WO2023205625A2

WO2023205625A2 - 2,4 dnp and prodrugs thereof for treatment of pulmonary and autoimmune diseases

Info

Publication number: WO2023205625A2
Application number: PCT/US2023/065876
Authority: WO
Inventors: John Gerard Geisler; Robert Alonso
Original assignee: Mitochon Pharmaceuticals Inc
Current assignee: Mitochon Pharmaceuticals Inc
Priority date: 2022-04-18
Filing date: 2023-04-18
Publication date: 2023-10-26
Anticipated expiration: 2024-10-18
Also published as: WO2023205625A3

Abstract

Compositions and methods for the treatment of pulmonary diseases or disorders and/or autoimmune diseases or disorders including DNP and/or prodrugs of DNP are disclosed.

Description

TITLE

2,4 DNP and Prodrugs Thereof for Treatment of Pulmonary and Autoimmune Diseases

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 63/332,083 filed April 18, 2022, the entirety of which is incorporated herein by reference.

FIELD

[0002] The present disclosure relates to methods of treating pulmonary diseases and disorders and autoimmune diseases and disorders by administering DNP and/or prodrugs of DNP, or pharmaceutically acceptable salts thereof.

BACKGROUND

[0003] Numerous abnormalities have been described in pulmonary and autoimmune diseases; however alternative mechanisms of action appear to be often overlooked. For example, autoimmune diseases have been overlooked as being related to mechanisms of action other than anti-inflammation.

[0004] Consequently, there is a profound need for improved treatments for pulmonary and autoimmune diseases and disorders.

SUMMARY

[0005] In one aspect, the present disclosure provides a method of treating pulmonary diseases or disorders and/or autoimmune diseases or disorders comprising: administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight. In one embodiment, the therapeutic amount of DNP is in the range of about 0.1 mg/kg of body weight to about 15 mg/kg of body weight, about 1 mg/kg of body weight to about 10 mg/kg of body weight, about 3 mg/kg of body weight to about 8 mg/kg of body weight, or about 4 mg/kg of body weight to about 6 mg/kg of body weight. In one embodiment, the therapeutic amount of DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, or about 10 mg/kg of body weight. In one embodiment, the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 10 mg/kg of body weight, about 0.001 mg/kg of body weight to about 8 mg/kg of body weight, about 0.001 mg/kg of body weight to about 6 mg/kg of body weight, about 0.001 mg/kg of body weight to about 4 mg/kg of body weight, about 0.001 mg/kg of body weight to about 2 mg/kg of body weight, about 0.01 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 1 mg/kg of body weight, or about 0.1 mg/kg of body weight to about 1 mg/kg of body weight. In one embodiment, the therapeutic amount of DNP is about 0.001 mg/kg of body weight, about 0.005 mg/kg of body weight, about 0.01 mg/kg of body weight, about 0.05 mg/kg of body weight, about 0.1 mg/kg of body weight, about 0.2 mg/kg of body weight, about 0.3 mg/kg of body weight, about 0.4 mg/kg of body weight, about 0.5 mg/kg of body weight, about 0.6 mg/kg of body weight, about 0.7 mg/kg of body weight, about 0.8 mg/kg of body weight, or about 0.9 mg/kg of body weight. In one embodiment, the DNP is selected from 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP. In one embodiment, the DNP is 2,4-DNP.

[0006] In another aspect, the present disclosure provides a method of treating pulmonary diseases or disorders and/or autoimmune diseases or disorders comprising: administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 200 mg/kg of body weight. In one embodiment, the therapeutic amount of the prodrug of DNP is in the range of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 20 mg/kg of body weight, about 5 mg/kg of body weight to about 10 mg/kg of body weight, about 7 mg/kg of body weight to about 9 mg/kg of body weight, about 10 mg/kg of body weight to about 20 mg/kg of body weight, about 15 mg/kg of body weight to about 17 mg/kg of body weight, about 50 mg/kg of body weight to about 100 mg/kg of body weight, about 60 mg/kg of body weight to about 90 mg/kg of body weight, about 75 mg/kg of body weight to about 85 mg/kg of body weight, or about 79 mg/kg of body weight to about 81 mg/kg of body weight. In one embodiment, the therapeutic amount of the prodrug of DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, 10 mg/kg of body weight, about 11 mg/kg of body weight, about 12 mg/kg of body weight, about 13 mg/kg of body weight, about 14 mg/kg of body weight, about 15 mg/kg of body weight, about 16 mg/kg of body weight, about 17 mg/kg of body weight, about 18 mg/kg of body weight, about 19 mg/kg of body weight, or about 20 mg/kg of body weight. In one embodiment, the therapeutic amount of the prodrug of DNP is about 71 mg/kg of body weight, about 72 mg/kg of body weight, about 73 mg/kg of body weight, about 74 mg/kg of body weight, about 75 mg/kg of body weight, about 76 mg/kg of body weight, about 77 mg/kg of body weight, about 78 mg/kg of body weight, about 79 mg/kg of body weight, 80 mg/kg of body weight, about 81 mg/kg of body weight, about 82 mg/kg of body weight, about 83 mg/kg of body weight, about 84 mg/kg of body weight, about 85 mg/kg of body weight, about 86 mg/kg of body weight, about 87 mg/kg of body weight, about 88 mg/kg of body weight, about 89 mg/kg of body weight, or about 90 mg/kg of body weight. In one embodiment, the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 10 mg/kg of body weight, about 0.001 mg/kg of body weight to about 8 mg/kg of body weight, about 0.001 mg/kg of body weight to about 6 mg/kg of body weight, about 0.001 mg/kg of body weight to about 4 mg/kg of body weight, about 0.001 mg/kg of body weight to about 2 mg/kg of body weight, about 0.01 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 1 mg/kg of body weight, or about 0.1 mg/kg of body weight to about 1 mg/kg of body weight. In one embodiment, the therapeutic amount of the prodrug of DNP is about 0.001 mg/kg of body weight, about 0.005 mg/kg of body weight, about 0.01 mg/kg of body weight, about 0.05 mg/kg of body weight, about 0.1 mg/kg of body weight, about 0.2 mg/kg of body weight, about 0.3 mg/kg of body weight, about 0.4 mg/kg of body weight, about 0.5 mg/kg of body weight, about 0.6 mg/kg of body weight, about 0.7 mg/kg of body weight, about 0.8 mg/kg of body weight, or about 0.9 mg/kg of body weight. In one embodiment, the prodrug of DNP is selected from: an amino acid (AA) ester of 2,3-DNP, an amino acid (AA) ester of 2,4-DNP, an amino acid (AA) ester of 2,5-DNP, an amino acid (AA) ester of 2,6-DNP, an amino acid (AA) ester of 3,4-DNP, or an amino acid (AA) ester of 3,5-DNP (Scheme 1, Formulas 1-1 to 1-10; Scheme 2, Formulas IT-1 to 11-10; Scheme 3, Formulas IIT-1 to ITI-10; Scheme 4, Formulas IV-1 to IV-10; Scheme 5, Formulas V-l to V-10; and Scheme 6, Formulas VI-1 to VI-10); AA esters incorporating a methylene dioxide (a formaldehyde equivalent) spacer (Scheme 1, Formulas 1-11 to 1-13; Scheme 2, Formulas II- 11 to 11-13; Scheme 3, Formulas III- 11 to III- 13 ; Scheme 4, Formulas IV- 11 to IV-13; Scheme 5, Formulas V-l l to V-13; and Scheme 6, Formulas VI-11 to VI-13); amino carbamate 2,3-DNP prodrugs, amino carbamate 2,4-DNP prodrugs, amino carbamate 2,5- DNP prodrugs, amino carbamate 2,6-DNP prodrugs, amino carbamate 3,4-DNP prodrugs, or amino carbamate 3,5-DNP prodrugs (Scheme 1, Formulas 1-14 to 1-17; Scheme 2, Formulas II- 14 to 11-17; Scheme 3, Formulas III- 14 to III- 17; Scheme 4, Formulas IV-14 to IV-17; Scheme 5, Formulas V-14 to V-17; and Scheme 6, Formulas VI-14 to VI-17); amino carbonate 2,3-DNP prodrugs, amino carbonate 2,4-DNP prodrugs, amino carbonate 2,5-DNP prodrugs, amino carbonate 2,6-DNP prodrugs, amino carbonate 3,4-DNP prodrugs, or amino carbonate 3,5-DNP prodrugs (Scheme 1, Formulas 1-18 and 1-19; Scheme 2, Formulas 11-18 and 11-19; Scheme 3, Formulas III-18 and III-19; Scheme 4, Formulas IV-18 and IV-19; Scheme 5, Formulas V-18 and V-19; and Scheme 6, Formulas VI-18 and VI-19); phosphate analogs 1-20, 1-21, 11-20, 11-21, III-20, III-21, IV-20, IV-21, V-20, V-21, VI-20, and VI-21 (Schemes 1-6); 1,3 diketo analogs I- 22 to 1-32; 11-22 to 11-32; III-22 to III-32; IV-22 to IV-32; V-22 to V-32; and VI-22 to VI-32

(Schemes 1-6); carbonate and carbamate analogs 1-33 to 1-39; 11-33 to 11-39; III-33 to III-39; IV- 33 to IV-39; V-33 to V-39; and VI-33 to VI-39 (Schemes 1-6); and benzoate analogs 1-40, 11-40, III-40, IV-40, V-40, and VI-40 (Schemes 1-6); and combinations thereof In one embodiment, the prodrug of DNP is selected from:

[0007] In one embodiment, the patient treated by a method described above is a human. In one embodiment, the DNP and/or the prodrug of DNP is administered orally. In one embodiment, the DNP and/or the prodrug of DNP is administered intravenously, subcutaneously, or transderm ally. In one embodiment, the DNP and/or the prodrug of DNP is administered at a frequency of once a day, twice a day, three times a day, four times a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, or once a month. In one embodiment, the DNP and/or the prodrug of DNP is administered at a frequency of once a day. In one embodiment, the DNP and/or the prodrug of DNP is administered at a frequency of once a day for one day, once a day for two consecutive days, once a day for three consecutive days, once a day for four consecutive days, once a day for five consecutive days, once a day for six consecutive days, once a day for 7 consecutive days, or once a day for two consecutive weeks. In one embodiment, the pulmonary disease or disorder is selected from cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea. In one embodiment, the pulmonary disease or disorder is cystic fibrosis. In one embodiment, the therapeutic amount of DNP and/or the prodrug of DNP prevents or reduces increases in blood glucose levels in a cystic fibrosis patient following a meal. In one embodiment, the therapeutic amount of DNP and/or the prodrug of DNP prevents the destruction of the pancreas of a cystic fibrosis patient. In one embodiment, the therapeutic amount of DNP and/or the prodrug of DNP prevents or reduces inflammation and/or scarring of the pancreas of a cystic fibrosis patient. In one embodiment, the therapeutic amount of DNP and/or the prodrug of DNP prevents insulin resistance and/or pre-diabetes in a cystic fibrosis patient. In one embodiment, the therapeutic amount of DNP and/or the prodrug of DNP prevents a cystic fibrosis patient from developing diabetes. In one embodiment, the therapeutic amount of DNP and/or the prodrug of DNP improves survivability in a cystic fibrosis patient compared to a patient who is not treated with a therapeutic amount of DNP and/or a prodrug of DNP. In one embodiment, the autoimmune disease or disorder is selected from diseases and disorders associated with inflammation. In one embodiment, the disease and disorder is selected from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, rheumatoid arthritis, ileitis and allergic rhinitis. BRIEF DESCRTPTTON OF THE DRAWINGS

[0008] FIG. 1 is a chart overview of the cystic fibrosis (CF) study in ferrets. Cystic fibrosis ferrets were treated with 2,4-DNP during the duration of the cystic fibrosis pancreatic stage. 2,4- DNP treatment can be continued during the pulmonary stages of cystic fibrosis.

[0009] FIG. 2 is a chart comparing glucose levels before and after a meal in CF ferrets treated with 2,4-DNP (0.5 mg/kg once a day) to control (untreated) CF ferrets. Administration of VX-770 to the control and treated ferrets was stopped at 30 days. The 2,4-DNP treatment group was treated once a day beginning at 25 days and was treated for the duration of the study. The glucose levels before and after a meal in CF ferrets treated with 2,4-DNP were compared to untreated control CF ferrets.

[0010] FIGS. 3A-3B demonstrate that CF ferrets treated with 2,4-DNP (0.5 mg/kg once per day) had improved survivability (decreased mortality) compared to historic controls. FIG. 3A: Comparison of mortality in CF ferrets that were about two months old and were treated for 70 days with 2,4-DNP versus historic placebo controls. None of the treated ferrets died compared to 20% mortality for the historic controls. FIG. 3B: Comparison of mortality in CF ferrets that were about three months and were treated for 92 days with 2,4-DNP versus historic placebo controls (dotted line shows current stage in days). One out of the ten treated ferrets died (10% mortality) compared to six out of fourteen (43% mortality) control CF ferrets.

DETAILED DESCRIPTION

Definitions.

[001 1] Hereinafter, unless defined otherwise, the term “prodrug” refers to an inactive or partially active drug that is metabolically changed in the body to an active drug.

[0012] Hereinafter, the term “depot nanoparticle formulation” unless defined otherwise refers to a biodeliverable nanoparticle, comprising a broad range of 1) bipartite 2,3- dinitrophenol, 2,4-dinitrophenol, 2,5-dinitrophenol, 2,6-dinitrophenol, 3,4- dinitrophenol, or 3,5- dinitrophenol (2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP) prodrugs, 2) Gemini prodrugs and 3) bioprecursor molecules for treating neurodegenerative or metabolic diseases.

[0013] Hereinafter, unless otherwise defined, the term “about” means plus or minus 10% of the value referenced For example, “about 1 mg/kg” means 0.9 mg/kg to 1 1 mg/kg. [0014] Hereinafter, unless defined otherwise, bipartite 2,3-dinitrophenol, 2,4-dinitrophenol, 2,5-dinitrophenol, 2,6-dinitrophenol, 3,4- dinitrophenol, or 3, 5 -di nitrophenol are represented by 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP; the prodrug of each isomer is represented in formulas I- VI; being selected from the group consisting of: an amino acid (AA) ester of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5- DNP (Scheme 1, Formulas 1-1 to 1-10; Scheme 2, Formulas II-l to 11-10; Scheme 3, Formulas III-l to III-10; Scheme 4, Formulas IV-1 to IV-10; Scheme 5, Formulas V-l to V-10; and Scheme 6, Formulas VI-1 to VI-10);

AA esters incorporating a methylene dioxide (a formaldehyde equivalent) spacer (Scheme 1, Formulas 1-11 to 1-13; Scheme 2, Formulas 11-11 to 11-13; Scheme 3, Formulas Hill to III-13; Scheme 4, Formulas IV-11 to IV-13; Scheme 5, Formulas V-ll to V-13; and Scheme 6, Formulas VI-11 to VI-13); amino carbamate 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP prodrugs (Scheme 1, Formulas 1-14 to 1-17; Scheme 2, Formulas 11-14 to 11-17; Scheme 3, Formulas HI- 14 to III-17; Scheme 4, Formulas IV-14 to IV-17; Scheme 5, Formulas V-14 to V-17; and Scheme 6, Formulas VI-14 to VI-17); amino carbonate 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP prodrugs (Scheme 1, Formulas 1-18 and 1-19; Scheme 2, Formulas 11-18 and 11-19; Scheme 3, Formulas

III-18 and III-19; Scheme 4, Formulas IV-18 and IV-19; Scheme 5, Formulas V-18 and V-19; and Scheme 6, Formulas VI-18 and VI-19); phosphate analogs 1-20, 1-21, 11-20, 11-21, HI-20, HI-21, IV-20, IV-21, V-20, V-21, VI- 20, and VI-21 (Schemes 1-6);

1,3 diketo analogs 1-22 to 1-32; 11-22 to 11-32; III-22 to III-32; IV-22 to IV-32; V-22 to V-32; and VI-22 to VI-32 (Schemes 1-6); carbonate and carbamate analogs 1-33 to 1-39; H-33 to 11-39; IH-33 to HI-39; IV-33 to

IV-39; V-33 to V-39; and VI-33 to VI-39 (Schemes 1-6); benzoate analogs 1-40, 11-40, III-40, IV-40, V-40, and VI-40 (Schemes 1-6), and combinations thereof

[0015] In one embodiment, the disclosure provides compositions and methods for treating pulmonary diseases and disorders, autoimmune diseases or disorders, insulin resistance, and/or pre-diabetes. In some embodiments, the compositions and methods include dinitrophenol (DNP) and/or prodrugs of DNP. As described herein in a non-limiting example, treatment with DNP and/or prodrugs of DNP can abolish F2-isoprostanes, a biomarker of free radicals (reactive oxygen species) at the peak of disease disability (paralysis).

[0016] In one embodiment, the disclosure provides compositions and methods for treating diseases and disorders associated with high isoprostanes by administering DNP and/or prodrugs of DNP. Non-limiting examples of diseases and disorders associated with high isoprostanes include the pulmonary diseases and disorders and autoimmune diseases or disorders described herein.

