Method of Treating Airway Diseases With Beta-Adrenergic Inverse Agonists

• US 20080254022A1
• Filed: 10/08/2004
• Published: 10/16/2008
• Est. Priority Date: 10/09/2003
• Status: Active Grant

• Current Assignee: EGB Advisors, LLC, Invion, Inc. (Invion, Ltd.)
• Original Assignee: Inverseon, Inc. (Invion, Ltd.)
• Inventors: Bond, Richard A.
• Granted Patent: US 9,539,221 B2
• Time in Patent Office: Days
• US Class Current: 424/131.1
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The use of β-adrenergic inverse agonists provides a new and highly efficient way of treating a number of pulmonary airway diseases, including asthma, emphysema, and chronic obstructive pulmonary diseases. In general, such a method comprises administering a therapeutically effective amount of a β-adrenergic inverse agonist to the subject to treat the pulmonary airway disease. Particularly preferred inverse agonists include nadolol and carvedilol.

Claims

1. A method for treatment of pulmonary airway disease in a subject suffering from pulmonary airway disease comprising administering a therapeutically effective amount of a β

-adrenergic inverse agonist to the subject to treat the pulmonary airway disease.

2. The method of claim 1 wherein the β

-adrenergic inverse agonist is selected from the group consisting of β

₂-selective inverse agonists, and non-selective inverse agonists having inverse agonist activity against both bi- and 2-adrenergic receptors.

3. The method of claim 2 wherein the β

-adrenergic inverse agonist is a β

₂-selective inverse agonist.

4. The method of claim 1 wherein the β

-adrenergic inverse agonist is selected from the group consisting of nadolol, bupranolol, butoxamine, carazolol, carvedilol, ICI-118,551, levobunolol, metoprolol, propranolol, sotalol, and timolol, and the salts, solvates, analogues, congeners, bioisosteres, hydrolysis products, metabolites, precursors, and prodrugs thereof.

5. The method of claim 4 wherein the β

-adrenergic inverse agonist is selected from the group consisting of nadolol and a compound of formula (I)

6. The method of claim 5 wherein the β

-adrenergic inverse agonist is nadolol.

7. The method of claim 4 wherein the β

-adrenergic inverse agonist is selected from the group consisting of carvedilol and a compound of formula

8. The method of claim 7 wherein the β

-adrenergic inverse agonist is carvedilol.

16. The method of claim 1 wherein the β

-adrenergic inverse agonist is administered by a route selected from the group consisting of oral, sustained-release oral, parenteral, sublingual, buccal, insufflation, and inhalation.

17. The method of claim 16 wherein the β

-adrenergic inverse agonist is administered by the sustained-release oral route.

18. The method of claim 1 wherein the pulmonary airway disease is selected from the group consisting of asthma, bronchiectasis, bronchitis, chronic obstructive pulmonary disease, Churg-Strauss syndrome, pulmonary sequelae of cystic fibrosis, emphysema, allergic rhinitis, and pneumonia.

19. The method of claim 18 wherein the pulmonary airway disease is asthma.

20. The method of claim 18 wherein the pulmonary airway disease is chronic obstructive pulmonary disease.

21. The method of claim 18 wherein the pulmonary airway disease is emphysema.

25. The method of claim 1 wherein the β

-adrenergic inverse agonist is administered over time in a series of graduated doses starting with the lowest dose and increasing to the highest dose.

26. The method of claim 25 wherein, when the highest dose is reached, the β

-adrenergic inverse agonist continues to be administered at that dose.

9-15. -15. (canceled)

22-24. -24. (canceled)

27. A pharmaceutical composition comprising:

(a) nadolol in a quantity selected from the group consisting of 1 mg, 3 mg, 5, mg, 10 mg, 15 mg, 30 mg, 50 mg, and 70 mg; and

(b) a pharmaceutically acceptable carrier.

28-39. -39. (canceled)

40. A method for treatment of pulmonary airway disease in a subject suffering from pulmonary airway disease comprising administering to the subject:

(1) a therapeutically effective amount of a β

-adrenergic inverse agonist and (2) a therapeutically effective amount of an additional agent selected from the group consisting of;

a β

₂-selective adrenergic agonist;

a steroid;

an anticholinergic drug;

a xanthine compound;

an anti-IgE antibody;

a leukotriene modifier; and

a phosphodiesterase inhibitor in order to treat the pulmonary airway disease.

41. The method of claim 40 wherein the additional agent is a β

₂-selective adrenergic agonist and the β

₂-selective adrenergic agonist is selected from the group consisting of albuterol, bitolterol, clenbuterol, clorprenaline, dobutamine, fenoterol, formoterol, isoetharine, isoprenaline, levabuterol, mabuterol, metaproterenol, pirbuterol, ritodrine, salbutamol, salmeterol, terbutaline, and the salts, solvates, analogues, congeners, bioisosteres, hydrolysis products, metabolites, precursors, and prodrugs thereof.

49. The method of claim 40 wherein the additional agent is a steroid and wherein the steroid is selected from the group consisting of beclomethasone, budenoside, ciclesonide, flunisolide, fluticasone, methylprednisolone, prednisolone, prednisone, and triamcinolone, and the salts, solvates, analogues, congeners, bioisosteres, hydrolysis products, metabolites, precursors, and prodrugs thereof.

57. The method of claim 40 wherein the additional agent is an anticholinergic drug and wherein the anticholinergic drug is selected from the group consisting of ipratropium bromide, tiotropium bromide, and oxitropium bromide, and the salts, solvates, analogues, congeners, bioisosteres, hydrolysis products, metabolites, precursors, and prodrugs thereof.

65. The method of claim 40 wherein the additional agent is a xanthine compound and wherein the xanthine compound is selected from the group consisting of theophylline, extended-release theophylline, aminophylline, theobromine, enprofylline, diprophylline, isbufylline, choline theophyllinate, albifylline, arofylline, bamifylline and caffeine.

73. The method of claim 40 wherein the additional agent is an anti-IgE antibody and wherein the anti-IgE antibody is a monoclonal antibody or a genetically engineered antibody that is derived from a monoclonal antibody.

84. The method of claim 40 wherein the additional agent is a leukotriene modifier and wherein the leukotriene modifier is selected from the group consisting of ibudilast, montelukast, pranlukast, and zafirlukast, and the salts, solvates, analogues, congeners, bioisosteres, hydrolysis products, metabolites, precursors, and prodrugs thereof.

92. The method of claim 40 wherein the additional agent is a phosphodiesterase IV inhibitor and wherein the phosphodiesterase IV inhibitor is selected from the group consisting of roflumilast and cilomilast, and the salts, solvates, analogues, congeners, bioisosteres, hydrolysis products, metabolites, precursors, and prodrugs thereof.

42-48. -48. (canceled)

50-56. -56. (canceled)

58-64. -64. (canceled)

66-72. -72. (canceled)

74-83. -83. (canceled)

85-91. -91. (canceled)

93-98. -98. (canceled)

99. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a β

-adrenergic inverse agonist;

(b) a therapeutically effective amount of a second therapeutic agent effective to treat a pulmonary airway disease, the second therapeutic agent being selected from the group consisting of a β

₂-selective adrenergic agonist, a steroid, an anticholinergic drug, a xanthine compound, an anti-IgE antibody, a leukotriene modifier, and a phosphodiesterase IV inhibitor; and

(c) a pharmaceutically acceptable carrier.

100-106. -106. (canceled)