# US 2025/0205276 A1 · Compositions and methods of treatment of disease using combination of a nitrodilator and a nitrogen oxide compound

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- Number: US 2025/0205276 A1
- Document ID: US20250205276A1
- Status: Published application
- Kind: A1
- Application number: 18/845,488
- Filed: 2023-03-13
- Published: 2025-06-26
- Earliest claimed: 2022-03-11
- Assignees: Loma Linda University
- Applicants: Loma Linda University
- Inventors: Arlin B. Blood; Taiming Liu
- Web page: https://patentgrep.com/patent/US20250205276A1

## CPC

- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 31/16: Amides, e.g. hydroxamic acids
- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/21: Esters, e.g. nitroglycerine, selenocyanates
- A61K 31/34: having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 33/26: Iron; Compounds thereof
- A61K 38/51: Lyases (4)
- A61P 9/08: Vasodilators for multiple indications
- A61P 11/08: Bronchodilators
- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided here are compositions and methods for treatment of vascular conditions or respiratory conditions by administering a therapeutically effective amount of a nitrogen oxide compound and a nitrodilator. The nitrogen oxide compound can be nitrite, one or more of a number of nitro-group containing compounds, a nitrate-group containing compound, an NO donor, or an endogenous NO producing amino acid. The nitrodilator can be one or more of nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, nitroprusside, amyl nitrite, nitrosothiols, or dinitrosyl iron complexes.

## Claims

### Claim 1

A method of treating a vascular or a respiratory condition in a subject, the method comprising:
administering to the subject a therapeutically effective amount of a nitrogen oxide compound and a nitrodilator.

### Claim 2 (depends on 1)

The method of claim 1, wherein the vascular condition is one or more of a coronary, a pulmonary, or a peripheral arterial disease.

### Claim 3 (depends on 1)

The method of claim 1, wherein the nitrogen oxide compound is one or more of a nitro-group containing compound, a nitrate-group containing compound, a nitric oxide (NO) donor, and an endogenous NO producing amino acid.

### Claim 4 (depends on 3)

The method of claim 3, wherein the nitro-group containing compound is one or more of a nitrite salt, a D-NG-Nitro arginine methyl ester, and a nitro-group containing low molecular weight molecules, or proteins, or lipids.

### Claim 5 (depends on 3)

The method of claim 3, wherein the nitrate-group containing compound is one or more of a nitrate salt or a nitrate-group containing low molecular weight molecules, or proteins, or lipids.

### Claim 6 (depends on 3)

The method of claim 3, wherein the NO donor is a NONOate or an hydroxamic acid such as deferoxamine, acetohydroxamic acid, and hydroxyurea.

### Claim 7 (depends on 3)

The method of claim 3, wherein the endogenous NO producing amino acid is arginine or citrulline or combinations thereof.

### Claim 8 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of a nitrogen oxide compound ranges from about 1 mg to about 10 g.

### Claim 9 (depends on 1)

The method of claim 1, wherein the nitrodilator is nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, nitroprusside, amyl nitrite, a S-nitrosothiol, an heme-NO, or a dinitrosyl iron complex.

### Claim 10 (depends on 9)

The method of claim 9, wherein the therapeutically effective amount of nitroglycerin is about 0.1 mg to about 0.6 mg.

### Claim 11 (depends on 9)

The method of claim 9, wherein the therapeutically effective amount of isosorbide mononitrate is about 10 mg to about 300 mg.

### Claim 12 (depends on 1)

The method of claim 1, wherein the nitrogen oxide compound is a nitrite compound.

### Claim 13 (depends on 12)

The method of claim 12, wherein the nitrodilator and the nitrite compound are administered to the subject at a ratio ranging from 1:1 to 1:3333.

### Claim 14 (depends on 13)

The method of claim 13, wherein the nitrodilator and the nitrite compound are administered to the subject as a fixed-dose combination.

### Claim 15 (depends on 1)

The method of claim 1, wherein the nitrogen oxide compound is a nitrate compound.

### Claim 16 (depends on 15)

The method of claim 15, wherein the nitrodilator and the nitrate compound are administered to the subject at a ratio ranging from 1:1 to 1:33333.

### Claim 17 (depends on 16)

The method of claim 16, wherein the nitrodilator and the nitrate compound are administered to the subject as a fixed-dose combination.

### Claim 18 (depends on 1)

The method of claim 1, further comprising the step of:
administering a therapeutically effective amount of a stimulator of soluble guanylyl cyclase to the subject.

### Claim 19 (depends on 18)

The method of claim 18, wherein the stimulator of soluble guanylyl cyclase is riociguat or vericiguat.

### Claim 20 (depends on 1)

method of claim 1, further comprising:
administering a therapeutically effective amount of an activator of soluble guanylyl cyclase to the subject.

### Claim 21 (depends on 20)

The method of claim 20, wherein the activator of soluble guanylyl cyclase is runcaciguat, cinaciguat, ataciguat, or kynurenine.

### Claim 22 (depends on 1)

The method of claim 1, further comprising:
administering a therapeutically effective amount of a cGMP-phosphodiesterase inhibitor to the subject.

### Claim 23 (depends on 22)

The method of claim 22, wherein the cGMP-phosphodiesterase inhibitor is sildenafil, vardenafil, or tadalafil.

### Claim 24 (depends on 1)

The method of claim 1, wherein the nitrodilator is nitric oxide administered via inhalation.

### Claim 25 (depends on 24)

The method of claim 24, wherein the nitric oxide is administered along with a nebulized thiol.

### Claim 26 (depends on 25)

The method of claim 25, wherein the nebulized thiol is L-cysteine or glutathione.

### Claim 27 (depends on 1)

The method of claim 1, wherein the respiratory condition is apnea, and pulmonary hypertension, or chronic obstructive pulmonary disease.

### Claim 28

A method of treating a vascular condition in a subject, the method comprising:
administering to the subject a therapeutically effective amount of a first nitrodilator in a first formulation to activate a nitrodilator-activatable intracellular NO store (NANOS) and a second nitrodilator in a second formulation to contribute to the NANOS.

### Claim 29 (depends on 28)

The method of claim 28, wherein the first nitrodilator is nitroglycerin and the first formulation is a sublingual tablet or a trans-lingual spray.

### Claim 30 (depends on 29)

The method of claim 29, wherein the second nitrodilator is nitroglycerin and the second formulation is a nanoliposome.

### Claim 31 (depends on 29)

The method of claim 29, wherein the second nitrodilator is a dinitrosyl iron complex, S-nitrosoglutathione, or heme-NO and the second formulation is a nanoliposome.

### Claim 32

A method of treating a vascular condition in a subject, the method comprising:
administering to the subject a therapeutically effective amount of a nitrogen oxide compound and a cGMP-phosphodiesterase inhibitor.

### Claim 33 (depends on 32)

The method of claim 32, wherein the nitrogen oxide compound is a nitrate-group containing compound or a nitrite compound.

### Claim 34 (depends on 32)

The method of claim 32, wherein the cGMP-phosphodiesterase inhibitor is sildenafil, vardenafil, or tadalafil.

### Claim 35 (depends on 32)

The method of claim 32, wherein the vascular condition is erectile dysfunction.