[0017] In one embodiment, the compositions described herein may be used to treat pulmonary diseases and disorders. In one embodiment, the compositions described herein may be used to treat autoimmune diseases and disorders. In one embodiment, the compositions described herein may be used to treat insulin resistance and/or pre-diabetes. In one such embodiment, 2, 4-dinitrophenol (DNP) may be used at a dose range independently selected from: 1 mg/day to 50 mg/day; 1 mg/day to 45 mg/day; 1 mg/day to 40 mg/day; 1 mg/day to 35 mg/day; 1 mg/day to 30 mg/day; 1 mg/day to 25 mg/day; 1 mg/day to 20 mg/day; 1 mg/day to 15 mg/day; 1 mg/day to 10 mg/day; 1 mg/day to 5 mg/day; 1 mg/day to 4 mg/day; 1 mg/day to 3 mg/day; 1 mg/day to 2 mg/day; 2 mg/day to 50 mg/day; 2 mg/day to 45 mg/day; 2 mg/day to 40 mg/day; 2 mg/day to 35 mg/day; 2 mg/day to 30 mg/day; 2 mg/day to 25 mg/day; 2 mg/day to 20 mg/day; 2 mg/day to 15 mg/day; 2 mg/day to 10 mg/day; 2 mg/day to 5 mg/day; 2 mg/day to 4 mg/day; 2 mg/day to 3 mg/day; 0.5 mg/day to 10 mg/day; 0.5 mg/day to 9 mg/day; 0.5 mg/day to 8 mg/day; 0.5 mg/day to 7 mg/day; 0.5 mg/day to 6 mg/day; 0.5 mg/day to 5 mg/day; 0.5 mg/day to 4 mg/day; 0.5 mg/day to 3 mg/day; 0.1 mg/day to 10 mg/day; 0.1 mg/day to 9 mg/day; 0.1 mg/day to 8 mg/day; 0.1 mg/day to 7 mg/day; 0.1 mg/day to 6 mg/day; 0.1 mg/day to 5 mg/day; 0.1 mg/day to 4 mg/day; 0.1 mg/day to 3 mg/day. In one such embodiment, 2, 4-dinitrophenol (DNP) may be used at a dose range independently selected from: about 1 mg/day to about 50 mg/day; about 1 mg/day to about 45 mg/day; about 1 mg/day to about 40 mg/day; about 1 mg/day to about 35 mg/day; about 1 mg/day to about 30 mg/day; about 1 mg/day to about 25 mg/day; about 1 mg/day to about 20 mg/day; about 1 mg/day to about 15 mg/day; about 1 mg/day to about 10 mg/day; about 1 mg/day to about 5 mg/day; about 1 mg/day to about 4 mg/day; about 1 mg/day to about 3 mg/day; about 1 mg/day to about 2 mg/day; about 2 mg/day to about 50 mg/day; about 2 mg/day to about 45 mg/day; about 2 mg/day to about 40 mg/day; about 2 mg/day to about 35 mg/day; about 2 mg/day to about 30 mg/day; about 2 mg/day to about 25 mg/day; about 2 mg/day to about 20 mg/day; about 2 mg/day to about 15 mg/day; about 2 mg/day to about 10 mg/day; about 2 mg/day to about 5 mg/day; about 2 mg/day to about 4 mg/day; about 2 mg/day to about 3 mg/day; about 0.5 mg/day to about 10 mg/day; about 0.5 mg/day to about 9 mg/day; about 0.5 mg/day to about 8 mg/day; about 0.5 mg/day to about 7 mg/day; about 0.5 mg/day to about 6 mg/day; about 0.5 mg/day to about 5 mg/day; about 0.5 mg/day to about 4 mg/day; about 0.5 mg/day to about 3 mg/day; about 0.1 mg/day to about 10 mg/day; about 0.1 mg/day to about 9 mg/day; about 0.1 mg/day to about 8 mg/day; about 0.1 mg/day to about 7 mg/day; about 0.1 mg/day to about 6 mg/day; about 0.1 mg/day to about 5 mg/day; about 0.1 mg/day to about 4 mg/day; about 0.1 mg/day to about 3 mg/day; about 0.01 mg/day to about 10 mg/day; about 0.01 mg/day to about 9 mg/day; about 0.01 mg/day to about 8 mg/day; about 0.01 mg/day to about 7 mg/day; about 0.01 mg/day to about 6 mg/day; about 0.01 mg/day to about 5 mg/day; about 0.01 mg/day to about 4 mg/day; about 0.01 mg/day to about 3 mg/day; about 0.01 mg/day to about 2 mg/day; about 0.01 mg/day to about 1 mg/day; or about 0.01 mg/day to about 0.5 mg/day.

[0018] In another such embodiment to treat pulmonary diseases and disorders, autoimmune diseases and disorders, insulin resistance, and/or pre-diabetes, a prodrug of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, as described herein, may be used at a dose range to achieve equivalent exposure (AUC) to DNP. In one such embodiment, a prodrug of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, as described herein, may be used at a dose range independently selected from: 20 mg/day to 800 mg/day; 20 mg/day to 750 mg/day; 20 mg/day to 700 mg/day; 20 mg/day to 600 mg/day; 20 mg/day to 700 mg/day; 20 mg/day to 600 mg/day; 20 mg/day to 500 mg/day; 30 mg/day to 800 mg/day; 30 mg/day to 700 mg/day; 30 mg/day to 600 mg/day; 30 mg/day to 500 mg/day; 30 mg/day to 400 mg/day; 30 mg/day to 360 mg/day; 30 mg/day to 300 mg/day; 30 mg/day to 250 mg/day; 30 mg/day to 200 mg/day; 30 mg/day to 150 mg/day; 30 mg/day to 100 mg/day; 35 mg/day to 360 mg/day; 40 mg/day to 300 mg/day, 50 mg/day to 250 mg/day; or 60 mg/day to 200 mg/day; 5 mg/day to 500 mg/day; 5 mg/day to 400 mg/day; 5 mg/day to 300 mg/day; 5 mg/day to 200 mg/day; 5 mg/day to 100 mg/day; 5 mg/day to 50 mg/day; 5 mg/day to 40 mg/day; 5 mg/day to 30 mg/day; 5 mg/day to 25 mg/day; 5 mg/day to 20 mg/day; 5 mg/day to 15 mg/day; 5 mg/day to 10 mg/day; 1 mg/day to 10 mg/day; 1 mg/day to 5 mg/day; 1 mg/day to 4 mg/day; 1 mg/day to 3 mg/day; 0.5 mg/day to 10 mg/day; 0.5 mg/day to 9 mg/day; 0.5 mg/day to 8 mg/day; 0.5 mg/day to 7 mg/day; 0.5 mg/day to 6 mg/day; 0.5 mg/day to 5 mg/day; 0.5 mg/day to 4 mg/day; 0.5 mg/day to 3 mg/day; 0.1 mg/day to 10 mg/day; 0.1 mg/day to 9 mg/day; 0.1 mg/day to 8 mg/day; 0.1 mg/day to 7 mg/day; 0.1 mg/day to 6 mg/day; 0.1 mg/day to 5 mg/day; 0.1 mg/day to 4 mg/day; 0.1 mg/day to 3 mg/day; 0.01 mg/day to 10 mg/day; 0.01 mg/day to 9 mg/day; 0.01 mg/day to 8 mg/day; 0.01 mg/day to 7 mg/day; 0.01 mg/day to 6 mg/day; 0.01 mg/day to 5 mg/day; 0.01 mg/day to 4 mg/day; 0.01 mg/day to 3 mg/day; 0.01 mg/day to 2 mg/day; 0.01 mg/day to 1 mg/day; or 0.01 mg/day to 0.5 mg/day.

[0019] In another such embodiment, a prodrug of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, as described herein, may be used at a dose range independently selected from: about 20 mg/day to about 800 mg/day; about 20 mg/day to about 750 mg/day; about 20 mg/day to about 700 mg/day; about 20 mg/day to about 600 mg/day; about 20 mg/day to about 700 mg/day; about 20 mg/day to about 600 mg/day; about 20 mg/day to about 500 mg/day; about 30 mg/day to about 800 mg/day; about 30 mg/day to about 700 mg/day; about 30 mg/day to about 600 mg/day; about 30 mg/day to about 500 mg/day; about 30 mg/day to about 400 mg/day; about 30 mg/day to about 360 mg/day; about 30 mg/day to about 300 mg/day; about 30 mg/day to about 250 mg/day; about 30 mg/day to about 200 mg/day; about 30 mg/day to about 150 mg/day; about 30 mg/day to about 100 mg/day; about 35 mg/day to about 360 mg/day; about 40 mg/day to about 300 mg/day; about 50 mg/day to about 250 mg/day; or about 60 mg/day to about 200 mg/day; about 5 mg/day to about 500 mg/day; about 5 mg/day to about 400 mg/day; about 5 mg/day to about 300 mg/day; about 5 mg/day to about 200 mg/day; about 5 mg/day to about 100 mg/day; about 5 mg/day to about 50 mg/day; about 5 mg/day to about 40 mg/day; or about 5 mg/day to about 30 mg/day.

[0020] In one embodiment, the compositions and methods of the disclosure relate to targeting oxidative stress upstream at the mitochondria that may be causative for many disorders. There have been a variety of attempts to lower cellular stress, such as administering antioxidants, however these drugs have limited tissue penetration into the brain and lower ROSs after they have been formed. It has been observed that wildtype mice chronically treated with an extraordinarily low dose of 2, 4-dinitrophenol resulted in treated mice living longer than untreated mice. While not being bound to theory, it is postulated that DNP modulates the mitochondrial membrane potential having a significant impact at preventing ROS formation in isolated mitochondria and in the treated wildtype mice. DNP treatment 3-hours post-ischemia reduced cerebral infarct volume 40% by protecting the penumbra or “threaten tissue” and could provide similar benefits after a blast to protect inner hair cells from eminent cell death. DNP comes with the benefits of known risks as it was used 80-years ago for weight loss at high doses (~300 mg) in over 100,000 people, however shown recently in models of neurodegeneration at very low hormetic doses to improve cognition and learning. The pharmacology, which is pleiotrophic, appears to provide broad neuroprotection by lowering ROS/mTOR and increasing protective factors such as cAMP, CREB, and BDNF, could be useful for treating hearing loss. Despite DNP tainted past and common incorrect dogma of being toxic, a 28-day toxicity studies was ran and demonstrated that low doses of DNP are not toxic, have at least a lOx Safety Index with no inhibition to ion channels, CYP, Caco-2, etc., and provide therapeutically striking benefits in host CNS models representing diverse indications, thereby suggesting possible merit for inner ear and central brain hearing mitochondrial dysfunction.

[0021] Numerous abnormalities have been described in pulmonary diseases and disorders, however mitochondrial abnormalities appear to be an often overlooked defect. For example, a high degree of mitochondrial dysfunction marked by high levels of oxidative stress (OS), as measured by F2-isoprostanes, a biomarker for reactive oxygen species (ROS), has been found in many pulmonary diseases. In addition, poor glucose oxidation have led to airway disturbances that further support the hypothesis that bioenergetics play a potentially central role in pulmonary diseases and disorders.

[0022] In addition to pulmonary diseases, autoimmune diseases and disorders have also been overlooked as mitochondrial-related in favor of the anti-inflammatory thesis. However, new experimental data supports the hypothesis that bioenergetics play a potential role in autoimmune diseases and disorders. For example, in autoimmune diseases and disorders, F2-isoprostanes have been found to be elevated, and other mitochondrial biomarkers have also implicated. Chemical Synthesis'.

[0023] In one embodiment, prodrugs which contain a self-cleavable spacer and a watersolubilizing moiety are synthesized, to maintain the prodrug in a soluble form in the GI tract fluids, and which will then gradually revert to the parent drug without precipitation. In some embodiments, these compounds are 1,3 diketo analogs 1-22 to 1-32; 11-22 to 11-32; III-22 to HI- 32; IV-22 to IV-32; V-22 to V-32; and VI-22 to VI-32 (Schemes 1-6). The increased solubility of the prodrug and the high membrane permeability of the well -dispersed parent drug will provide a higher driving force for it to be readily absorbed via the intestinal lumen. Conversion of prodrug-to-parent drug involves a chemical cleavage at the self-cleavable spacer through a unique intramolecular cyclization-elimination reaction via imide formation under physiological conditions. The conversion time is tunable by modifying the structure of the solubilizing moiety, the bond length of the spacer, the pKa of the amine group, and the pH of the medium. Although the in silico predicted bioavailability may be low, it is likely to be much higher when one takes into account the unique pH-dependent and tunable hydrolysis mechanism. Also, the generation of parent drug does not rely on enzyme action, which may be an advantage in dealing with genetic variability associated with enzymatic prodrug hydrolysis in plasma.

[0024] In other embodiments, one or more isomers of dinitrophenol, i.e.. 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, and/or a broad range of 1) bipartite 2,3-dinitrophenol,

2.4-dinitrophenol, 2,5-dinitrophenol, 2,6-dinitrophenol, 3,4- dinitrophenol, or 3, 5 -dinitrophenol (2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP) prodrugs, 2) Gemini prodrugs and 3) bioprecursor molecules, are used for treating neurodegenerative or metabolic diseases.

[0025] Synthesis of bipartite 2,3-dinitrophenol, 2,4-dinitrophenol, 2,5-dinitrophenol, 2,6- dinitrophenol, 3,4- dinitrophenol, or 3,5-dinitrophenol (2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP,

3.4-DNP, or 3,5-DNP) prodrugs may be performed; the prodrug being selected from the group consisting of: an amino acid (AA) ester of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5- DNP (Scheme 1, Formulas 1-1 to 1-10; Scheme 2, Formulas II-l to 11-10; Scheme 3, Formulas III-l to III-10; Scheme 4, Formulas IV-1 to IV-10; Scheme 5, Formulas V-l to V-10; and Scheme 6, Formulas VI-1 to VI-10);

III-18 and III-19; Scheme 4, Formulas IV-18 and IV-19; Scheme 5, Formulas V-18 and V-19; and Scheme 6, Formulas VI-18 and VI-19); phosphate analogs 1-20, 1-21, 11-20, 11-21, III-20, ID-21, IV-20, IV-21, V-20, V-21, VI- 20, and VI-21 (Schemes 1-6);

1,3 diketo analogs 1-22 to 1-32; 11-22 to 11-32; III-22 to III-32; IV-22 to IV-32; V-22 to V-32; and VI-22 to VI-32 (Schemes 1-6); carbonate and carbamate analogs 1-33 to 1-39; 11-33 to 11-39; III-33 to III-39; IV-33 to

IV-39; V-33 to V-39; and VI-33 to VI-39 (Schemes 1-6);

[0026] benzoate analogs 1-40, 11-40, III-40, IV-40, V-40, and VI-40 (Schemes 1-6); and combinations thereof, wherein the prodrug is represented by formulas I- VI:

Scheme 1

Scheme 2

Scheme 4

Scheme 6

[0027] In some embodiments, a broad range of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4- DNP, or 3,5-DNP prodrugs can be considered. In some embodiments, the prodrugs are represented by formulas 1-1 to 1-40; II- 1 to 11-40; III-l to III-40; IV-1 to IV-40; V-l to V-40; and VI- 1 to VI-40 are considered. A computational screen utilizing Pharma Algorithms’ ADME- Tox calculator is conducted in order to identify virtual ‘hits’ (i.e. prodrugs with acceptable “predicted” oral bioavailabilities and water solubilities from the 32 prodrugs listed). The virtual screen allows ranking the 10 best prodrug molecules for synthesis and testing.

[0028] Amino acid (AA) esters of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5- DNP (Scheme 1, Formulas 1-1 to 1-10; Scheme 2, Formulas II-l to 11-10; Scheme 3, Formulas

III-l to III-10; Scheme 4, Formulas IV-1 to IV-10; Scheme 5, Formulas V-l to V-10; and Scheme 6, Formulas VI-1 to VI-10); AA esters incorporating a methylene dioxide (a formaldehyde equivalent) spacer (Scheme 1, Formulas 1-11 to 1-13; Scheme 2, Formulas 11-11 to 11-13; Scheme 3, Formulas III-ll to III-13; Scheme 4, Formulas IV-11 to IV-13; Scheme 5, Formulas V-ll to V-13; and Scheme 6, Formulas VI-11 to VI-13); amino carbamates 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP prodrugs (Scheme 1, Formulas 1-14 to 1-17; Scheme 2, Formulas 11-14 to 11-17; Scheme 3, Formulas III-14 to III-17; Scheme 4, Formulas

IV-14 to IV-17; Scheme 5, Formulas V-14 to V-17; and Scheme 6, Formulas VI-14 to VI-17); amino carbonates 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP prodrugs (Scheme 1, Formulas 1-18 and 1-19; Scheme 2, Formulas 11-18 and 11-19; Scheme 3, Formulas TTT-18 and TTT-19; Scheme 4, Formulas TV-18 and TV-19; Scheme 5, Formulas V-18 and V-19; and Scheme 6, Formulas VI-18 and VI-19); phosphate analogs 1-20, 1-21, 11-20, 11-21, TIT-20, HI-21, IV-20, IV-21, V-20, V-21, VI-20, and VI-21 (Schemes 1-6); 1,3 diketo analogs 1-22 to I- 32; 11-22 to 11-32; III-22 to III-32; IV-22 to IV-32; V-22 to V-32; and VI-22 to VI-32 (Schemes 1-6); carbonate and carbamate analogs 1-33 to 1-39; 11-33 to 11-39; III-33 to III-39; IV-33 to IV-39; V-33 to V-39; and VI-33 to VI-39 (Schemes 1-6); benzoate analogs 1-40, 11-40, III-40, IV-40, V-40, and VI-40 (Schemes 1-6); and combinations thereof, may be considered. [0029] Examples of ionizable amine-containing prodrugs have increased water-solubility compared to the parent compound. In addition, AA ester prodrugs have the potential to further increase oral bioavailability due to active absorption by transporters (e g., small peptide transporter PEPT1). For example, the valine-containing prodrugs valacyclovir and valganciclovir are substrates for the enzyme PEPT1. These AA containing prodrugs are hydrolyzed to the parent drug by aminopeptidase enzymes in the brush border membrane of the GI tract. Prodrugs which can penetrate into the peripheral circulation by passive permeation and/or by active transport are hydrolyzed by various peptidase enzymes in plasma.

[0030] Two types of phosphate prodrugs of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4- DNP, or 3,5-DNP of formulas 1-20, 1-21, 11-20, 11-21, III-20, III-21, IV-20, IV-21, V-20, V-21, VI-20, and VI-21 (Schemes 1-6) are synthesized. According to ADME-Tox computational data, the oral bioavailability of these prodrugs can be poor, given the fact that the prediction by ADME-Tox calculator is mainly based on the physicochemical proprieties of the molecule. Since phosphoric acid is a highly polar and extensively ionized pro-moiety, phosphate prodrugs can have significantly decreased membrane permeability compared to the parent drug.

