Method for reducing lung inflammation
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Publication Number
US-11491126-B2
Publication Date
2022-11-08
Expiration Date
Abstract
A method of treating or preventing inflammation in the lung by administering a high concentration of an inhaled chelating agent.
Core Innovation
The invention provides a method of treating inflammation in the lung by administering an inhaled chelating agent at a defined daily amount. The chelating agent is provided at a concentration of at least 50 mM in one or more doses, and each dose is administered over a period of no more than 2h. The approach is applied to lung inflammation, including cystic fibrosis-associated inflammation.
The invention addresses lung inflammation by using chelation activity of inhaled chelating agents. The documented rationale focuses on zinc chelation to reduce zinc-dependent matrix metalloproteinases (MMPs) activity, and iron chelation to reduce reactive oxygen species and hydroxyl radicals. The method is presented as capable of reducing bacterial and biofilm burden and cation-dependent proteases.
The disclosed chelation approach is associated with biological and clinical outcomes in the lung. In vitro results are described in which EDTA, including CaEDTA, synergizes with nebulized tobramycin against P. aeruginosa biofilms. Clinical evidence is described for cystic fibrosis in which EDTA compared with placebo increases FEV1 and reduces sputum bacterial counts, and mouse data show reduced cigarette-smoke-induced lung inflammation, including reduced leukocytes, lung weight, and BALF iron.
Claims Coverage
The provided claims include one independent claim directed to a method of treating lung inflammation using an inhaled chelating agent with specified dose amount, concentration, and dosing duration. Dependent claims refine the method by specifying particular chelating agents, formulation components, and treatment-associated response features.
Inhaled chelating agent with defined daily dose, concentration, and ≤2h per dose
A method of treating inflammation in the lung by administering from 37.5 mg/day to 1,200 mg/day of an inhaled chelating agent, where the chelating agent is at a concentration of at least 50 mM in one or more doses, and wherein each of the one or more doses is administered over a period of no more than 2h.
CaEDTA inhaled chelating agent
The method wherein the chelating agent is CaEDTA.
Treatment associated with increased FEV
The method wherein the treatment causes an increase in FEV.
Treatment associated with decreased MMP activity
The method wherein MMP activity decreases as a result of treating inflammation.
Treatment associated with decreased hydroxyl radical production
The method wherein the treatment is associated with decreased production of hydroxyl radicals.
Chelating agent combined with TRIS
The method wherein the chelating agent is combined with tris(hydroxymethyl)aminomethane (TRIS).
The claims cover lung inflammation treatment with an inhaled chelating agent delivered at a specified daily amount, at at least 50 mM concentration, with each dose administered for no more than 2h, with dependent refinements including CaEDTA, TRIS combination, and treatment-associated increases in FEV and decreases in MMP activity and hydroxyl radical production.
Stated Advantages
Increases FEV1 versus placebo in cystic fibrosis.
Reduces sputum bacterial counts in cystic fibrosis.
Synergizes EDTA, including CaEDTA, with nebulized tobramycin against P. aeruginosa biofilms.
Achieves measurable sputum concentrations of EDTA after dosing.
Reduces cigarette-smoke-induced lung inflammation, including reduced leukocytes, lung weight, and BALF iron.
Documented Applications
Treatment or prevention of lung inflammation, including cystic fibrosis-associated inflammation.
Use in synergy with nebulized tobramycin against P. aeruginosa biofilms.
Cystic fibrosis clinical use involving improved lung function (FEV1) and reduced sputum bacterial counts after EDTA versus placebo.
Mouse lung-inflammation use showing reduction of cigarette-smoke-induced lung inflammation in the absence of infection.
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