Method of treating airway diseases with beta-adrenergic inverse agonists

• US 20060194882A1
• Filed: 10/07/2005
• Published: 08/31/2006
• Est. Priority Date: 10/08/2004
• Status: Active Grant

• Current Assignee: Invion, Inc. (Invion, Ltd.)
• Original Assignee: Inverseon, Inc. (Invion, Ltd.)
• Inventors: Bond, Richard A.
• Granted Patent: US 7,528,175 B2
• Time in Patent Office: Days
• US Class Current: 514/651
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61P 11/06 Antiasthmatics

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. In addition, methods are described for long-term administration of such inverse agonists and for determining the suitability of patients for long-term inverse agonist therapy.

Claims

1. A pharmaceutical composition comprising:

(a) a dosage of nadolol selected from the group consisting of 1 mg, 3 mg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 50 mg, 60 mg, 70 mg, 90 mg, 100 mg, 110 mg, 130 mg, 140 mg, and 150 mg; and

(b) a pharmaceutically acceptable carrier;

the pharmaceutical composition being formulated for long-term treatment of a disease or condition treatable by chronic administration of a β

-adrenergic inverse agonist.

2. The pharmaceutical composition of claim 1 wherein the disease or condition treatable by chronic administration of a β

-adrenergic inverse agonist is selected from the group consisting of asthma and chronic obstructive pulmonary disease.

3. The pharmaceutical composition of claim 2 wherein the disease or condition treatable by chronic administration of a β

-adrenergic inverse agonist is asthma.

4. The pharmaceutical composition of claim 1 wherein the dosage of nadolol is 10 mg.

5. The pharmaceutical composition of claim 1 wherein the composition is formulated for immediate release.

6. The pharmaceutical composition of claim 1 wherein the composition is formulated for sustained release.

7. A method for the treatment of a disease or condition treatable by chronic administration of a β

-adrenergic inverse agonist comprising the steps of;

(a) selecting an initial dose of a β

-adrenergic inverse agonist;

(b) administering the initial dose of the β

-adrenergic inverse agonist to a patient with a disease or condition treatable by chronic administration of a β

-adrenergic inverse agonist;

(c) monitoring the response of the patient to the initial dose according to one or more preset criteria that indicates the response of the patient to the dose;

(d) if the response to the dose is within expected pulmonary and optionally cardiovascular parameters, subsequently administering a higher dose of the β

-adrenergic inverse agonist;

(e) repeating steps (b)-(d) with the higher dose until the maximum tolerated dose is attained; and

(f) maintaining the patient on the maximum tolerated dose.

8. The method of claim 7 wherein the disease or condition treatable by chronic administration of a β

-adrenergic inverse agonist is selected from the group consisting of asthma and chronic obstructive pulmonary disease.

9. The method of claim 8 wherein the disease or condition is asthma.

10. The method of claim 7 wherein the β

-adrenergic inverse agonist is nadolol.

11. The method of claim 10 wherein the disease or condition is asthma.

12. The method of claim 11 wherein the initial dose is 10 mg of nadolol per day.

13. The method of claim 12 wherein the subsequent doses are 20 mg, 40 mg, 80 mg, 120 mg, and 160 mg of nadolol per day.

14. The method of claim 11 wherein the one or more preset criteria consists of lung function and optionally at least one criterion selected from the group consisting of pulmonary symptoms, heart rate, and blood pressure.

15. The method of claim 14 wherein the one or more preset criteria are all of lung function, heart rate, and blood pressure.

16. The method of claim 14 wherein the criterion is lung function and lung function is assessed by at least one parameter selected from the group consisting of:

(1) FEV₁;

(2) PC₂₀.for methacholine challenge;

(3) prebronchodilator FEV₁ (4) postbronchodilator FEV₁;

(5) FVC;

(6) FEF25-75%;

(7) PEFR;

(8) TLC;

(9) VC;

(10) FRC;

(11) exhaled nitrous oxide;

(12) eosinophil levels in lung and/or blood;

(13) IgE levels;

(14) rescue medication use per day or other time period;

(15) asthma exacerbations over a defined time period;

(16) alteration in inhaled/oral steroid dose level;

(17) Juniper asthma control questionnaire symptom score; and

(18) Asthma Symptom Score.

17. The method of claim 16 wherein lung function is assessed by at least one parameter selected from the group consisting of:

(1) FEV₁;

(2) PC₂₀.for methacholine challenge; and

(3) PEFR.