[00 1] The reasons for the success of phosphate prodrugs of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP shown in formulas 1-20, 1-21, 11-20, 11-21, III-20, HI-21, IV- 20, IV-21, V-20, V-21, VI-20, and VI-21 (Schemes 1-6), e.g., phosphate esters as oral prodrugs, are: 1) oral absorption is not limited by dissolution-rate, since phosphate prodrugs are highly soluble in GI tract fluids; 2) phosphate esters are chemically stable enough to prevent the precipitation of the parent drug in the GI tract; 3) phosphates are rapidly hydrolyzed by membrane-bound alkaline phosphatases, which are in abundance on the brush border surface of the cells lining the small intestine, i.e., the enterocytes. Thus, the more permeable parent drug will be released, and readily cross the enterocyte membranes and enter the systemic circulation Scheme 8

Parent druq~| . imide

self cleavable linker

[0032] The prodrugs that are synthesized are modified to ensure water solubility. In some embodiments, acceptable solubility is tested prior to dosing in animals. If solubility is an issue, the structure of the prodrug is altered by introducing a water-soluble prodrug moiety into the molecule through conjugation with the free phenolic functionality. In other embodiments, a prodrug linker moiety that confers water-solubility properties on the prodrug molecule is utilized. In some embodiments, a solution to any water solubility issues is utilizing soft alkyl ether prodrugs that incorporate ethyleneoxy groups into promoieties such as alkyloxycarbonylmethyl (AOCOM) and A-alkyl-A-alkyloxycarbonylamino methyl (NANAOCAM) prodrugs. These prodrugs have been found to be useful for the delivery of phenolic drug molecules and have generally acceptable water solubility and membrane permeation characteristics, since they associate strongly with water molecules have good lipid solubility.

Synthesis of “Gemini” prodrugs of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5- DNP

[0033] In an embodiment, 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP “Gemini” prodrugs may be prepared by reacting 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4- DNP, or 3,5-DNP with triphosgene, in the presence of K2CO3 in dichloromethane to get 2,4- dinitrophenyl carbonochloridate, which on further reaction with bases like morpholine, piperidine, piperazine, A -alkyl piperazine yields the DNP prodrugs as illustrated in Scheme 9. Scheme 9

[0034] In one embodiment, 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP “Gemini” prodrugs are prepared by reacting 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP with 5-(/c77-butyldimcthylsiloxy)isophthaloyl dichloride (2) in the presence of pyridine/ dichloromethane to afford precursor (3); the TBDMS protecting group will then be removed in acetone/HCl to afford prodrug (4), which will afford two equivalents of 2, 4-DNP upon hydrolysis in plasma. While the prodrug linker moiety in (4) is an ester group, other alternative linkers, such as sterically hindered ester linkers, carbonate linkers, carbamate linkers, phosphate linkers, and AOCOM and NANAOCAM based linkers may also be incorporated into the prodrug structure in order to achieve appropriate sustained release kinetics. The presence of the free phenolic group in (4) can also be utilized to improve water-solubility, if this is deemed necessary, through conjugation with appropriate hydrophilic moieties (Scheme 10).

Scheme 10

2.3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3, 5-DNP Bioprecursors

[0035] Bioprecursors of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3, 5-DNP that may release 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3, 5-DNP after oxidative metabolism by cytochrome P-450 may be utilized. Scheme 8 shows the design of two bioprecursors that can release 2- and 4-equivalents of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP,

3.4-DNP, or 3, 5-DNP after oxidation at the benzylic carbon by Cyt P-450 (oxidation site shown by arrows). This oxidation converts the benzylic CH2 group into a CO group to afford an ester moiety, which can then be cleaved by esterolysis to afford 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6- DNP, 3,4-DNP, or 3, 5-DNP. The use of bioprecursors is often a good alternative to the prodrug approach and may provide metabolically activated slow release of 2, 4-DNP.

Scheme 11

Alternative Strategies Conjugation

[0036] In some embodiments, DNP prodrugs and bioprecursors with linkers containing open functional groups are utilized, which allow conjugation of each of these entities to nanoparticles, such as dendrimers, in order to modulate the pharmacokinetics of the molecule to enable “trickle” drug delivery. Such DNP prodrugs and bioprecursors are delivered as depot nanoparticle formulations that release DNP in a slow, sustained fashion at low doses, compared to dose and release of DNP alone, to avoid possible toxicity issues.

[0037] Nanotechnology presents an opportunity to increase the bioavailability of drug particles. A decrease in particle size results in increased surface area, results in faster dissolution. In some embodiments, the decrease is by a small order of magnitude. In other embodiments, this may be enough to result in increased bioavailability. However, faster dissolution may not be sufficient to overcome exposure to acid and enzymes in the gut. Additionally, as in the case with oral insulin, this exposure may require higher dosing of the drug, resulting in unnecessary and potentially undesirable subject exposure to breakdown products as well as create significant waste.

[0038] A depot nanoparticle formulation is specially formulated to provide slow absorption of the drug from the site of administration, often keeping therapeutic levels of the drug in the patient’s system for days or weeks at a time. Alternatively, a depot nanoparticle formulation may provide convenience for a patient in need of chronic medication. By delivering drug without exposure to the GI tract, the potential issue of drug degradation is avoided. Moreover, a depot nanoparticle formulation may provide better compliance due to the infrequent dosing regimen and convenience. Additional characteristics of a depot nanoparticle formulation that will enhance patient compliance are good local tolerance at the injection site and ease of administration. Good local tolerance means minimal irritation and inflammation at the site of injection; ease of administration refers to the size of needle and length of time required to administer a dose of a particular drug formulation.

In vitro and in vivo evaluation of prodrugs/bioprecursors

[0039] The prodrugs and bioprecursors of the disclosure encounter a wide range of pHs and enzymes when administered orally to patients. In one embodiment, the prodrug/bioprecursor is stable in the environment of the GI tract, but releases parent drug in the plasma in a sustained manner after absorption from the GT tract. Oral dosing exposes compounds to pH 1 to 2 in the stomach, pH 4.5 at the beginning of the small intestine, pH 6.6 as an average pH for the small intestine, and pHs of 5 to 9 in the colon. Stability-indicating methods are performed in aqueous buffer solutions and simulated GI fluids to determine the resilience of the 2,3-DNP, 2,4-DNP,

2.5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP prodrugs/bioprecursors in the GI tract, and also their susceptibility to enzymatic conversion to the parent drug in rat plasma. These are useful methods for in vitro evaluation of the chemical stability of a prodrug candidate.

[0040] Determining pH stability in aqueous buffers (37 °C, pH 1-9)

1) Determining GI stability in simulated gastric fluid (USP, 37 °C)

2) Determining GI stability in simulated intestinal fluid (USP, 37 °C)

3) Determining plasma: stability in rat plasma (37 °C)

[0041] Single compound dosing studies, are carried out on 2,3-DNP, 2,4-DNP, 2,5-DNP,

2.6-DNP, 3,4-DNP, or 3,5-DNP prodrug/bioprecursor candidates to determine their clinical potential. Most promising preclinical prodrug/bioprecursor candidates are absorbed intact from the gastrointestinal tract and are efficiently cleaved enzymatically in plasma to afford the parent drug. The presence and identification of the prodrug and the parent drug can also provide important information on the mechanism of action of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, the identification of which is of value in the selection of new structural entities for consideration in structure-activity and structural optimization studies.

[0042] Pharmacokinetic studies are carried out on the most promising prodrug/bioprecursor candidate (i.e., the prodrug/bioprecursor that exhibits the greatest stability in the GI tract and affords sustained release of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP in vitro and in vivo in rat plasma) in the Sprague-Dawley rat. A complete PK profile is obtained for the orally administered prodrug in jugular and femoral vein catheterized rats to determine half-life (ti/2), maximum plasma concentration (tmax), time to reach maximum plasma concentration (tmax), volume of distribution (Vss), area under the plasma concentration versus time curve from time 0 to infinity (AUCo-®), and bioavailability (F%), as well as other important PK parameters such as protein binding. LC/MS/MS is used as the analytical methodology to determine both the above pharmacokinetic parameters of the prodrug, and the plasma concentration and release kinetics of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5- DNP resulting from enzymatic conversion of the prodrug to 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6- DNP, 3,4-DNP, or 3,5-DNP in the plasma.

[0043] Although DNP is orally bioavailable, with good distribution and ~6-hour half-life in rats, the prodrug approach allows extending the plasma residence time at lower concentrations of the parent drug (DNP), by appropriate design of the prodrug release characteristics.

[0044] In an embodiment, the composition for treatment of pulmonary diseases and disorders, autoimmune diseases and disorders, insulin resistance, and/or pre-diabetes is independently selected from the group consisting of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4- DNP, or 3,5-DNP, bipartite 2,3 -dinitrophenol, 2,4-dinitrophenol, 2,5-dinitrophenol, 2,6- dinitrophenol, 3,4- dinitrophenol, or 3,5-dinitrophenol (2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP) prodrugs; Gemini prodrugs, bioprecursor molecules, and combinations thereof.

[0045] In one embodiment, a dose of any of the foregoing embodiments of the compositions, of DNP, DNP prodrugs, Gemini prodrugs, bioprecursor molecules, and combinations thereof, for treatment of pulmonary diseases and disorders, autoimmune diseases and disorders, insulin resistance, and/or pre-diabetes, may be from about 0.01 mg/kg to about 50 mg/kg of body weight of the patient in need of treatment; from about 25 mg/kg to about 100 mg/kg of body weight of the patient in need of treatment; or from about 25 mg/kg to about 100 mg/kg of body weight of the patient in need of treatment. In one embodiment, a dose of any of the foregoing embodiments of the compositions for treatment of neuromuscular, neuromuscular degenerative, neurodegenerative, autoimmune, developmental, traumatic, hearing loss related, and/or metabolic diseases may be from 0.01 mg/kg to 50 mg/kg of body weight of the patient in need of treatment; from 25 mg/kg to 100 mg/kg of body weight of the patient in need of treatment; or from 25 mg/kg to 100 mg/kg of body weight of the patient in need of treatment. In an embodiment, the present disclosure relates to a pharmaceutical composition of DNP, or a pharmaceutically acceptable salt, solvate, hydrate and/or prodrug thereof as described herein, comprising a unit dose, wherein the unit dose is in the range of about 0.1 mg to about 3000 mg. In an embodiment, the present disclosure relates to a pharmaceutical composition of DNP, or a pharmaceutically acceptable salt, solvate, hydrate and/or prodrug thereof as described herein, comprising a unit dose, wherein the unit dose is in the range of 0.1 mg to 3000 mg. [0046] In one embodiment, a dose of any of the foregoing embodiments of the compositions, of DNP, DNP prodrugs, Gemini prodrugs, bioprecursor molecules, and combinations thereof, for treatment of pulmonary diseases and disorders including cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea, may be independently selected from about 0.01 mg/kg to about 50 mg/kg of body weight; about 0.01 mg/kg to about 40 mg/kg of body weight; about 0.01 mg/kg to about 30 mg/kg of body weight; about 0.01 mg/kg to about 20 mg/kg of body weight; about 0.01 mg/kg to about 10 mg/kg of body weight; about 0.01 mg/kg to about 5 mg/kg of body weight; about 0.01 mg/kg to about 1 mg/kg of body weight; about 0.05 mg/kg to about 50 mg/kg of body weight; about 0.05 mg/kg to about 40 mg/kg of body weight; about 0.05 mg/kg to about 30 mg/kg of body weight; about 0.05 mg/kg to about 20 mg/kg of body weight; about 0.05 mg/kg to about 10 mg/kg of body weight; about 0.05 mg/kg to about 1.0 mg/kg of body weight; about 0.05 mg/kg to about 0.1 mg/kg of body weight; about 0.1 mg/kg to about 40 mg/kg of body weight; about 0.1 mg/kg to about 50 mg/kg of body weight; about 0.1 mg/kg to about 30 mg/kg of body weight; about 0.1 mg/kg to about 20 mg/kg of body weight; about 0.1 mg/kg to about 15 mg/kg of body weight; about 0.1 mg/kg to about 12 mg/kg of body weight; about 0.1 mg/kg to about 10 mg/kg of body weight; about 0.1 mg/kg to about 9 mg/kg of body weight; about 0.1 mg/kg to about 8 mg/kg of body weight; about 0.1 mg/kg to about 7 mg/kg of body weight; about 0.1 mg/kg to about 6 mg/kg of body weight; about 0.1 mg/kg to about 5 mg/kg of body weight; about 0.1 mg/kg to about 4 mg/kg of body weight; about 0.1 mg/kg to about 3 mg/kg of body weight; about 0.1 mg/kg to about 2 mg/kg of body weight; 0.1 mg/kg to about 1.0 mg/kg of body weight; about 0.3 mg/kg to about 20 mg/kg of body weight; about 0.3 mg/kg to about 15 mg/kg of body weight; about 0.3 mg/kg to about 12 mg/kg of body weight; about 0.3 mg/kg to about 10 mg/kg of body weight; about 0.3 mg/kg to about 9 mg/kg of body weight; about 0.3 mg/kg to about 8 mg/kg of body weight; about 0.3 mg/kg to about 7 mg/kg of body weight; about 0.3 mg/kg to about 6 mg/kg of body weight; about 0.3 mg/kg to about 5 mg/kg of body weight; about 0.3 mg/kg to about 4 mg/kg of body weight; about 0.3 mg/kg to about 3 mg/kg of body weight; about 0.3 mg/kg to about 2 mg/kg of body weight; about 0.3 mg/kg to about 1.0 mg/kg of body weight; about 0.5 mg/kg to about 15 mg/kg of body weight; about 0.5 mg/kg to about 12 mg/kg of body weight; about 0.5 mg/kg to about 10 mg/kg of body weight; about 0.5 mg/kg to about 9 mg/kg of body weight; about 0.5 mg/kg to about 8 mg/kg of body weight; about 0.5 mg/kg to about 7 mg/kg of body weight; about 0.5 mg/kg to about 6 mg/kg of body weight; about 0.5 mg/kg to about 5 mg/kg of body weight; about 0.5 mg/kg to about 4 mg/kg of body weight; about 0.5 mg/kg to about 3 mg/kg of body weight; about 0.5 mg/kg to about 2 mg/kg of body weight; about 0.5 mg/kg to about 1.0 mg/kg of body weight; about 0.8 mg/kg to about 15 mg/kg of body weight; about 0.8 mg/kg to about 12 mg/kg of body weight; about 0.8 mg/kg to about 10 mg/kg of body weight; about 0.8 mg/kg to about 9 mg/kg of body weight; about 0.8 mg/kg to about 8 mg/kg of body weight; about 0.8 mg/kg to about 7 mg/kg of body weight; about 0.8 mg/kg to about 6 mg/kg of body weight; about 0.8 mg/kg to about 5 mg/kg of body weight; about 0.8 mg/kg to about 4 mg/kg of body weight; about 0.8 mg/kg to about 3 mg/kg of body weight; about 0.8 mg/kg to about 2 mg/kg of body weight; about 0.8 mg/kg to about 1.0 mg/kg of body weight; about 1 mg/kg to about 3.0 mg/kg of body; about 1.5 mg/kg to about 3.0 mg/kg of body; about 1.0 mg/kg to about 2.0 mg/kg of body; about 2.0 mg/kg to about 3.0 mg/kg of body; about 0.5 mg/kg to about 2.5 mg/kg of body weight; about 0.5 mg/kg to about 2.0 mg/kg of body weight.

