tablets, minitablets, pills, lozenges, choking preparations, capsules, ingestible preparations, oral suspensions, soluble films, powders, ointments, creams, pastes, encapsulated gels, patches, liposomes, sprayable aerosols, and vapors.

13. A method for regulating cytokine levels in a subject, comprising administering the composition of claim 1.

14. The method according to claim 13, wherein the level of at least one inflammatory cytokine is reduced.

15. The method according to claim 14, wherein the inflammatory cytokine is selected from the group consisting of IL-1α, IL-6, TNF-α, IL-17, and combinations thereof.

16. The method according to claim 13, wherein the level of at least one anti-inflammatory cytokine is increased.

17. The method according to claim 16, wherein the anti-inflammatory cytokine is selected from the group consisting of IL-13, IL-4, IL-10, and combinations thereof.

18. A method for treating a disease, disorder, or condition in a subject requiring such treatment, comprising administering the composition described in claim 1, The disease, disorder, or condition is type 2 diabetes, metabolic syndrome, any other diabetes-related condition and complications, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NAFLD) Steatohepatitis (NASH), Wilson's disease; type 1 diabetes and its complications; neoplastic diseases with inflammatory elements in pathophysiology; diseases of the blood and hematopoietic organs related to the immune system; metabolic disorders related to inflammatory elements; neurodegenerative and demyelinating disorders such as multiple sclerosis, amyotrophic lateral sclerosis, age-related macular degeneration, Parkinson's disease, and Alzheimer's disease; inflammatory diseases of the central nervous system; immune-related disorders of the circulatory and cardiovascular systems; inflammatory diseases of the respiratory system, especially asthma, cystic fibrosis, allergic rhinitis, nasal polyps, and COPD; inflammatory skin disorders, especially psoriasis, rheumatoid arthritis, psoriatic arthritis, wound healing, injury from exposure to chemicals, heat or cold; ischemia and re-opening injury; stroke; immune-related diseases of the digestive system, especially inflammatory bowel disease; tetracholastic anemia; hemochromatosis; autoimmune disorders; inflammatory diseases of the oral cavity and salivary glands; Escherichia coli A method selected from the group consisting of infections caused by coli, Staphylococcus aureus, Alcaligenes faecalis, Neisseria meningitidis, Prevotella intermedia, Porphyromonas gingivalis, as well as Salmonella, Shigella, Proteus, Providencia, Enterobacter, Morganella, and Pseudomonas.

19. The method according to claim 18, wherein the composition is administered in a dose within the range of 0.1 mg / kg to 10.0 mg / kg.

Images