18. The method of claim 17 wherein lung function is assessed by FEV₁.

19. The method of claim 17 wherein lung function is assessed by PC₂₀.for methacholine challenge.

20. The method of claim 17 wherein lung function is assessed by PEFR.

21. The method of claim 15 wherein lung function is assessed by at least one parameter selected from the group consisting of:

(1) FEV₁;

(2) PC₂₀.for methacholine challenge;

(3) prebronchodilator FEV₁ (4) postbronchodilator FEV₁;

(5) FVC;

(6) FEF25-75%;

(7) PEFR;

(8) TLC;

(9) VC;

(10) FRC;

(11) exhaled nitrous oxide;

(12) eosinophil levels in lung and/or blood;

(13) IgE levels;

(14) rescue medication use per day or other time period;

(15) asthma exacerbations over a defined time period;

(16) alteration in inhaled/oral steroid dose level;

(17) Juniper asthma control questionnaire symptom score; and

(18) Asthma Symptom Score.

22. The method of claim 21 wherein lung function is assessed by at least one parameter selected from the group consisting of:

(1) FEV₁; and

(2) PC₂₀.for methacholine challenge.

23. The method of claim 22 wherein lung function is assessed by FEV₁.

24. The method of claim 22 wherein lung function is assessed by PC₂₀.for methacholine challenge.

25. The method of claim 22 wherein lung function is assessed by PEFR.

26. The method of claim 15 wherein the dose is increased over a prior dose if the measured reduction in FEV₁ is ≦

20%, if the measured blood pressure is ≧

95/60, and if the measured heart rate is ≧

55 bpm.

27. The method of claim 15 wherein the dose is maintained at the prior dose if the measured reduction in FEV₁ is >

20% but ≦

30%, if the measured blood pressure is ≧

90/55, and if the measured heart rate is ≦

50 bpm.

28. The method of claim 15 wherein the dose is maintained for a period from 7 to 14 days and then increased according to the preset criteria.

29. The method of claim 13 wherein, at the maximum tolerated dose of nadolol, the doubling dose for methacholine PC₂₀ increases by at least about 25%.

30. The method of claim 29 wherein, at the maximum tolerated dose of nadolol, the doubling dose for methacholine PC₂₀ increases by at least about 50%.

31. The method of claim 30 wherein, at the maximum tolerated dose of nadolol, the doubling dose for methacholine PC₂₀ increases by at least about 75%.

32. A method of testing a patient suffering from a disease or condition treatable by administration of a β

-adrenergic inverse agonist to determine the suitability of the patient for long-term treatment with a β

-adrenergic inverse agonist comprising the steps of;

(a) measuring at least one pulmonary and optionally at least one cardiovascular diagnostic parameter potentially affected by the administration of the β

-adrenergic inverse agonist in the patient to be tested;

(b) administering a minimum daily dose of the β

-adrenergic inverse agonist to the patient for a predetermined period of time; and

(c) measuring at least one pulmonary and optionally at least one cardiovascular diagnostic parameter subsequent to the administration of the β

-adrenergic inverse agonist in order to determine whether the patient is suitable for long-term treatment with the β

-adrenergic inverse agonist.

33. The method of claim 32 wherein the β

-adrenergic inverse agonist is nadolol.

34. The method of claim 33 wherein the minimum daily dose of nadolol is 10 mg per day.

35. The method of claim 32 wherein the disease or condition treatable by the β

-adrenergic inverse agonist is selected from the group consisting of asthma and chronic obstructive pulmonary disease.

36. The method of claim 35 wherein the disease or condition treatable by the β

-adrenergic inverse agonist is asthma.

37. The method of claim 36 wherein the β

-adrenergic inverse agonist is nadolol.

38. The method of claim 37 wherein the at least one pulmonary diagnostic parameter and optionally at least one cardiovascular parameter is selected from the group consisting of heart rate, and blood pressure.

39. The method of claim 38 wherein the at least one diagnostic parameters are all of lung function, heart rate, and blood pressure.