[0047J In one embodiment, a dose of any of the foregoing embodiments of the compositions, of DNP, DNP prodrugs, Gemini prodrugs, bioprecursor molecules, and combinations thereof, for treatment of autoimmune diseases and disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, systemic lupus erythematosus, rheumatoid arthritis, ileitis and allergic rhinitis, may be independently selected from about 0.01 mg/kg to about 50 mg/kg of body weight; about 0.01 mg/kg to about 40 mg/kg of body weight; about 0.01 mg/kg to about 30 mg/kg of body weight; about 0.01 mg/kg to about 20 mg/kg of body weight; about 0.01 mg/kg to about 10 mg/kg of body weight; about 0.01 mg/kg to about 5 mg/kg of body weight; about 0.01 mg/kg to about 1 mg/kg of body weight; about 0.05 mg/kg to about 50 mg/kg of body weight; about 0.05 mg/kg to about 40 mg/kg of body weight; about 0.05 mg/kg to about 30 mg/kg of body weight; about 0.05 mg/kg to about 20 mg/kg of body weight; about 0.05 mg/kg to about 10 mg/kg of body weight; about 0.05 mg/kg to about 1.0 mg/kg of body weight; about 0.05 mg/kg to about 0.1 mg/kg of body weight; about 0.1 mg/kg to about 40 mg/kg of body weight; about 0.1 mg/kg to about 50 mg/kg of body weight; about 0.1 mg/kg to about 30 mg/kg of body weight; about 0.1 mg/kg to about 20 mg/kg of body weight; about 0.1 mg/kg to about 15 mg/kg of body weight; about 0.1 mg/kg to about 12 mg/kg of body weight; about 0.1 mg/kg to about 10 mg/kg of body weight; about 0.1 mg/kg to about 9 mg/kg of body weight; about 0.1 mg/kg to about 8 mg/kg of body weight; about 0.1 mg/kg to about 7 mg/kg of body weight; about 0.1 mg/kg to about 6 mg/kg of body weight; about 0.1 mg/kg to about 5 mg/kg of body weight; about 0.1 mg/kg to about 4 mg/kg of body weight; about 0.1 mg/kg to about 3 mg/kg of body weight; about 0.1 mg/kg to about 2 mg/kg of body weight; 0.1 mg/kg to about 1.0 mg/kg of body weight; about 0.3 mg/kg to about 20 mg/kg of body weight; about 0.3 mg/kg to about 15 mg/kg of body weight; about 0.3 mg/kg to about 12 mg/kg of body weight; about 0.3 mg/kg to about 10 mg/kg of body weight; about 0.3 mg/kg to about 9 mg/kg of body weight; about 0.3 mg/kg to about 8 mg/kg of body weight; about 0.3 mg/kg to about 7 mg/kg of body weight; about 0.3 mg/kg to about 6 mg/kg of body weight; about 0.3 mg/kg to about 5 mg/kg of body weight; about 0.3 mg/kg to about 4 mg/kg of body weight; about 0.3 mg/kg to about 3 mg/kg of body weight; about 0.3 mg/kg to about 2 mg/kg of body weight; about 0.3 mg/kg to about 1.0 mg/kg of body weight; about 0.5 mg/kg to about 15 mg/kg of body weight; about 0.5 mg/kg to about 12 mg/kg of body weight; about 0.5 mg/kg to about 10 mg/kg of body weight; about 0.5 mg/kg to about 9 mg/kg of body weight; about 0.5 mg/kg to about 8 mg/kg of body weight; about 0.5 mg/kg to about 7 mg/kg of body weight; about 0.5 mg/kg to about 6 mg/kg of body weight; about 0.5 mg/kg to about 5 mg/kg of body weight; about 0.5 mg/kg to about 4 mg/kg of body weight; about 0.5 mg/kg to about 3 mg/kg of body weight; about 0.5 mg/kg to about 2 mg/kg of body weight; about 0.5 mg/kg to about 1.0 mg/kg of body weight; about 0.8 mg/kg to about 15 mg/kg of body weight; about 0.8 mg/kg to about 12 mg/kg of body weight; about 0.8 mg/kg to about 10 mg/kg of body weight; about 0.8 mg/kg to about 9 mg/kg of body weight; about 0.8 mg/kg to about 8 mg/kg of body weight; about 0.8 mg/kg to about 7 mg/kg of body weight; about 0.8 mg/kg to about 6 mg/kg of body weight; about 0.8 mg/kg to about 5 mg/kg of body weight; about 0.8 mg/kg to about 4 mg/kg of body weight; about 0.8 mg/kg to about 3 mg/kg of body weight; about 0.8 mg/kg to about 2 mg/kg of body weight; about 0.8 mg/kg to about 1.0 mg/kg of body weight; about 1 mg/kg to about 3.0 mg/kg of body; about 1.5 mg/kg to about 3.0 mg/kg of body; about 1.0 mg/kg to about 2.0 mg/kg of body; about 2.0 mg/kg to about 3.0 mg/kg of body; about 0.5 mg/kg to about 2.5 mg/kg of body weight; about 0.5 mg/kg to about 2.0 mg/kg of body weight. [0048] In one embodiment, a dose of any of the foregoing embodiments of the compositions, of DNP, DNP prodrugs, Gemini prodrugs, bioprecursor molecules, and combinations thereof, for treatment of pulmonary diseases and disorders including cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea, may be independently selected from 0.01 mg/kg to 50 mg/kg of body weight; 0.01 mg/kg to 40 mg/kg of body weight; 0.01 mg/kg to 30 mg/kg of body weight; 0.01 mg/kg to 20 mg/kg of body weight; 0.01 mg/kg to 10 mg/kg of body weight; 0.01 mg/kg to 5 mg/kg of body weight; 0.01 mg/kg to 1 mg/kg of body weight; 0.05 mg/kg to 50 mg/kg of body weight; 0.05 mg/kg to 40 mg/kg of body weight; 0.05 mg/kg to 30 mg/kg of body weight; 0.05 mg/kg to 20 mg/kg of body weight; 0.05 mg/kg to 10 mg/kg of body weight; 0.05 mg/kg to 1.0 mg/kg of body weight; 0.05 mg/kg to 0.1 mg/kg of body weight; 0.1 mg/kg to 40 mg/kg of body weight; 0.1 mg/kg to 50 mg/kg of body weight; 0.1 mg/kg to 30 mg/kg of body weight; 0.1 mg/kg to 20 mg/kg of body weight; 0.1 mg/kg to 15 mg/kg of body weight; 0.1 mg/kg to 12 mg/kg of body weight; 0.1 mg/kg to 10 mg/kg of body weight; 0.1 mg/kg to 9 mg/kg of body weight; 0.1 mg/kg to 8 mg/kg of body weight; 0.1 mg/kg to 7 mg/kg of body weight; 0.1 mg/kg to 6 mg/kg of body weight; 0.1 mg/kg to 5 mg/kg of body weight; 0.1 mg/kg to 4 mg/kg of body weight; 0.1 mg/kg to 3 mg/kg of body weight; 0.1 mg/kg to 2 mg/kg of body weight; 0.1 mg/kg to 1.0 mg/kg of body weight; 0.3 mg/kg to 20 mg/kg of body weight; 0.3 mg/kg to 15 mg/kg of body weight; 0.3 mg/kg to 12 mg/kg of body weight; 0.3 mg/kg to 10 mg/kg of body weight; 0.3 mg/kg to 9 mg/kg of body weight; 0.3 mg/kg to 8 mg/kg of body weight; 0.3 mg/kg to 7 mg/kg of body weight; 0.3 mg/kg to 6 mg/kg of body weight; 0.3 mg/kg to 5 mg/kg of body weight; 0.3 mg/kg to 4 mg/kg of body weight; 0.3 mg/kg to 3 mg/kg of body weight; 0.3 mg/kg to 2 mg/kg of body weight; 0.3 mg/kg to 1.0 mg/kg of body weight; 0.5 mg/kg to 10 mg/kg of body weight; 0.5 mg/kg to 9 mg/kg of body weight; 0.5 mg/kg to 8 mg/kg of body weight; 0.5 mg/kg to 7 mg/kg of body weight; 0.5 mg/kg to 6 mg/kg of body weight; 0.5 mg/kg to 5 mg/kg of body weight; 0.5 mg/kg to about 4 mg/kg of body weight; 0.5 mg/kg to 3 mg/kg of body weight; 0.5 mg/kg to 2 mg/kg of body weight; 0.5 mg/kg to 1.0 mg/kg of body weight; 0.8 mg/kg to 15 mg/kg of body weight; 0.8 mg/kg to 12 mg/kg of body weight; 0.8 mg/kg to 8 10 mg/kg of body weight; 0.8 mg/kg to 9 mg/kg of body weight; 0.8 mg/kg to 8 mg/kg of body weight; 0.8 mg/kg to 7 mg/kg of body weight; 0.8 mg/kg to 6 mg/kg of body weight; 0.8 mg/kg to 5 mg/kg of body weight; 0.8 mg/kg to 4 mg/kg of body weight; 0.8 mg/kg to 3 mg/kg of body weight; 0.8 mg/kg to 2 mg/kg of body weight; 0.8 mg/kg to 1.0 mg/kg of body weight; 1 mg/kg to 3.0 mg/kg of body; 1.5 mg/kg to 3.0 mg/kg of body; 1.0 mg/kg to 2.0 mg/kg of body; 2.0 mg/kg to 3.0 mg/kg of body; 0.5 mg/kg to 2.5 mg/kg of body weight; 0.5 mg/kg to 2.0 mg/kg of body weight. In some embodiments, a dose described above treats cystic fibrosis by improving the survivability of CF patients.

[0049] In one embodiment, administration of DNP, or the DNP prodrugs, Gemini prodrugs, bioprecursor molecules, and combinations thereof described herein prevents or reduces inflammation and/or scarring in the pancreas of cystic fibrosis patients. In some embodiments, administration of DNP, or the DNP prodrugs; Gemini prodrugs, bioprecursor molecules, and combinations thereof described herein prevents or reduces increases in blood glucose levels in cystic fibrosis patients following a meal, thus preventing or reducing inflammation and/or scarring in the pancreas of cystic fibrosis patients. In one embodiment, inflammation and/or scarring in the pancreas leads to type 1 or type 2 diabetes in cystic fibrosis patients, thus the administration of DNP, or the DNP prodrugs; Gemini prodrugs, bioprecursor molecules, and combinations thereof described herein prevents cystic fibrosis diabetes in CF patients. In one embodiment, a dose of any of the foregoing embodiments of the compositions, of DNP, DNP prodrugs; Gemini prodrugs, bioprecursor molecules, and combinations thereof, for the prevention of cystic fibrosis diabetes may be independently selected from 0.01 mg/kg to 50 mg/kg of body weight; 0.01 mg/kg to 40 mg/kg of body weight; 0.01 mg/kg to 30 mg/kg of body weight; 0.01 mg/kg to 20 mg/kg of body weight; 0.01 mg/kg to 10 mg/kg of body weight; 0.01 mg/kg to 5 mg/kg of body weight; 0.01 mg/kg to 1 mg/kg of body weight; 0.05 mg/kg to 50 mg/kg of body weight; 0.05 mg/kg to 40 mg/kg of body weight; 0.05 mg/kg to 30 mg/kg of body weight; 0.05 mg/kg to 20 mg/kg of body weight; 0.05 mg/kg to 10 mg/kg of body weight; 0.05 mg/kg to 1.0 mg/kg of body weight; 0.05 mg/kg to 0.1 mg/kg of body weight; 0.1 mg/kg to 40 mg/kg of body weight; 0.1 mg/kg to 50 mg/kg of body weight; 0.1 mg/kg to 30 mg/kg of body weight; 0.1 mg/kg to 20 mg/kg of body weight; 0.1 mg/kg to 15 mg/kg of body weight; 0.1 mg/kg to 12 mg/kg of body weight; 0.1 mg/kg to 10 mg/kg of body weight; 0.1 mg/kg to 9 mg/kg of body weight; 0.1 mg/kg to 8 mg/kg of body weight; 0.1 mg/kg to 7 mg/kg of body weight; 0.1 mg/kg to 6 mg/kg of body weight; 0.1 mg/kg to 5 mg/kg of body weight; 0.1 mg/kg to 4 mg/kg of body weight; 0.1 mg/kg to 3 mg/kg of body weight; 0.1 mg/kg to 2 mg/kg of body weight; 0.1 mg/kg to 1.0 mg/kg of body weight; 0.3 mg/kg to 20 mg/kg of body weight; 0.3 mg/kg to 15 mg/kg of body weight; 0.3 mg/kg to 12 mg/kg of body weight; 0.3 mg/kg to 10 mg/kg of body weight; 0.3 mg/kg to 9 mg/kg of body weight; 0.3 mg/kg to 8 mg/kg of body weight; 0.3 mg/kg to 7 mg/kg of body weight; 0.3 mg/kg to 6 mg/kg of body weight; 0.3 mg/kg to 5 mg/kg of body weight; 0.3 mg/kg to 4 mg/kg of body weight; 0.3 mg/kg to 3 mg/kg of body weight; 0.3 mg/kg to 2 mg/kg of body weight; 0.3 mg/kg to 1.0 mg/kg of body weight; 0.5 mg/kg to 10 mg/kg of body weight; 0.5 mg/kg to 9 mg/kg of body weight; 0.5 mg/kg to 8 mg/kg of body weight; 0.5 mg/kg to 7 mg/kg of body weight; 0.5 mg/kg to 6 mg/kg of body weight; 0.5 mg/kg to 5 mg/kg of body weight; 0.5 mg/kg to about 4 mg/kg of body weight; 0.5 mg/kg to 3 mg/kg of body weight; 0.5 mg/kg to 2 mg/kg of body weight; 0.5 mg/kg to 1.0 mg/kg of body weight; 0.8 mg/kg to 15 mg/kg of body weight; 0.8 mg/kg to 12 mg/kg of body weight; 0.8 mg/kg to 8 10 mg/kg of body weight; 0.8 mg/kg to 9 mg/kg of body weight; 0.8 mg/kg to 8 mg/kg of body weight; 0.8 mg/kg to 7 mg/kg of body weight; 0.8 mg/kg to 6 mg/kg of body weight; 0.8 mg/kg to 5 mg/kg of body weight; 0.8 mg/kg to 4 mg/kg of body weight; 0.8 mg/kg to 3 mg/kg of body weight; 0.8 mg/kg to 2 mg/kg of body weight; 0.8 mg/kg to 1.0 mg/kg of body weight; 1 mg/kg to 3.0 mg/kg of body; 1.5 mg/kg to 3.0 mg/kg of body; 1.0 mg/kg to 2.0 mg/kg of body; 2.0 mg/kg to 3.0 mg/kg of body; 0.5 mg/kg to 2.5 mg/kg of body weight; 0.5 mg/kg to 2.0 mg/kg of body weight.

[0050] In one embodiment, a dose of any of the foregoing embodiments of the compositions, of DNP, DNP prodrugs; Gemini prodrugs, bioprecursor molecules, and combinations thereof, for treatment of autoimmune diseases and disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, systemic lupus erythematosus, rheumatoid arthritis, ileitis and allergic rhinitis, may be independently selected from 0.01 mg/kg to 50 mg/kg of body weight; 0.01 mg/kg to 40 mg/kg of body weight; 0.01 mg/kg to 30 mg/kg of body weight; 0.01 mg/kg to 20 mg/kg of body weight; 0.01 mg/kg to 10 mg/kg of body weight; 0.01 mg/kg to 5 mg/kg of body weight; 0.01 mg/kg to 1 mg/kg of body weight; 0.05 mg/kg to 50 mg/kg of body weight; 0.05 mg/kg to 40 mg/kg of body weight; 0.05 mg/kg to 30 mg/kg of body weight; 0.05 mg/kg to 20 mg/kg of body weight; 0.05 mg/kg to 10 mg/kg of body weight; 0.05 mg/kg to 1.0 mg/kg of body weight; 0.05 mg/kg to 0.1 mg/kg of body weight; 0.1 mg/kg to 40 mg/kg of body weight; 0.1 mg/kg to 50 mg/kg of body weight; 0.1 mg/kg to 30 mg/kg of body weight; 0.1 mg/kg to 20 mg/kg of body weight; 0.1 mg/kg to 15 mg/kg of body weight; 0.1 mg/kg to 12 mg/kg of body weight; 0.1 mg/kg to 10 mg/kg of body weight; 0.1 mg/kg to 9 mg/kg of body weight; 0.1 mg/kg to 8 mg/kg of body weight; 0.1 mg/kg to 7 mg/kg of body weight; 0.1 mg/kg to 6 mg/kg of body weight; 0.1 mg/kg to 5 mg/kg of body weight; 0.1 mg/kg to 4 mg/kg of body weight; 0.1 mg/kg to 3 mg/kg of body weight; 0.1 mg/kg to 2 mg/kg of body weight; 0.1 mg/kg to 1.0 mg/kg of body weight; 0.3 mg/kg to 20 mg/kg of body weight; 0.3 mg/kg to 15 mg/kg of body weight; 0.3 mg/kg to 12 mg/kg of body weight; 0.3 mg/kg to 10 mg/kg of body weight; 0.3 mg/kg to 9 mg/kg of body weight; 0.3 mg/kg to 8 mg/kg of body weight; 0.3 mg/kg to 7 mg/kg of body weight; 0.3 mg/kg to 6 mg/kg of body weight; 0.3 mg/kg to 5 mg/kg of body weight; 0.3 mg/kg to 4 mg/kg of body weight; 0.3 mg/kg to 3 mg/kg of body weight; 0.3 mg/kg to 2 mg/kg of body weight; 0.3 mg/kg to 1.0 mg/kg of body weight; 0.5 mg/kg to 10 mg/kg of body weight; 0.5 mg/kg to 9 mg/kg of body weight; 0.5 mg/kg to 8 mg/kg of body weight; 0.5 mg/kg to 7 mg/kg of body weight; 0.5 mg/kg to 6 mg/kg of body weight; 0.5 mg/kg to 5 mg/kg of body weight; 0.5 mg/kg to about 4 mg/kg of body weight; 0.5 mg/kg to 3 mg/kg of body weight; 0.5 mg/kg to 2 mg/kg of body weight; 0.5 mg/kg to 1.0 mg/kg of body weight; 0.8 mg/kg to 15 mg/kg of body weight; 0.8 mg/kg to 12 mg/kg of body weight; 0.8 mg/kg to 8 10 mg/kg of body weight; 0.8 mg/kg to 9 mg/kg of body weight; 0.8 mg/kg to 8 mg/kg of body weight; 0.8 mg/kg to 7 mg/kg of body weight; 0.8 mg/kg to 6 mg/kg of body weight; 0.8 mg/kg to 5 mg/kg of body weight; 0.8 mg/kg to 4 mg/kg of body weight; 0.8 mg/kg to 3 mg/kg of body weight; 0.8 mg/kg to 2 mg/kg of body weight; 0.8 mg/kg to 1.0 mg/kg of body weight; 1 mg/kg to 3.0 mg/kg of body; 1.5 mg/kg to 3.0 mg/kg of body; 1.0 mg/kg to 2.0 mg/kg of body; 2.0 mg/kg to 3.0 mg/kg of body; 0.5 mg/kg to 2.5 mg/kg of body weight; 0.5 mg/kg to 2.0 mg/kg of body weight.

[0051] In one embodiment, a dose of any of the foregoing embodiments of the compositions, of DNP, DNP prodrugs, Gemini prodrugs, bioprecursor molecules, and combinations thereof, for treatment of insulin resistance and/or pre-diabetes, may be independently selected from about 0.01 mg/kg to about 50 mg/kg of body weight; about 0.01 mg/kg to about 40 mg/kg of body weight; about 0.01 mg/kg to about 30 mg/kg of body weight; about 0.01 mg/kg to about 20 mg/kg of body weight; about 0.01 mg/kg to about 10 mg/kg of body weight; about 0.01 mg/kg to about 5 mg/kg of body weight; about 0.01 mg/kg to about 1 mg/kg of body weight; about 0.05 mg/kg to about 50 mg/kg of body weight; about 0.05 mg/kg to about 40 mg/kg of body weight; about 0.05 mg/kg to about 30 mg/kg of body weight; about 0.05 mg/kg to about 20 mg/kg of body weight; about 0.05 mg/kg to about 10 mg/kg of body weight; about 0 05 mg/kg to about 1 .0 mg/kg of body weight; about 0.05 mg/kg to about 0.1 mg/kg of body weight; about 0.1 mg/kg to about 40 mg/kg of body weight; about 0.1 mg/kg to about 50 mg/kg of body weight; about 0.1 mg/kg to about 30 mg/kg of body weight; about 0.1 mg/kg to about 20 mg/kg of body weight; about 0.1 mg/kg to about 15 mg/kg of body weight; about 0.1 mg/kg to about 12 mg/kg of body weight; about 0.1 mg/kg to about 10 mg/kg of body weight; about 0.1 mg/kg to about 9 mg/kg of body weight; about 0.1 mg/kg to about 8 mg/kg of body weight; about 0.1 mg/kg to about 7 mg/kg of body weight; about 0.1 mg/kg to about 6 mg/kg of body weight; about 0.1 mg/kg to about 5 mg/kg of body weight; about 0.1 mg/kg to about 4 mg/kg of body weight; about 0.1 mg/kg to about 3 mg/kg of body weight; about 0.1 mg/kg to about 2 mg/kg of body weight; 0.1 mg/kg to about 1.0 mg/kg of body weight; about 0.3 mg/kg to about 20 mg/kg of body weight; about 0.3 mg/kg to about 15 mg/kg of body weight; about 0.3 mg/kg to about 12 mg/kg of body weight; about 0.3 mg/kg to about 10 mg/kg of body weight; about 0.3 mg/kg to about 9 mg/kg of body weight; about 0.3 mg/kg to about 8 mg/kg of body weight; about 0.3 mg/kg to about 7 mg/kg of body weight; about 0.3 mg/kg to about 6 mg/kg of body weight; about 0.3 mg/kg to about 5 mg/kg of body weight; about 0.3 mg/kg to about 4 mg/kg of body weight; about 0.3 mg/kg to about 3 mg/kg of body weight; about 0.3 mg/kg to about 2 mg/kg of body weight; about 0.3 mg/kg to about 1.0 mg/kg of body weight; about 0.5 mg/kg to about 15 mg/kg of body weight; about 0.5 mg/kg to about 12 mg/kg of body weight; about 0.5 mg/kg to about 10 mg/kg of body weight; about 0.5 mg/kg to about 9 mg/kg of body weight; about 0.5 mg/kg to about 8 mg/kg of body weight; about 0.5 mg/kg to about 7 mg/kg of body weight; about 0.5 mg/kg to about 6 mg/kg of body weight; about 0.5 mg/kg to about 5 mg/kg of body weight; about 0.5 mg/kg to about 4 mg/kg of body weight; about 0.5 mg/kg to about 3 mg/kg of body weight; about 0.5 mg/kg to about 2 mg/kg of body weight; about 0.5 mg/kg to about 1.0 mg/kg of body weight; about 0.8 mg/kg to about 15 mg/kg of body weight; about 0.8 mg/kg to about 12 mg/kg of body weight; about 0.8 mg/kg to about 10 mg/kg of body weight; about 0.8 mg/kg to about 9 mg/kg of body weight; about 0.8 mg/kg to about 8 mg/kg of body weight; about 0.8 mg/kg to about 7 mg/kg of body weight; about 0.8 mg/kg to about 6 mg/kg of body weight; about 0.8 mg/kg to about 5 mg/kg of body weight; about 0.8 mg/kg to about 4 mg/kg of body weight; about 0.8 mg/kg to about 3 mg/kg of body weight; about 0.8 mg/kg to about 2 mg/kg of body weight; about 0.8 mg/kg to about 1.0 mg/kg of body weight; about 1 mg/kg to about 3.0 mg/kg of body; about 1.5 mg/kg to about 3.0 mg/kg of body; about 1.0 mg/kg to about 2.0 mg/kg of body; about 2.0 mg/kg to about 3.0 mg/kg of body; about 0.5 mg/kg to about 2.5 mg/kg of body weight; about 0.5 mg/kg to about 2.0 mg/kg of body weight.

[0052] In one embodiment, a dose of any of the foregoing embodiments of the compositions, of DNP, DNP prodrugs, Gemini prodrugs, bioprecursor molecules, and combinations thereof, for treatment of pulmonary diseases and disorders including cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea, may be independently selected from 0.01 mg/kg to 50 mg/kg of body weight; 0.01 mg/kg to 40 mg/kg of body weight; 0.01 mg/kg to 30 mg/kg of body weight; 0.01 mg/kg to 20 mg/kg of body weight; 0.01 mg/kg to 10 mg/kg of body weight; 0.01 mg/kg to 5 mg/kg of body weight; 0.01 mg/kg to 1 mg/kg of body weight; 0.05 mg/kg to 50 mg/kg of body weight; 0.05 mg/kg to 40 mg/kg of body weight; 0.05 mg/kg to 30 mg/kg of body weight; 0.05 mg/kg to 20 mg/kg of body weight; 0.05 mg/kg to 10 mg/kg of body weight; 0.05 mg/kg to 1.0 mg/kg of body weight; 0.05 mg/kg to 0.1 mg/kg of body weight; 0.1 mg/kg to 40 mg/kg of body weight; 0.1 mg/kg to 50 mg/kg of body weight; 0.1 mg/kg to 30 mg/kg of body weight; 0.1 mg/kg to 20 mg/kg of body weight; 0.1 mg/kg to 15 mg/kg of body weight; 0.1 mg/kg to 12 mg/kg of body weight; 0.1 mg/kg to 10 mg/kg of body weight; 0.1 mg/kg to 9 mg/kg of body weight; 0.1 mg/kg to 8 mg/kg of body weight; 0.1 mg/kg to 7 mg/kg of body weight; 0.1 mg/kg to 6 mg/kg of body weight; 0.1 mg/kg to 5 mg/kg of body weight; 0.1 mg/kg to 4 mg/kg of body weight; 0.1 mg/kg to 3 mg/kg of body weight; 0.1 mg/kg to 2 mg/kg of body weight; 0.1 mg/kg to 1.0 mg/kg of body weight; 0.3 mg/kg to 20 mg/kg of body weight; 0.3 mg/kg to 15 mg/kg of body weight; 0.3 mg/kg to 12 mg/kg of body weight; 0.3 mg/kg to 10 mg/kg of body weight; 0.3 mg/kg to 9 mg/kg of body weight; 0.3 mg/kg to 8 mg/kg of body weight; 0.3 mg/kg to 7 mg/kg of body weight; 0.3 mg/kg to 6 mg/kg of body weight; 0.3 mg/kg to 5 mg/kg of body weight; 0.3 mg/kg to 4 mg/kg of body weight; 0.3 mg/kg to 3 mg/kg of body weight; 0.3 mg/kg to 2 mg/kg of body weight, 0.3 mg/kg to 1.0 mg/kg of body weight; 0.5 mg/kg to 10 mg/kg of body weight; 0.5 mg/kg to 9 mg/kg of body weight; 0.5 mg/kg to 8 mg/kg of body weight; 0.5 mg/kg to 7 mg/kg of body weight; 0.5 mg/kg to 6 mg/kg of body weight; 0.5 mg/kg to 5 mg/kg of body weight; 0.5 mg/kg to about 4 mg/kg of body weight; 0.5 mg/kg to 3 mg/kg of body weight; 0.5 mg/kg to 2 mg/kg of body weight; 0.5 mg/kg to 1.0 mg/kg of body weight; 0.8 mg/kg to 15 mg/kg of body weight; 0.8 mg/kg to 12 mg/kg of body weight; 0.8 mg/kg to 8 10 mg/kg of body weight; 0.8 mg/kg to 9 mg/kg of body weight; 0.8 mg/kg to 8 mg/kg of body weight; 0.8 mg/kg to 7 mg/kg of body weight; 0.8 mg/kg to 6 mg/kg of body weight; 0.8 mg/kg to 5 mg/kg of body weight; 0.8 mg/kg to 4 mg/kg of body weight; 0.8 mg/kg to 3 mg/kg of body weight; 0.8 mg/kg to 2 mg/kg of body weight; 0.8 mg/kg to 1.0 mg/kg of body weight; 1 mg/kg to 3.0 mg/kg of body; 1.5 mg/kg to 3.0 mg/kg of body; 1.0 mg/kg to 2.0 mg/kg of body; 2.0 mg/kg to 3.0 mg/kg of body; 0.5 mg/kg to 2.5 mg/kg of body weight; 0.5 mg/kg to 2.0 mg/kg of body weight. In some embodiments, a dose described above for the treats cystic fibrosis by improving the survivability of CF patients.

[0053] In one embodiment, a dose of any of the foregoing embodiments of the compositions for treatment of pulmonary diseases and disorders including cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea, may be independently from about 1 mg/day/70kg of body weight to about 300 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 200 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 100 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 50 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 30 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 20 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 10 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 5 mg/day/70kg of body weight of the patient in need of treatment.

[ 0054] In one embodiment, a dose of any of the foregoing embodiments of the compositions for treatment of pulmonary diseases and disorders including cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea, may be independently from about 1 mg/day/70kg of body weight to about 300 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 200 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 100 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 50 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 30 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 20 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 10 mg/day/70kg of body weight of the patient in need of treatment; about 1 mg/day/70kg of body weight to about 5 mg/day/70kg of body weight of the patient in need of treatment.

[0055] In one embodiment, a dose of any of the foregoing embodiments of the compositions for treatment of autoimmune diseases and disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, systemic lupus erythematosus, rheumatoid arthritis, ileitis and allergic rhinitis, may be independently from 1 mg/day/70kg of body weight to 300 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 200 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 100 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 50 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 30 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 20 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 10 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 5 mg/day/70kg of body weight of the patient in need of treatment.

[0056] In one embodiment, a dose of any of the foregoing embodiments of the compositions for treatment of insulin resistance and/or pre-diabetes, may be independently from 1 mg/day/70kg of body weight to 300 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 200 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 100 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 50 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 30 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 20 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 10 mg/day/70kg of body weight of the patient in need of treatment; 1 mg/day/70kg of body weight to 5 mg/day/70kg of body weight of the patient in need of treatment.

[0057] In one embodiment, the therapeutic amount of any of the foregoing embodiments of the compositions of DNP, DNP prodrugs; Gemini prodrugs, bioprecursor molecules, and combinations thereof for treatment of insulin resistance and/or pre-diabetes prevents or reduces increases in blood glucose levels following a meal in the patient in need thereof, thereby treating insulin resistance and/or pre-diabetes.

[0058] In one embodiment, the therapeutic amount of any of the foregoing embodiments of the compositions of DNP, DNP prodrugs, Gemini prodrugs, bioprecursor molecules, and combinations thereof for the treatment of pulmonary diseases or disorders, autoimmune diseases or disorders, insulin resistance, and/or pre-diabetes is in the range of about 0.001 mg/kg of body weight to about 10 mg/kg of body weight, about 0.001 mg/kg of body weight to about 8 mg/kg of body weight, about 0.001 mg/kg of body weight to about 6 mg/kg of body weight, about 0.001 mg/kg of body weight to about 4 mg/kg of body weight, about 0.001 mg/kg of body weight to about 2 mg/kg of body weight, about 0.01 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 1 mg/kg of body weight, or about 0.1 mg/kg of body weight to about 1 mg/kg of body weight.

[0059] In one embodiment, the therapeutic amount of any of the foregoing embodiments of the compositions of DNP, DNP prodrugs, Gemini prodrugs, bioprecursor molecules, and combinations thereof for the treatment of pulmonary diseases or disorders, autoimmune diseases or disorders, insulin resistance, and/or pre-diabetes is about 0.001 mg/kg of body weight, about 0.005 mg/kg of body weight, about 0.01 mg/kg of body weight, about 0.05 mg/kg of body weight, about 0.1 mg/kg of body weight, about 0.2 mg/kg of body weight, about 0.3 mg/kg of body weight, about 0.4 mg/kg of body weight, about 0.5 mg/kg of body weight, about 0.6 mg/kg of body weight, about 0.7 mg/kg of body weight, about 0.8 mg/kg of body weight, or about 0.9 mg/kg of body weight.

[0060] In some embodiments, a pharmaceutical composition includes DNP, selected from the group consisting of DNP, 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, bipartite 2,3 -dinitrophenol, 2,4-dinitrophenol, 2,5-dinitrophenol, 2,6-dinitrophenol, 3,4- dinitrophenol, or 3,5-dinitrophenol (2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5- DNP) prodrugs or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising a unit dose, independently selected from: wherein the unit dose is in the range of about 0.1 mg to about 3000 mg; wherein the unit dose is in the range of about 0.1 mg to about 1000 mg; wherein the unit dose is in the range of about 0.1 mg to about 500 mg; wherein the unit dose is in the range of about 0.1 mg to about 100 mg; wherein the unit dose is in the range of about 1 mg to about 50 mg; wherein the unit dose is about 1 mg; wherein the unit dose is about 2 mg; wherein the unit dose is about 3 mg; wherein the unit dose is about 4 mg; wherein the unit dose is about 5 mg; wherein the unit dose is the range of about 5 mg to about 10 mg; wherein the unit dose is about 6 mg; wherein the unit dose is about 7 mg; wherein the unit dose is about 8 mg; wherein the unit dose is about 9 mg; wherein the unit dose is about 10 mg; wherein the unit dose is the range of about 10 mg to about 15 mg; wherein the unit dose is about 11 mg; wherein the unit dose is about 12 mg; wherein the unit dose is about 13 mg; wherein the unit dose is about 14 mg; wherein the unit dose is about 15 mg; wherein the unit dose is the range of about 15 mg to about 20 mg; wherein the unit dose is about 16 mg; wherein the unit dose is about 17 mg; wherein the unit dose is about 18 mg; wherein the unit dose is about 19 mg; wherein the unit dose is about 20 mg; wherein the unit dose is the range of about 20 mg to about 30 mg; wherein the unit dose is about 25 mg; wherein the unit dose is about 30 mg; wherein the unit dose is the range of about 30 mg to about 40 mg; wherein the unit dose is about 35 mg; wherein the unit dose is about 40 mg; wherein the unit dose is the range of about 40 mg to about 50 mg; wherein the unit dose is about 45 mg; wherein the unit dose is about 50 mg; wherein the unit dose is the range of about 50 mg to about 100 mg; wherein the unit dose is about 75 mg; wherein the unit dose is about 100 mg; wherein the unit dose is the range of about 100 mg to about 200 mg; wherein the unit dose is about 150 mg; wherein the unit dose is about 200 mg; wherein the unit dose is the range of about 200 mg to about 300 mg; wherein the unit dose is about 200 mg; wherein the unit dose is about 250 mg; wherein the unit dose is about 300 mg; wherein the unit dose is about 350 mg; wherein the unit dose is about 400 mg; wherein the unit dose is about 450 mg; wherein the unit dose is about 500 mg; wherein the unit dose is about 750 mg; wherein the unit dose is about 1000 mg; wherein the unit dose is about 1500 mg; wherein the unit dose is about 2000 mg; wherein the unit dose is about 2500 mg; or wherein the unit dose is about 3000 mg. [0061 ] In some embodiments, a pharmaceutical composition includes DNP, selected from the group consisting of DNP, 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, bipartite 2,3 -dinitrophenol, 2,4-dinitrophenol, 2,5-dinitrophenol, 2,6-dinitrophenol, 3,4- dinitrophenol, or 3, 5 -dinitrophenol (2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5- DNP) prodrugs or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising a unit dose, independently selected from: wherein the unit dose is from the range of 0.1 mg to 3000 mg; wherein the unit dose is in the range of 0.1 mg to 1000 mg; wherein the unit dose is in the range of 0.1 mg to 500 mg; wherein the unit dose is in the range of 0.1 mg to 1000 mg; wherein the unit dose is in the range of 0.1 mg to 500 mg; wherein the unit dose is in the range of 0.1 mg to 100 mg; wherein the unit dose is in the range of 1 mg to 50 mg; wherein the unit dose is 1 mg; wherein the unit dose is 2 mg; wherein the unit dose is 3 mg; wherein the unit dose is 4 mg; wherein the unit dose is 5 mg; wherein the unit dose is the range of 5 mg to 10 mg; wherein the unit dose is 6 mg; wherein the unit dose is 7 mg; wherein the unit dose is 8 mg; wherein the unit dose is 9 mg; wherein the unit dose is 10 mg; wherein the unit dose is the range of 10 mg to 15 mg; wherein the unit dose is 11 mg; wherein the unit dose is 12 mg; wherein the unit dose is 13 mg; wherein the unit dose is 14 mg; wherein the unit dose is 15 mg; wherein the unit dose is the range of 15 mg to 20 mg; wherein the unit dose is 16 mg; wherein the unit dose is 17 mg; wherein the unit dose is 18 mg; wherein the unit dose is 19 mg; wherein the unit dose is 20 mg; wherein the unit dose is the range of 20 mg to 30 mg; wherein the unit dose is 25 mg; wherein the unit dose is 30 mg; wherein the unit dose is the range of 30 mg to 40 mg; wherein the unit dose is 35 mg; wherein the unit dose is 40 mg; wherein the unit dose is the range of 40 mg to 50 mg; wherein the unit dose is 45 mg; wherein the unit dose is 50 mg; wherein the unit dose is the range of 50 mg to 100 mg; wherein the unit dose is 75 mg; wherein the unit dose is 100 mg; wherein the unit dose is the range of 100 mg to 200 mg; wherein the unit dose is 150 mg; wherein the unit dose is 200 mg; wherein the unit dose is the range of 200 mg to 300 mg; wherein the unit dose is 200 mg; wherein the unit dose is 250 mg; wherein the unit dose is 300 mg; wherein the unit dose is 350 mg; wherein the unit dose is 400 mg; wherein the unit dose is 450 mg; wherein the unit dose is 500 mg; wherein the unit dose is 750 mg; wherein the unit dose is 1000 mg; wherein the unit dose is 1500 mg; wherein the unit dose is 2000 mg; wherein the unit dose is 2500 mg; or wherein the unit dose is 3000 mg. [0062] In some embodiments of the foregoing embodiments of the composition for treatment of a disease, the unit dose is an immediate release formation. In some embodiments of the foregoing embodiments of the composition for treatment of a disease, the unit dose is an extended release formation. In some embodiments of the foregoing embodiments of the composition for treatment of a disease, the unit dose is a sustained release formation. In some embodiments of the foregoing embodiments of the composition for treatment of a disease, the unit dose is a controlled release formation. In some embodiments of the foregoing embodiments of the composition for treatment of a disease, the unit dose is an oral dosage form. In some embodiments, the oral dosage form is a tablet. In some embodiments of the foregoing embodiments of the composition for treatment of a disease, the oral dosage form is a capsule. In some embodiments of the foregoing embodiments of the composition for treatment of a disease, the unit dose is a capsule with no filler. In some embodiments of the foregoing embodiments of the composition for treatment of a disease, the oral dosage form is rapidly dissolving. In each of the foregoing embodiments, the disease may be independently selected from pulmonary diseases or disorders, autoimmune diseases and disorders, insulin resistance, and/or pre-diabetes. Nonlimiting examples of pulmonary diseases or disorders include cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea. In some embodiments, the autoimmune disease or disorder is one or more diseases or disorders associated with inflammation. Non-limiting examples of autoimmune diseases and disorders include irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, systemic lupus erythematosus, rheumatoid arthritis, ileitis and allergic rhinitis. Non-limiting examples of diseases or disorders associated with inflammation include irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, systemic lupus erythematosus, rheumatoid arthritis, ileitis and allergic rhinitis.