40. The method of claim 38 wherein the pulmonary diagnostic parameter is lung function and lung function is assessed by at least one parameter selected from the group consisting of:

(1) FEV₁;

(2) PC₂₀.for methacholine challenge;

(3) prebronchodilator FEV₁ (4) postbronchodilator FEV₁;

(5) FVC;

(6) FEF25-75%;

(7) PEFR;

(8) TLC;

(9) VC;

(10) FRC;

(11) exhaled nitrous oxide;

(12) eosinophil levels in lung and/or blood;

(13) IgE levels;

(14) rescue medication use per day or other time period;

(15) asthma exacerbations over a defined time period;

(16) alteration in inhaled/oral steroid dose level;

(17) Juniper asthma control questionnaire symptom score; and

(18) Asthma Symptom Score.

41. The method of claim 40 wherein lung function is assessed by use of a spirometer.

42. The method of claim 40 wherein lung function is assessed by at least one parameter selected from the group consisting of:

(1) FEV₁;

(2) PC₂₀.for methacholine challenge; and

(3) PEFR.

43. The method of claim 42 wherein lung function is assessed by FEV₁.

44. The method of claim 42 wherein lung function is assessed by PC₂₀.for methacholine challenge.

45. The method of claim 42 wherein lung function is assessed by PEFR.

46. The method of claim 39 wherein lung function is assessed by at least one parameter selected from the group consisting of:

(1) FEV₁;

(2) PC₂₀.for methacholine challenge;

(3) prebronchodilator FEV₁ (4) postbronchodilator FEV₁;

(5) FVC;

(6) FEF25-75%;

(7) PEFR;

(8) TLC;

(9) VC;

(10) FRC;

(11) exhaled nitrous oxide;

(12) eosinophil levels in lung and/or blood;

(13) IgE levels;

(14) rescue medication use per day or other time period;

(15) asthma exacerbations over a defined time period;

(16) alteration in inhaled/oral steroid dose level;

(17) Juniper asthma control questionnaire symptom score; and

(18) Asthma Symptom Score.

47. The method of claim 46 wherein lung function is assessed by at least one parameter selected from the group consisting of:

(1) FEV₁;

(2) PC₂₀.for methacholine challenge; and

(3) PEFR.

48. The method of claim 47 wherein lung function is assessed by FEV₁.

49. The method of claim 47 wherein lung function is assessed by PC₂₀.for methacholine challenge.

50. The method of claim 47 wherein lung function is assessed by PEFR.

51. A kit comprising:

(a) a labeled container;

(b) a plurality of dosage forms of a β

-adrenergic inverse agonist in the container, each dosage form identified as to the quantity of the β

-adrenergic inverse agonist contained in the dosage form; and

;

(c) instructions for the use of the dosage forms attached to the container, the instructions being for a patient with a pulmonary airway disease or condition treatable by chronic administration of a β

-adrenergic inverse agonist.

52. The kit of claim 51 wherein the disease or condition treatable by chronic administration of a β

-adrenergic inverse agonist is selected from the group consisting of asthma and chronic obstructive pulmonary disease.

53. The kit of claim 52 wherein the disease or condition treatable by chronic administration of a β

-adrenergic inverse agonist is selected from the group consisting of asthma and chronic obstructive pulmonary disease.

54. The kit of claim 53 wherein the condition treatable by chronic administration of a β

-adrenergic inverse agonist is asthma.

55. The kit of claim 54 wherein the β

-adrenergic inverse agonist is nadolol.

56. The kit of claim 55 wherein the plurality of dosage forms is selected from the group consisting of:

10 mg and 20 mg;

10 mg, 20 mg, and 40 mg;

10 mg, 20 mg, 40 mg, and 80 mg;

10 mg, 20 mg, 40 mg, 80 mg, and 120 mg;

or 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, and 160 mg.

57. The kit of claim 56 wherein the plurality of dosage forms is 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, and 160 mg.

58. A method of administering nadolol as a therapeutic agent for a disease or condition selected from the group consisting of asthma and chronic obstructive pulmonary disease comprising the steps of:

(a) enhancing the safety profile of nadolol by informing a prescribing physician that a transient decrease of lung function or cardiovascular function can result from nadolol administration and instructing the prescribing physician to monitor a patient who is prescribed nadolol for decrease in lung function or cardiovascular function, the physician being informed and instructed by means of product label information; and

(b) recommending that when a clinically meaningful decrease in lung function or cardiovascular function is seen beyond prescribed criteria for the dosage escalation and maintenance of the drug for the treatment of asthma, the physician remove, reduce, or taper off the administration of nadolol in the patient and initiate appropriate supportive therapy.

59. The method of claim 58 wherein the disease or condition is asthma.