[0063] In one aspect, the disclosure provides a method of treating pulmonary diseases or disorders, autoimmune diseases or disorders, insulin resistance, and/or pre-diabetes. In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0064] In one aspect, the disclosure provides a method of treating cystic fibrosis (CF). In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0065] In one aspect, the disclosure provides a method of treating pulmonary arterial hypertension (PAH). In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0066] In one aspect, the disclosure provides a method of treating irritable bowel syndrome (IBS). In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0067] In one aspect, the disclosure provides a method of treating ulcerative colitis. In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0068] In one aspect, the disclosure provides a method of treating rheumatoid arthritis. In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight. [0069] In one aspect, the disclosure provides a method of treating insulin resistance and/or pre-diabetes. In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0070] In one aspect, the disclosure provides a method of improving whole body flux. In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0071] In some embodiments, the therapeutic amount of DNP is in the range of about 0.1 mg/kg of body weight to about 15 mg/kg of body weight, about 1 mg/kg of body weight to about 10 mg/kg of body weight, about 3 mg/kg of body weight to about 8 mg/kg of body weight, or about 4 mg/kg of body weight to about 6 mg/kg of body weight.

[0072] In some embodiments, the therapeutic amount of DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, or about 10 mg/kg of body weight. In some embodiments, the therapeutic amount of DNP is about 8 mg/kg of body weight.

[0073] In some embodiments, the therapeutic amount of DNP is about 0.001 mg/kg of body weight to about 10 mg/kg of body weight, about 0.001 mg/kg of body weight to about 8 mg/kg of body weight, about 0.001 mg/kg of body weight to about 6 mg/kg of body weight, about 0.001 mg/kg of body weight to about 4 mg/kg of body weight, about 0.001 mg/kg of body weight to about 2 mg/kg of body weight, about 0.01 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 1 mg/kg of body weight, or about 0.1 mg/kg of body weight to about 1 mg/kg of body weight. [0074] In one aspect, the disclosure provides a method of treating pulmonary diseases or disorders, autoimmune diseases or disorders, insulin resistance and/or pre-diabetes. In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.01 mg/kg of body weight to about 200 mg/kg of body weight.

[0075] In one aspect, the disclosure provides a method of treating cystic fibrosis (CF). In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 200 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 200 mg/kg of body weight.

[0076] In one aspect, the disclosure provides a method of treating pulmonary arterial hypertension (PAH). In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 200 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 200 mg/kg of body weight.

[0077] In one aspect, the disclosure provides a method of treating irritable bowel syndrome (IBS). In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of 0.001 mg/kg of body weight to about 200 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 200 mg/kg of body weight.

[0078] In one aspect, the disclosure provides a method of treating ulcerative colitis. In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 200 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 200 mg/kg of body weight. [0079] In one aspect, the disclosure provides a method of treating rheumatoid arthritis. Tn some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0080] In one aspect, the disclosure provides a method of treating insulin resistance and/or pre-diabetes. In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0081] In one aspect, the disclosure provides a method of improving whole body flux. In some embodiments, the method comprises administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight, or about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[0082] In some embodiments, the therapeutic amount of the prodrug of DNP is in the range of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 20 mg/kg of body weight, about 5 mg/kg of body weight to about 10 mg/kg of body weight, about 7 mg/kg of body weight to about 9 mg/kg of body weight, about 10 mg/kg of body weight to about 20 mg/kg of body weight, about 15 mg/kg of body weight to about 17 mg/kg of body weight, about 50 mg/kg of body weight to about 100 mg/kg of body weight, about 60 mg/kg of body weight to about 90 mg/kg of body weight, about 75 mg/kg of body weight to about 85 mg/kg of body weight, or about 79 mg/kg of body weight to about 81 mg/kg of body weight.

[0083] In some embodiments, the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 10 mg/kg of body weight, about 0.001 mg/kg of body weight to about 8 mg/kg of body weight, about 0.001 mg/kg of body weight to about 6 mg/kg of body weight, about 0.001 mg/kg of body weight to about 4 mg/kg of body weight, about 0.001 mg/kg of body weight to about 2 mg/kg of body weight, about 0.01 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 1 mg/kg of body weight, or about 0.1 mg/kg of body weight to about 1 mg/kg of body weight.

[0084] In some embodiments, the therapeutic amount of the prodrug of DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, 10 mg/kg of body weight, about 11 mg/kg of body weight, about 12 mg/kg of body weight, about 13 mg/kg of body weight, about 14 mg/kg of body weight, about 15 mg/kg of body weight, about 16 mg/kg of body weight, about 17 mg/kg of body weight, about 18 mg/kg of body weight, about 19 mg/kg of body weight, or about 20 mg/kg of body weight. In some embodiments, the therapeutic amount of the prodrug of DNP is about 8 mg/kg of body weight. In some embodiments, the therapeutic amount of the prodrug of DNP is about 16 mg/kg of body weight.

[0085] In some embodiments, the therapeutic amount of the prodrug of DNP is about 71 mg/kg of body weight, about 72 mg/kg of body weight, about 73 mg/kg of body weight, about 74 mg/kg of body weight, about 75 mg/kg of body weight, about 76 mg/kg of body weight, about 77 mg/kg of body weight, about 78 mg/kg of body weight, about 79 mg/kg of body weight, 80 mg/kg of body weight, about 81 mg/kg of body weight, about 82 mg/kg of body weight, about 83 mg/kg of body weight, about 84 mg/kg of body weight, about 85 mg/kg of body weight, about 86 mg/kg of body weight, about 87 mg/kg of body weight, about 88 mg/kg of body weight, about 89 mg/kg of body weight, or about 90 mg/kg of body weight. In some embodiments, the therapeutic amount of the prodrug of DNP is about 80 mg/kg of body weight.

[0086] In some embodiments, the therapeutic amount of the prodrug of DNP is about 0.001 mg/kg of body weight, about 0.005 mg/kg of body weight, about 0.01 mg/kg of body weight, about 0.05 mg/kg of body weight, about 0.1 mg/kg of body weight, about 0.2 mg/kg of body weight, about 0.3 mg/kg of body weight, about 0.4 mg/kg of body weight, about 0.5 mg/kg of body weight, about 0.6 mg/kg of body weight, about 0.7 mg/kg of body weight, about 0.8 mg/kg of body weight, or about 0.9 mg/kg of body weight.

[0087] In some embodiments, the DNP is selected from 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6- DNP, 3,4-DNP, or 3,5-DNP. In some embodiments, the DNP is 2,4-DNP. [0088] In some embodiments, the prodrug of DNP is selected from: an amino acid (AA) ester of 2,3-DNP, an amino acid (AA) ester of 2,4-DNP, an amino acid (AA) ester of 2,5-DNP, an amino acid (AA) ester of 2,6-DNP, an amino acid (AA) ester of 3,4-DNP, or an amino acid (AA) ester of 3,5-DNP (Scheme 1, Formulas 1-1 to 1-10; Scheme 2, Formulas II-l to 11-10; Scheme 3, Formulas III-l to III-10; Scheme 4, Formulas IV-1 to IV-10; Scheme 5, Formulas V-l to V-10; and Scheme 6, Formulas VI-1 to VI-10);

AA esters incorporating a methylene dioxide (a formaldehyde equivalent) spacer (Scheme 1, Formulas 1-11 to 1-13; Scheme 2, Formulas II- 11 to 11-13; Scheme 3, Formulas III-l 1 to III-13; Scheme 4, Formulas IV-11 to IV-13; Scheme 5, Formulas V-l l to V-13; and Scheme 6, Formulas VI- 11 to VI- 13); amino carbamate 2,3-DNP prodrugs, amino carbamate 2,4-DNP prodrugs, amino carbamate 2,5-DNP prodrugs, amino carbamate 2,6-DNP prodrugs, amino carbamate 3,4-DNP prodrugs, or amino carbamate 3,5-DNP prodrugs (Scheme 1, Formulas 1-14 to 1-17; Scheme 2, Formulas 11-14 to 11-17; Scheme 3, Formulas III- 14 to III-17; Scheme 4, Formulas IV-14 to IV- 17; Scheme 5, Formulas V-14 to V-17; and Scheme 6, Formulas VI-14 to VI-17); amino carbonate 2,3-DNP prodrugs, amino carbonate 2,4-DNP prodrugs, amino carbonate 2,5-DNP prodrugs, amino carbonate 2,6-DNP prodrugs, amino carbonate 3,4-DNP prodrugs, or amino carbonate 3,5-DNP prodrugs (Scheme 1, Formulas 1-18 and 1-19; Scheme 2, Formulas 11-18 and 11-19; Scheme 3, Formulas III-l 8 and III-19; Scheme 4, Formulas IV-18 and IV-19; Scheme 5, Formulas V-18 and V-19; and Scheme 6, Formulas VI-18 and VI-19); phosphate analogs 1-20, 1-21, 11-20, 11-21, III-20, III-21, IV-20, IV-21, V-20, V-21, VI- 20, and VI-21 (Schemes 1-6);

1,3 diketo analogs 1-22 to 1-32; 11-22 to 11-32; III-22 to III-32; IV-22 to IV-32; V-22 to V- 32; and VI-22 to VI-32 (Schemes 1-6); carbonate and carbamate analogs 1-33 to 1-39; 11-33 to 11-39; III-33 to III-39; IV-33 to IV- 39; V-33 to V-39; and VI-33 to VI-39 (Schemes 1-6); and benzoate analogs 1-40, 11-40, III-40, IV-40, V-40, and VI-40 (Schemes 1-6); and combinations thereof

[0089] In some embodiments, the prodrug of DNP is selected from:

[0090] In some embodiments, the prodrug

[0091] In some embodiments, the DNP and/or the prodrug of DNP is administered orally, intravenously, subcutaneously, or transdermally.

[0092] In some embodiments, the DNP and/or the prodrug of DNP is administered at a frequency of once a day, twice a day, three times a day, four times a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once a month. In some embodiments, the DNP and/or the prodrug of DNP is administered at a frequency of once a day. In some embodiments, the DNP and/or the prodrug of DNP is administered at a frequency of once a day for one day, once a day for two consecutive days, once a day for three consecutive days, once a day for four consecutive days, once a day for five consecutive days, once a day for six consecutive days, once a day for 7 consecutive days, or once a day for two consecutive weeks.

[0093] In one embodiment, the disclosure provides for a method of treatment of cystic fibrosis (CF) using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of pulmonary fibrosis using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of chronic obstructive pulmonary disease (COPD) using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of asthma using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure provides for a method of treatment of bronchitis using embodiments of the compositions and dosages described herein. Tn one embodiment, the disclosure relates to a method of treatment of bronchiectasis using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of idiopathic pulmonary fibrosis (IPF) using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of pulmonary arterial hypertension (PAH) using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of hypertension using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of sarcoidosis using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of silicosis using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of systemic sclerosis using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of lung infection, such as pneumonia, using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of lung cancer using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of obstructive sleep apnea using embodiments of the compositions and dosages described herein.

[0094] In one embodiment, the disclosure relates to a method of treatment of inflammatory bowel syndrome (IBD) using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of ulcerative colitis using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of Crohn’s Disease using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of pouchitis using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of systemic lupus erythematosus using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of rheumatoid arthritis using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of ileitis using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of allergic rhinitis using embodiments of the compositions and dosages described herein.

[0095 ] In one embodiment, the disclosure relates to a method of treatment of insulin resistance using embodiments of the compositions and dosages described herein. In one embodiment, the disclosure relates to a method of treatment of pre-diabetes using embodiments of the compositions and dosages described herein.

[0096] In one embodiment, the disclosure relates to a method of treatment of pulmonary diseases and disorders, autoimmune diseases and disorders, insulin resistance, and/or prediabetes using embodiments of the compositions and dosages described herein. In one such embodiment, such dosages for an adult independently ranging from: 10 mg/day to 150 mg/day; 20 mg/day to 150 mg/day; 30 mg/day to 150 mg/day; 40 mg/day to 150 mg/day; 50 mg/day to 150 mg/day; 60 mg/day to 150 mg/day; 70 mg/day to 150 mg/day; 80 mg/day to 150 mg/day; 90 mg/day to 150 mg/day; 80 mg/day to 100 mg/day; 90 mg/day to 100 mg/day; 91 mg/day to 100 mg/day 92 mg/day to 100 mg/day; 93 mg/day to 100 mg/day; 94 mg/day to 100 mg/day; or independently dosages of 90 mg/day; 91 mg/day; 92 mg/day; 93 mg/day; 94 mg/day; 95 mg/day; 96 mg/day; 97 mg/day; 98 mg/day or 99 mg/day. In one such embodiment, such dosages for an adolescent independently ranging from: 1 mg/day to 45 mg/day; 1 mg/day to 50 mg/day; 5 mg/day to 45 mg/day; 5 mg/day to 50 mg/day; 10 mg/day to 45 mg/day; 15 mg/day to 45 mg/day; 20 mg/day to 45 mg/day; 25 mg/day to 45 mg/day; 30 mg/day to 45 mg/day; 35 mg/day to 45 mg/day; 35 mg/day to 40 mg/day; or independently dosages of 35 mg/day; 35 mg/day; 37 mg/day; 38 mg/day; 39 mg/day; 40 mg/day; 41 mg/day; 42 mg/day; 43 mg/day; 44 mg/day or 45 mg/day. In another such embodiment, such dosages for an adult independently ranging from: about 10 mg/day to about 150 mg/day; about 20 mg/day to about 150 mg/day; about 30 mg/day to about 150 mg/day; about 40 mg/day to about 150 mg/day; about 50 mg/day to about 150 mg/day; about 60 mg/day to about 150 mg/day; about 70 mg/day to about 150 mg/day; about 80 mg/day to about 150 mg/day; about 90 mg/day to about 150 mg/day; about 80 mg/day to about 100 mg/day; about 90 mg/day to about 100 mg/day; about 91 mg/day to about 100 mg/day; about 92 mg/day to about 100 mg/day; about 93 mg/day to about 100 mg/day; about 94 mg/day to about 100 mg/day; or independently dosages of about 90 mg/day; about 91 mg/day; about 92 mg/day; about 93 mg/day; about 94 mg/day; about 95 mg/day; about 96 mg/day; about 97 mg/day; about 98 mg/day or about 99 mg/day. In another such embodiment, such dosages for an adult independently ranging from: 0.001 mg/day to about 20 mg/day; about 0.001 mg/day to about 15 mg/day; about 0.001 mg/day to about 10 mg/day; about 0.01 mg/day to about 10 mg/day; about 0.01 mg/day to about 5 mg/day; or about 0.1 mg/day to about 5 mg/day. In another such embodiment, such dosages for an adolescent independently ranging from: about 1 mg/day to about 45 mg/day; about 1 mg/day to about 50 mg/day; about 5 mg/day to about 45 mg/day; about 5 mg/day to about 50 mg/day; about 10 mg/day to about 45 mg/day; about 15 mg/day to about 45 mg/day; about 20 mg/day to about 45 mg/day; about 25 mg/day to about 45 mg/day; about 30 mg/day to about 45 mg/day; about 35 mg/day to about 45 mg/day; about 35 mg/day to about 40 mg/day or; independently dosages of about 35 mg/day; about 35 mg/day; about 37 mg/day; about 38 mg/day; about 39 mg/day; about 40 mg/day; about 41 mg/day; about 42 mg/day; about 43 mg/day; about 44 mg/day or about 45 mg/day. In another such embodiment, such dosages for an adolescent independently ranging from: 0.001 mg/day to about 20 mg/day; about 0.001 mg/day to about 15 mg/day; about 0.001 mg/day to about 10 mg/day; about 0.01 mg/day to about 10 mg/day; about 0.01 mg/day to about 5 mg/day; or about 0.1 mg/day to about 5 mg/day. In some embodiments, the pulmonary disease or disorder is selected from cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea. In some embodiments, the autoimmune disease or disorder is selected from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, systemic lupus erythematosus, ileitis and allergic rhinitis.

[0097] In one embodiment, the disclosure relates to a method of treatment of pulmonary diseases and disorders, autoimmune diseases and disorders, insulin resistance, and/or prediabetes using embodiments of the compositions and dosages described herein. In one such embodiment, such dosages independently ranging from: 1 mg/day to 45 mg/day; 5 mg/day to 45 mg/day; 10 mg/day to 45 mg/day; 15 mg/day to 45 mg/day; 20 mg/day to 45 mg/day; 25 mg/day to 45 mg/day; 30 mg/day to 45 mg/day; 35 mg/day to 45 mg/day; 35 mg/day to 40 mg/day or , independently dosages of 31 mg/day; 32 mg/day; 33 mg/day; 34 mg/day; 35 mg/day; 36 mg/day; 37 mg/day; 38 mg/day; 39 mg/day or 40 mg/day. In another such embodiment, such dosages independently ranging from: about 1 mg/day to about 45 mg/day; about 5 mg/day to about 45 mg/day; about 10 mg/day to about 45 mg/day; about 15 mg/day to about 45 mg/day; about 20 mg/day to about 45 mg/day; about 25 mg/day to about 45 mg/day; about 30 mg/day to about 45 mg/day; about 35 mg/day to about 45 mg/day; about 35 mg/day to about 40 mg/day or; independently dosages of about 31 mg/day; about 32 mg/day; about 33 mg/day; about 34 mg/day; about 35 mg/day; about 36 mg/day; about 37 mg/day; about 38 mg/day; about 39 mg/day or about 40 mg/day. In another such embodiment, such dosages independently ranging from: 0.001 mg/day to about 20 mg/day; about 0.001 mg/day to about 15 mg/day; about 0.001 mg/day to about 10 mg/day; about 0.01 mg/day to about 10 mg/day; about 0.01 mg/day to about 5 mg/day; or about 0.1 mg/day to about 5 mg/day. In some embodiments, the pulmonary disease or disorder is selected from cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea. In some embodiments, the autoimmune disease or disorder is selected from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, systemic lupus erythematosus, rheumatoid arthritis, ileitis and allergic rhinitis. In some embodiments, the disease or disorder is insulin resistance. In some embodiments, the disease or disorder is pre-diabetes.

[0098] In some embodiments, the unit dose is delivered intravenously. In some embodiments, the unit dose is delivered by means of an intravenous drip along with saline. In some embodiments, the unit dose is delivered by means of an intravenous drip along with saline, other medications, vitamins and/or nourishment. In some embodiments, the unit dose is delivered subcutaneously. In some embodiments, the unit dose is delivered topically. In some embodiments, the unit dose is delivered transdermally. In some embodiments, the unit dose is in the form of a patch.

[0099] The dose may be administered as a single daily dose, a twice-daily dose, three times daily, or more frequently. The dose may be administered three times weekly, twice weekly, once weekly, or less frequently. In an embodiment, administration frequency may be between 1 and 5 times a day. In another embodiment, administration frequency may be between 2 and 4 times a day. In another embodiment, administration frequency may be at least 3 times a day. In another embodiment, administration frequency may be twice a day. In another embodiment, administration frequency may be once a day. In another embodiment, administration frequency may be less frequent than once a day. Tn other embodiments, administration frequency may be once every 2 days or once every 3 days or once every 4 days or once every 5 days or once every 6 days. In another embodiment, administration frequency may be once a week. In another embodiment, administration frequency may change with time, starting at a certain rate, such as once or twice a day, and then decreasing to less frequently, such as once every 2 days or once every 3 days, or once a week, after the first day of treatment. In another embodiment, administration frequency may change with time, starting at a certain rate, such as once or twice a day, and then decreasing to less frequently, such as once every 2 days or once every 3 days, or once a week, after the first two or three days of treatment. In another embodiment, administration frequency may change with time, starting at a certain rate, such as once or twice a day, and then decreasing to less frequently, such as once every 2 days or once every 3 days, or once a week, after the first week of treatment. In another embodiment, administration frequency may be on demand, as therapeutic treatment is required or desired.

[00100] It will be understood, based on the disclosure encompassed herein, how to determine whether a subject needs an additional and/or continued dose. It will also be understood that the selected dosing frequency may require an adjustment of the dosage of active ingredient. It will also be understood, based on the disclosure encompassed herein, that the selected dosage of active ingredient may require an adjustment of the dosing frequency. The disclosure encompassed herein, in combination with the skill in the art, will enable the skilled artisan to optimize both the dosage of the active ingredient and the frequency of administration of the active ingredient to treat a subject in need thereof.

[00101] The unit dose may also be adjusted based upon the size of the patient. In one embodiment, the numbers provided herein are based upon a 60 kg patient. The same therapy could be provided for a smaller or larger sized patient, by respectively reducing or increasing the dose size. By way of example only, a 20 kg child patient would need a much smaller dose than a 60 kg adult patient.

[00102] Formulation approaches are employed such as controlled release technologies (polymers, liposomes, etc.) to achieve once a day PK profde for DNP. In some embodiments, DNP prodrugs and bioprecursors with linkers containing open functional groups are synthesized, which allows conjugation of each of these entities to nanoparticles, such as dendrimers, in order to modulate the pharmacokinetics of the molecule to enable “trickle” drug delivery. Such DNP prodrugs and bioprecursors are delivered as depot nanoparticle formulation that release DNP in a slow, sustained fashion at low doses, compared to dose and release of DNP alone, to avoid possible toxicity issues. The in vitro stability, in vivo plasma release kinetics and PK profiles are evaluated. In vivo studies are carried out in Sprague-Dawley rats. LC/MS/MS is used to analyze plasma DNP released from the various prodrug-nanoparticle formulations to determine the PK profile of DNP release in the rat model.

[00103 J The following clauses describe certain embodiments.

[00104] Clause 1. A method of treating pulmonary diseases or disorders and/or autoimmune diseases or disorders comprising: administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.01 mg/kg of body weight to about 20 mg/kg of body weight.

[00105] Clause 2. The method of clause 1, wherein the therapeutic amount of DNP is in the range of about 0.1 mg/kg of body weight to about 15 mg/kg of body weight, about 1 mg/kg of body weight to about 10 mg/kg of body weight, about 3 mg/kg of body weight to about 8 mg/kg of body weight, or about 4 mg/kg of body weight to about 6 mg/kg of body weight.

[00106] Clause 3. The method of clause 1 or 2, wherein the therapeutic amount of DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, or about 10 mg/kg of body weight.

[00107] Clause 4. A method of treating pulmonary diseases or disorders and/or autoimmune diseases or disorders comprising: administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.01 mg/kg of body weight to about 200 mg/kg of body weight.

[00108] Clause 5. The method of clause 4, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 20 mg/kg of body weight, about 5 mg/kg of body weight to about 10 mg/kg of body weight, about 7 mg/kg of body weight to about 9 mg/kg of body weight, about 10 mg/kg of body weight to about 20 mg/kg of body weight, about 15 mg/kg of body weight to about 17 mg/kg of body weight, about 50 mg/kg of body weight to about 100 mg/kg of body weight, about 60 mg/kg of body weight to about 90 mg/kg of body weight, about 75 mg/kg of body weight to about 85 mg/kg of body weight, or about 79 mg/kg of body weight to about 81 mg/kg of body weight.

[00109] Clause 6. The method of clause 4 or 5, wherein the therapeutic amount of DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, 10 mg/kg of body weight, about 11 mg/kg of body weight, about 12 mg/kg of body weight, about 13 mg/kg of body weight, about 14 mg/kg of body weight, about 15 mg/kg of body weight, about 16 mg/kg of body weight, about 17 mg/kg of body weight, about 18 mg/kg of body weight, about 19 mg/kg of body weight, or about 20 mg/kg of body weight.

[00110] Clause 7. The method of clause 4 or 5, wherein the therapeutic amount of DNP is about 71 mg/kg of body weight, about 72 mg/kg of body weight, about 73 mg/kg of body weight, about 74 mg/kg of body weight, about 75 mg/kg of body weight, about 76 mg/kg of body weight, about 77 mg/kg of body weight, about 78 mg/kg of body weight, about 79 mg/kg of body weight, 80 mg/kg of body weight, about 81 mg/kg of body weight, about 82 mg/kg of body weight, about

83 mg/kg of body weight, about 84 mg/kg of body weight, about 85 mg/kg of body weight, about

86 mg/kg of body weight, about 87 mg/kg of body weight, about 88 mg/kg of body weight, about

89 mg/kg of body weight, or about 90 mg/kg of body weight.

[00111] Clause 8. The method of any one of clauses 4-7, wherein the DNP is selected from

2.3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP.

[001 12] Clause 9. The method of any one of clauses 4-8, wherein the DNP is 2,4-DNP.

[00113] Clause 10. The method of any one of clauses 4-7, wherein the prodrug of DNP is selected from: an amino acid (AA) ester of 2,3-DNP, an amino acid (AA) ester of 2,4-DNP, an amino acid (AA) ester of 2,5-DNP, an amino acid (AA) ester of 2,6-DNP, an amino acid (AA) ester of

3.4-DNP, or an amino acid (AA) ester of 3,5-DNP (Scheme 1, Formulas 1-1 to 1-10; Scheme 2, Formulas TT-1 to TT-10; Scheme 3, Formulas TTT-1 to TIT-10; Scheme 4, Formulas TV-1 to TV-10; Scheme 5, Formulas V-l to V-10; and Scheme 6, Formulas VI-1 to VI-10);

[00114] AA esters incorporating a methylene dioxide (a formaldehyde equivalent) spacer (Scheme 1, Formulas 1-11 to 1-13; Scheme 2, Formulas IT- 11 to 11-13; Scheme 3, Formulas III-l 1 to III-13; Scheme 4, Formulas IV-11 to IV-13; Scheme 5, Formulas V-l l to V-13; and Scheme 6, Formulas VI-11 to VI-13); amino carbamate 2,3-DNP prodrugs, amino carbamate 2,4-DNP prodrugs, amino carbamate 2,5-DNP prodrugs, amino carbamate 2,6-DNP prodrugs, amino carbamate 3,4-DNP prodrugs, or amino carbamate 3,5-DNP prodrugs (Scheme 1, Formulas 1-14 to 1-17; Scheme 2, Formulas 11-14 to 11-17; Scheme 3, Formulas III-14 to III-17; Scheme 4, Formulas IV-14 to IV- 17; Scheme 5, Formulas V-14 to V-17; and Scheme 6, Formulas VI-14 to VI-17); amino carbonate 2,3-DNP prodrugs, amino carbonate 2,4-DNP prodrugs, amino carbonate 2,5-DNP prodrugs, amino carbonate 2,6-DNP prodrugs, amino carbonate 3,4-DNP prodrugs, or amino carbonate 3,5-DNP prodrugs (Scheme 1, Formulas 1-18 and 1-19; Scheme 2, Formulas 11-18 and 11-19; Scheme 3, Formulas III-18 and III-19; Scheme 4, Formulas IV-18 and IV-19; Scheme 5, Formulas V-18 and V-19; and Scheme 6, Formulas VI-18 and VI-19); phosphate analogs 1-20, 1-21, 11-20, 11-21, III-20, III-21, IV-20, IV-21, V-20, V-21, VI- 20, and VI-21 (Schemes 1-6);

1,3 diketo analogs 1-22 to 1-32; 11-22 to 11-32; III-22 to III-32; IV-22 to IV-32; V-22 to V- 32; and VI-22 to VI-32 (Schemes 1-6); carbonate and carbamate analogs 1-33 to 1-39; 11-33 to 11-39; III-33 to III-39; IV-33 to IV- 39; V-33 to V-39; and VI-33 to VI-39 (Schemes 1-6); and benzoate analogs 1-40, 11-40, III-40, IV-40, V-40, and VI-40 (Schemes 1-6); and combinations thereof.

[001 15] Clause 11. The method of any one of clauses 4-7, wherein the prodrug of DNP is selected from:

[00116] Clause 12. The method of any one of clauses 1-11, wherein the DNP and/or the prodrug of DNP is administered orally.

[00117] Clause 13. The method of any one of clauses 1-11, wherein the DNP and/or the prodrug of DNP is administered intravenously, subcutaneously, or transdermally.

[001 18] Clause 14. The method of any one of clauses 1-13, wherein the DNP and/or the prodrug of DNP is administered at a frequency of once a day, twice a day, three times a day, four times a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once a month.

[00119] Clause 15. The method of any one of clauses 1-14, wherein the DNP and/or the prodrug of DNP is administered at a frequency of once a day.

[00120] Clause 16. The method of clause 15, wherein the DNP and/or the prodrug of DNP is administered at a frequency of once a day for one day, once a day for two consecutive days, once a day for three consecutive days, once a day for four consecutive days, once a day for five consecutive days, once a day for six consecutive days, once a day for 7 consecutive days, or once a day for two consecutive weeks.

[00121] Clause 17. The method of any one of clauses 1-16, wherein the pulmonary disease or disorder is selected from cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea.

[00122] Clause 18. The method of any one of clauses 1-16, wherein the autoimmune disease or disorder is selected from diseases and disorders associated with inflammation. [00123] Clause 19. The method of clause 17 or 18, wherein the disease and disorder is selected from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, ileitis and allergic rhinitis.

[00124] Clause 101. A method of treating pulmonary diseases or disorders and/or autoimmune diseases or disorders comprising: administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight.

[00125] Clause 102. The method of clause 101, wherein the therapeutic amount of DNP is in the range of about 0.1 mg/kg of body weight to about 15 mg/kg of body weight, about 1 mg/kg of body weight to about 10 mg/kg of body weight, about 3 mg/kg of body weight to about 8 mg/kg of body weight, or about 4 mg/kg of body weight to about 6 mg/kg of body weight.

[00126] Clause 103. The method of clause 101 or 102, wherein the therapeutic amount of

DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, or about 10 mg/kg of body weight.

[00127] Clause 104. The method of clause 101, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 10 mg/kg of body weight, about 0.001 mg/kg of body weight to about 8 mg/kg of body weight, about 0.001 mg/kg of body weight to about 6 mg/kg of body weight, about 0.001 mg/kg of body weight to about 4 mg/kg of body weight, about 0.001 mg/kg of body weight to about 2 mg/kg of body weight, about 0.01 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 1 mg/kg of body weight, or about 0.1 mg/kg of body weight to about 1 mg/kg of body weight.

[00128] Clause 105. The method of clause 101 or 104, wherein the therapeutic amount of DNP is about 0.001 mg/kg of body weight, about 0.005 mg/kg of body weight, about 0.01 mg/kg of body weight, about 0.05 mg/kg of body weight, about 0.1 mg/kg of body weight, about 0.2 mg/kg of body weight, about 0.3 mg/kg of body weight, about 0.4 mg/kg of body weight, about 0.5 mg/kg of body weight, about 0.6 mg/kg of body weight, about 0.7 mg/kg of body weight, about 0.8 mg/kg of body weight, or about 0.9 mg/kg of body weight.

[00129] Clause 106. The method of any one of clauses 101-105, wherein the DNP is selected from 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP.

[00130] Clause 107. The method of any one of clauses 101-106, wherein the DNP is 2,4-DNP. [00131 ] Clause 108. A method of treating pulmonary diseases or disorders and/or autoimmune diseases or disorders comprising: administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 200 mg/kg of body weight.

[00132] Clause 109. The method of clause 108, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 20 mg/kg of body weight, about 5 mg/kg of body weight to about 10 mg/kg of body weight, about 7 mg/kg of body weight to about 9 mg/kg of body weight, about 10 mg/kg of body weight to about 20 mg/kg of body weight, about 15 mg/kg of body weight to about 17 mg/kg of body weight, about 50 mg/kg of body weight to about 100 mg/kg of body weight, about 60 mg/kg of body weight to about 90 mg/kg of body weight, about 75 mg/kg of body weight to about 85 mg/kg of body weight, or about 79 mg/kg of body weight to about 81 mg/kg of body weight.

[00133] Clause 110. The method of clause 108 or 109, wherein the therapeutic amount of the prodrug of DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, 10 mg/kg of body weight, about 11 mg/kg of body weight, about 12 mg/kg of body weight, about 13 mg/kg of body weight, about 14 mg/kg of body weight, about 15 mg/kg of body weight, about 16 mg/kg of body weight, about 17 mg/kg of body weight, about 18 mg/kg of body weight, about 19 mg/kg of body weight, or about 20 mg/kg of body weight.

[00134] Clause 111. The method of clause 108 or 109, wherein the therapeutic amount of the prodrug of DNP is about 71 mg/kg of body weight, about 72 mg/kg of body weight, about 73 mg/kg of body weight, about 74 mg/kg of body weight, about 75 mg/kg of body weight, about 76 mg/kg of body weight, about 77 mg/kg of body weight, about 78 mg/kg of body weight, about 79 mg/kg of body weight, 80 mg/kg of body weight, about 81 mg/kg of body weight, about 82 mg/kg of body weight, about 83 mg/kg of body weight, about 84 mg/kg of body weight, about 85 mg/kg of body weight, about 86 mg/kg of body weight, about 87 mg/kg of body weight, about 88 mg/kg of body weight, about 89 mg/kg of body weight, or about 90 mg/kg of body weight.

[00135] Clause 112. The method of clause 108, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 10 mg/kg of body weight, about 0.001 mg/kg of body weight to about 8 mg/kg of body weight, about 0.001 mg/kg of body weight to about 6 mg/kg of body weight, about 0.001 mg/kg of body weight to about 4 mg/kg of body weight, about 0.001 mg/kg of body weight to about 2 mg/kg of body weight, about 0.01 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 1 mg/kg of body weight, or about 0.1 mg/kg of body weight to about 1 mg/kg of body weight.

[00136] Clause 113. The method of clause 108 or 112, wherein the therapeutic amount of the prodrug of DNP is about 0.001 mg/kg of body weight, about 0.005 mg/kg of body weight, about 0.01 mg/kg of body weight, about 0.05 mg/kg of body weight, about 0.1 mg/kg of body weight, about 0.2 mg/kg of body weight, about 0.3 mg/kg of body weight, about 0.4 mg/kg of body weight, about 0.5 mg/kg of body weight, about 0.6 mg/kg of body weight, about 0.7 mg/kg of body weight, about 0.8 mg/kg of body weight, or about 0.9 mg/kg of body weight.

[00137] Clause 114. The method of any one of clauses 108-113, wherein the prodrug of DNP is selected from: an amino acid (AA) ester of 2,3-DNP, an amino acid (AA) ester of 2,4-DNP, an amino acid (AA) ester of 2,5-DNP, an amino acid (AA) ester of 2,6-DNP, an amino acid (AA) ester of 3,4-DNP, or an amino acid (AA) ester of 3,5-DNP (Scheme 1, Formulas 1-1 to 1-10; Scheme 2, Formulas II-l to 11-10; Scheme 3, Formulas III-l to III-10; Scheme 4, Formulas IV-1 to IV-10; Scheme 5, Formulas V-l to V-10; and Scheme 6, Formulas VI-1 to VI-10);

AA esters incorporating a methylene dioxide (a formaldehyde equivalent) spacer (Scheme 1, Formulas 1-11 to 1-13; Scheme 2, Formulas II- 11 to 11-13; Scheme 3, Formulas III-l 1 to III-13; Scheme 4, Formulas IV-11 to IV-13; Scheme 5, Formulas V-l l to V-13; and Scheme 6, Formulas VI- 11 to VI- 13); amino carbamate 2,3-DNP prodrugs, amino carbamate 2,4-DNP prodrugs, amino carbamate 2,5-DNP prodrugs, amino carbamate 2,6-DNP prodrugs, amino carbamate 3,4-DNP prodrugs, or amino carbamate 3,5-DNP prodrugs (Scheme 1, Formulas 1-14 to 1-17; Scheme 2, Formulas 11-14 to 11-17; Scheme 3, Formulas III-14 to III-17; Scheme 4, Formulas IV-14 to IV- 17; Scheme 5, Formulas V-14 to V-17; and Scheme 6, Formulas VI-14 to VI-17); amino carbonate 2,3-DNP prodrugs, amino carbonate 2,4-DNP prodrugs, amino carbonate 2,5-DNP prodrugs, amino carbonate 2,6-DNP prodrugs, amino carbonate 3,4-DNP prodrugs, or amino carbonate 3,5-DNP prodrugs (Scheme 1, Formulas 1-18 and 1-19; Scheme 2, Formulas 11-18 and 11-19; Scheme 3, Formulas III-18 and III-19; Scheme 4, Formulas IV-18 and IV-19; Scheme 5, Formulas V-18 and V-19; and Scheme 6, Formulas VI-18 and VI-19); phosphate analogs 1-20, 1-21, 11-20, 11-21, III-20, III-21, IV-20, IV-21, V-20, V-21, VI- 20, and VI-21 (Schemes 1-6);

[00138] Clause 115. The method of any one of clauses 108-113, wherein the prodrug of DNP is selected from:

[00139] Clause 116. The method of any one of clauses 101-115, wherein the patient is a human.

[00140] Clause 117. The method of any one of clauses 101-116, wherein the DNP and/or the prodrug of DNP is administered orally. [00141 ] Clause 1 18. The method of any one of clauses 101 -1 16, wherein the DNP and/or the prodrug of DNP is administered intravenously, subcutaneously, or transdermally.

[00142] Clause 119. The method of any one of clauses 101-118, wherein the DNP and/or the prodrug of DNP is administered at a frequency of once a day, twice a day, three times a day, four times a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, or once a month.

[00143] Clause 120. The method of any one of clauses 101-119, wherein the DNP and/or the prodrug of DNP is administered at a frequency of once a day.

[00144] Clause 121. The method of clause 120, wherein the DNP and/or the prodrug of DNP is administered at a frequency of once a day for one day, once a day for two consecutive days, once a day for three consecutive days, once a day for four consecutive days, once a day for five consecutive days, once a day for six consecutive days, once a day for 7 consecutive days, or once a day for two consecutive weeks.

[00145] Clause 122. The method of any one of clauses 101-121, wherein the pulmonary disease or disorder is selected from cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea.

[00146] Clause 123. The method of clause 122, wherein the pulmonary disease or disorder is cystic fibrosis.

[00147] Clause 124. The method of clause 123, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents or reduces increases in blood glucose levels in a cystic fibrosis patient following a meal.

[00148] Clause 125. The method of clause 123 or 124, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents the destruction of the pancreas of a cystic fibrosis patient.

[00149] Clause 126. The method of any one of clauses 123-125, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents or reduces inflammation and/or scarring of the pancreas of a cystic fibrosis patient. [00150] Clause 127. The method of any one of clauses 123-126, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents insulin resistance and/or pre-diabetes in a cystic fibrosis patient.

[00151] Clause 128. The method of any one of clauses 123-127, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents a cystic fibrosis patient from developing diabetes.

[00152] Clause 129. The method of any one of clauses 123-128, wherein the therapeutic amount of DNP and/or the prodrug of DNP improves survivability in a cystic fibrosis patient compared to a patient who is not treated with a therapeutic amount of DNP and/or a prodrug of DNP.

[00153] Clause 130. The method of any one of clauses 101-121, wherein the autoimmune disease or disorder is selected from diseases and disorders associated with inflammation.

[00154] Clause 131. The method of clause 128, wherein the disease and disorder is selected from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, rheumatoid arthritis, ileitis and allergic rhinitis.

EXAMPLES

Example 1. Treatment of Cystic Fibrosis with 2,4-DNP

[00155] A cystic fibrosis (CF) study was conducted in ferrets (FIG. 1). Twenty-five day aged cystic fibrosis ferrets began ~5 month oral gavage treatment with 2,4-DNP. Ferrets were treated with VX-770 to protect the pancreas and were still on VX-770 for five days while being treated with 2,4-DNP. After five days, the administration of VX-770 was halted and treatment continued with 2,4-DNP only. Two major stages are seen in CF patients, pancreatic failure followed by pulmonary distress. To probe the CF ferrets for possible pancreatic failure, weekly glucose measurements were taken before and after meals for the first two months followed by a meal tolerance test (MTT) and oral glucose tolerance test (OGTT) at a later date.

[00156] Weekly glucose measurements were obtained for cystic fibrosis ferrets treated orally with 0.5 mg/kg 2,4-DNP once-per-day starting at 5 weeks of age while still on VX-770, and then treated with 2,4-DNP only for weeks 6-12. CF ferrets treated with 2,4-DNP showed no rise in glucose before or 1 hour after a meal, whereas untreated CF ferrets show a significant rise before and after (FIG. 2). While not wishing to be bound by any particular theory, the rise in glucose in untreated CF ferrets suggests islet beta-cell and/or insulin secretion impairment and/or destruction.

[00157] FIGS. 3A-3B are Kaplan Meier curves showing death counts in cystic fibrosis ferrets off VX-770, but on treatment with 2,4-DNP once-per-day oral gavage at 0.5 mg/kg. Once VX- 770 treatment is discontinued, CF ferrets historically show significant loss in survivability. FIG.

3 A demonstrates that, at just over two months of age, the CF ferrets treated with 2,4-DNP show a delay in death rates compared to untreated CF ferrets. This improved survivability continues in CF ferrets by three months of age compared to historic untreated CF ferrets (FIG. 3B, dotted line shows current stage in days). While not wishing to be bound by any particular theory, these results suggest that DNP is blocking the destruction of the pancreas and that DNP is improving the survival of the ferrets.

[00158] While not wishing to be limited by theory, it is believed that VX-770 does not have an impact on these findings. Without the administration of VX-770 to protect the pancreas, historically more than 50% of the ferrets die. However, as is demonstrated by the data herein, ferrets treated with 2,4-DNP had significantly higher survival than historic placebo data (red line in FIG. 3B). Bronchoalveolar lavage fluid (BALF) can be taken to measure inflammation and bacteria counts at the pulmonary distress phase of cystic fibrosis.

[00159] In cystic fibrosis patients, the pancreas is affected first, resulting in all patients becoming diabetic (a blend of Type 1 and Type 2). Cystic fibrosis then moves into the pulmonary stage. The data herein suggests that DNP or prodrugs thereof could be useful to block pancreatic destruction and thus treat cystic fibrosis patients before they transition into diabetes. DNP and prodrugs thereof may also be useful to lower insulin resistance in cystic fibrosis patients by improving whole body flux.

Reference

1. van ‘t Erve TJ, Kadiiska MB, London SJ, Mason RP. Classifying oxidative stress by F2- isoprostane levels across human diseases: A meta-analysis. Redox Biol. 2017;12:582-99. Epub 2017/04/10. doi: 10.1016/j.redox.2017.03.024. PubMed PMID: 28391180; PMCID: PMC5384299.

Claims

1. A method of treating pulmonary diseases or disorders and/or autoimmune diseases or disorders comprising: administering to a patient in need thereof a therapeutic amount of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 20 mg/kg of body weight.

2. The method of claim 1, wherein the therapeutic amount of DNP is in the range of about 0.1 mg/kg of body weight to about 15 mg/kg of body weight, about 1 mg/kg of body weight to about 10 mg/kg of body weight, about 3 mg/kg of body weight to about 8 mg/kg of body weight, or about 4 mg/kg of body weight to about 6 mg/kg of body weight.

3. The method of claim 1 or 2, wherein the therapeutic amount of DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, or about 10 mg/kg of body weight.

4. The method of claim 1, wherein the therapeutic amount of DNP is in the range of about 0.001 mg/kg of body weight to about 10 mg/kg of body weight, about 0.001 mg/kg of body weight to about 8 mg/kg of body weight, about 0.001 mg/kg of body weight to about 6 mg/kg of body weight, about 0.001 mg/kg of body weight to about 4 mg/kg of body weight, about 0.001 mg/kg of body weight to about 2 mg/kg of body weight, about 0.01 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 1 mg/kg of body weight, or about 0.1 mg/kg of body weight to about 1 mg/kg of body weight.

5. The method of claim 1 or 4, wherein the therapeutic amount of DNP is about 0.001 mg/kg of body weight, about 0.005 mg/kg of body weight, about 0.01 mg/kg of body weight, about 0.05 mg/kg of body weight, about 0.1 mg/kg of body weight, about 0.2 mg/kg of body weight, about 0.3 mg/kg of body weight, about 0.4 mg/kg of body weight, about 0.5 mg/kg of body weight, about 0.6 mg/kg of body weight, about 0.7 mg/kg of body weight, about 0.8 mg/kg of body weight, or about 0.9 mg/kg of body weight.

6. The method of any one of claims 1-5, wherein the DNP is selected from 2,3-DNP, 2,4- DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP.

7. The method of any one of claims 1-6, wherein the DNP is 2,4-DNP.

8. A method of treating pulmonary diseases or disorders and/or autoimmune diseases or disorders comprising: administering to a patient in need thereof a therapeutic amount of a prodrug of dinitrophenol (DNP) or a pharmaceutically acceptable salt thereof, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 200 mg/kg of body weight.

9. The method of claim 8, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 100 mg/kg of body weight, about 1 mg/kg of body weight to about 20 mg/kg of body weight, about 5 mg/kg of body weight to about 10 mg/kg of body weight, about 7 mg/kg of body weight to about 9 mg/kg of body weight, about 10 mg/kg of body weight to about 20 mg/kg of body weight, about 15 mg/kg of body weight to about 17 mg/kg of body weight, about 50 mg/kg of body weight to about 100 mg/kg of body weight, about 60 mg/kg of body weight to about 90 mg/kg of body weight, about 75 mg/kg of body weight to about 85 mg/kg of body weight, or about 79 mg/kg of body weight to about 81 mg/kg of body weight.

10. The method of claim 8 or 9, wherein the therapeutic amount of the prodrug of DNP is about 1 mg/kg of body weight, about 2 mg/kg of body weight, about 3 mg/kg of body weight, about 4 mg/kg of body weight, about 5 mg/kg of body weight, about 6 mg/kg of body weight, about 7 mg/kg of body weight, about 8 mg/kg of body weight, about 9 mg/kg of body weight, 10 mg/kg of body weight, about 1 1 mg/kg of body weight, about 12 mg/kg of body weight, about 13 mg/kg of body weight, about 14 mg/kg of body weight, about 15 mg/kg of body weight, about 16 mg/kg of body weight, about 17 mg/kg of body weight, about 18 mg/kg of body weight, about 19 mg/kg of body weight, or about 20 mg/kg of body weight.

11. The method of claim 8 or 9, wherein the therapeutic amount of the prodrug of DNP is about 71 mg/kg of body weight, about 72 mg/kg of body weight, about 73 mg/kg of body weight, about 74 mg/kg of body weight, about 75 mg/kg of body weight, about 76 mg/kg of body weight, about 77 mg/kg of body weight, about 78 mg/kg of body weight, about 79 mg/kg of body weight,

80 mg/kg of body weight, about 81 mg/kg of body weight, about 82 mg/kg of body weight, about

89 mg/kg of body weight, or about 90 mg/kg of body weight.

12. The method of claim 8, wherein the therapeutic amount of the prodrug of DNP is in the range of about 0.001 mg/kg of body weight to about 10 mg/kg of body weight, about 0.001 mg/kg of body weight to about 8 mg/kg of body weight, about 0.001 mg/kg of body weight to about 6 mg/kg of body weight, about 0.001 mg/kg of body weight to about 4 mg/kg of body weight, about 0.001 mg/kg of body weight to about 2 mg/kg of body weight, about 0.01 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 2 mg/kg of body weight, about 0.05 mg/kg of body weight to about 1 mg/kg of body weight, or about 0.1 mg/kg of body weight to about 1 mg/kg of body weight.

13. The method of claim 8 or 12, wherein the therapeutic amount of the prodrug of DNP is about 0.001 mg/kg of body weight, about 0.005 mg/kg of body weight, about 0.01 mg/kg of body weight, about 0.05 mg/kg of body weight, about 0.1 mg/kg of body weight, about 0.2 mg/kg of body weight, about 0.3 mg/kg of body weight, about 0.4 mg/kg of body weight, about 0.5 mg/kg of body weight, about 0.6 mg/kg of body weight, about 0.7 mg/kg of body weight, about 0.8 mg/kg of body weight, or about 0.9 mg/kg of body weight.

14. The method of any one of claims 8-13, wherein the prodrug of DNP is selected from: an amino acid (AA) ester of 2,3-DNP, an amino acid (AA) ester of 2,4-DNP, an amino acid (AA) ester of 2,5-DNP, an amino acid (AA) ester of 2,6-DNP, an amino acid (AA) ester of 3,4-DNP, or an amino acid (AA) ester of 3,5-DNP (Scheme 1, Formulas 1-1 to 1-10; Scheme 2, Formulas II-l to 11-10; Scheme 3, Formulas III-l to III-10; Scheme 4, Formulas IV-1 to IV-10; Scheme 5, Formulas V-l to V-10; and Scheme 6, Formulas VI-1 to VI-10);

AA esters incorporating a methylene dioxide (a formaldehyde equivalent) spacer (Scheme 1, Formulas 1-11 to 1-13; Scheme 2, Formulas II-l 1 to 11-13; Scheme 3, Formulas III-l 1 to III-13; Scheme 4, Formulas IV-11 to IV-13; Scheme 5, Formulas V-l l to V-13; and Scheme 6, Formulas VI- 11 to VI- 13); amino carbamate 2,3-DNP prodrugs, amino carbamate 2,4-DNP prodrugs, amino carbamate 2,5-DNP prodrugs, amino carbamate 2,6-DNP prodrugs, amino carbamate 3,4-DNP prodrugs, or amino carbamate 3,5-DNP prodrugs (Scheme 1, Formulas 1-14 to 1-17; Scheme 2, Formulas 11-14 to 11-17; Scheme 3, Formulas III- 14 to III-17; Scheme 4, Formulas IV-14 to IV- 17; Scheme 5, Formulas V-14 to V-17; and Scheme 6, Formulas VI-14 to VI-17); amino carbonate 2,3-DNP prodrugs, amino carbonate 2,4-DNP prodrugs, amino carbonate 2,5-DNP prodrugs, amino carbonate 2,6-DNP prodrugs, amino carbonate 3,4-DNP prodrugs, or amino carbonate 3,5-DNP prodrugs (Scheme 1, Formulas 1-18 and 1-19; Scheme 2, Formulas 11-18 and 11-19; Scheme 3, Formulas III-l 8 and III-19; Scheme 4, Formulas IV-18 and IV-19; Scheme 5, Formulas V-18 and V-19; and Scheme 6, Formulas VI-18 and VI-19); phosphate analogs 1-20, 1-21, 11-20, 11-21, III-20, III-21, IV-20, IV-21, V-20, V-21, VI- 20, and VI-21 (Schemes 1-6);

15. The method of any one of claims 8-13, wherein the prodrug of DNP is selected from:

16. The method of any one of claims 1-15, wherein the patient is a human.

17. The method of any one of claims 1-16, wherein the DNP and/or the prodrug of DNP is administered orally.

18. The method of any one of claims 1-16, wherein the DNP and/or the prodrug of DNP is administered intravenously, subcutaneously, or transdermally.

19. The method of any one of claims 1-18, wherein the DNP and/or the prodrug of DNP is administered at a frequency of once a day, twice a day, three times a day, four times a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, or once a month.

20. The method of any one of claims 1-19, wherein the DNP and/or the prodrug of DNP is administered at a frequency of once a day.

21. The method of claim 20, wherein the DNP and/or the prodrug of DNP is administered at a frequency of once a day for one day, once a day for two consecutive days, once a day for three consecutive days, once a day for four consecutive days, once a day for five consecutive days, once a day for six consecutive days, once a day for 7 consecutive days, or once a day for two consecutive weeks.

22. The method of any one of claims 1-21, wherein the pulmonary disease or disorder is selected from cystic fibrosis (CF), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, bronchiectasis, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), hypertension, sarcoidosis, silicosis, systemic sclerosis, lung infection (pneumonia), lung cancer and obstructive sleep apnea.

23. The method of claim 22, wherein the pulmonary disease or disorder is cystic fibrosis.

24. The method of claim 23, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents or reduces increases in blood glucose levels in a cystic fibrosis patient following a meal.

25. The method of claim 23 or 24, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents the destruction of the pancreas of a cystic fibrosis patient.

26. The method of any one of claims 23-25, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents or reduces inflammation and/or scarring of the pancreas of a cystic fibrosis patient.

27. The method of any one of claims 23-26, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents insulin resistance and/or pre-diabetes in a cystic fibrosis patient.

28. The method of any one of claims 23-27, wherein the therapeutic amount of DNP and/or the prodrug of DNP prevents a cystic fibrosis patient from developing diabetes.

29. The method of any one of claims 23-28, wherein the therapeutic amount of DNP and/or the prodrug of DNP improves survivability in a cystic fibrosis patient compared to a patient who is not treated with a therapeutic amount of DNP and/or a prodrug of DNP.

30. The method of any one of claims 1-21, wherein the autoimmune disease or disorder is selected from diseases and disorders associated with inflammation.

31 . The method of claim 28, wherein the disease and disorder is selected from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s Disease, pouchitis, rheumatoid arthritis, ileitis and allergic rhinitis.