Method to slow ventricular rate
Disclosed herein are methods, formulations, and kits for treating or preventing a heart condition, e.g., cardiac arrhythmia, e.g., atrial arrhythmia, using selective β1 adrenergic receptor blockers. Also disclosed herein are methods, formulations, and kits for treating a heart condition via inhalation or intranasal spray administration of selective β1 adrenergic receptor blocker and class I antiarrhythmic agent.
1. A method of treating a subject suffering from atrial arrhythmia, comprising administering to said subject via inhalation:
(i) a therapeutically effective amount of a β1-selective adrenergic receptor blocker; and
(ii) a therapeutically effective amount of a class I antiarrhythmic agent,
wherein said therapeutically effective amount of said β1-selective adrenergic receptor blocker and said therapeutically effective amount of said class I antiarrhythmic agent, when both are administered via inhalation to an experimental subject suffering from said atrial arrhythmia in a clinical study, induce a faster cardioversion of said atrial arrhythmia in said experimental subject as compared to:
(a) administering said therapeutically effective amount of said β1-selective adrenergic receptor blocker via inhalation to a control subject suffering from said atrial arrhythmia in said clinical study without a class I antiarrhythmic agent; or
(b) administering said therapeutically effective amount of said class I antiarrhythmic agent via inhalation to a control subject suffering from said atrial arrhythmia in said clinical study without a β1-selective adrenergic receptor blocker; and
wherein said inhalation administration of both said therapeutically effective amount of said β1-selective adrenergic receptor blocker and said therapeutically effective amount of said class I antiarrhythmic agent slows atrioventricular node conduction during said cardioversion.
2. The method of claim 1 , wherein said administering of both said therapeutically effective amount of said β1-selective adrenergic receptor blocker and said therapeutically effective amount of said class I antiarrhythmic agent prolongs PR interval in said experimental subject during said cardioversion as measured by electrocardiograph.
3. The method of claim 2 , wherein said PR interval in said experimental subject is prolonged by at least 5%.
4. The method of claim 1 , wherein said administering of both said therapeutically effective amount of said β1-selective adrenergic receptor blocker and said therapeutically effective amount of said class I antiarrhythmic agent reduces average ventricular rate in said experimental subject during said cardioversion by at least 10%.
5. The method of claim 1 , comprising administering about 1 mg to about 4 mg of said β1-selective adrenergic receptor blocker.
6. The method of claim 1 , wherein said β1-selective adrenergic receptor blocker is administered at a concentration of about 2 mg/mL to about 30 mg/mL.
7. The method of claim 1 , wherein said β1-selective adrenergic receptor blocker comprises metoprolol or a pharmaceutically acceptable salt or solvate thereof.
8. The method of claim 7 , comprising administering about 1 mg to about 4 mg metoprolol or a pharmaceutically acceptable salt or solvate thereof at a concentration of about 2 mg/mL to about 30 mg/mL.
9. The method of claim 1 , wherein said β1-selective adrenergic receptor blocker comprises nebivolol or a pharmaceutically acceptable salt or solvate thereof.
10. The method of claim 1 , wherein said β1-selective adrenergic receptor blocker is administered up to about 90 minutes earlier than said therapeutically effective amount of said class I antiarrhythmic agent.
11. The method of claim 1 , wherein said β1-selective adrenergic receptor blocker is administered concurrently with said class I antiarrhythmic agent.
12. The method of claim 1 , comprising administering about 1 mg to about 4 mg metoprolol or a pharmaceutically acceptable salt or solvate thereof at a concentration of about 2 mg/mL to about 30 mg/mL up to 90 minutes prior to administering about 20 mg to about 150 mg flecainide or a pharmaceutically acceptable salt or solvate thereof via aerosolization.
13. The method of claim 1 , comprising administering concurrently via aerosolization about 1 mg to about 4 mg metoprolol or a pharmaceutically acceptable salt or solvate thereof at a concentration of about 2 mg/mL to about 30 mg/mL and about 20 mg to about 150 mg flecainide or a pharmaceutically acceptable salt or solvate thereof.
14. The method of claim 1 , wherein said atrial arrhythmia comprises atrial fibrillation.
15. A method of treating a patient suffering from atrial arrhythmia, comprising administering to said patient via inhalation:
(i) a therapeutically effective amount of a β1-selective adrenergic receptor blocker; and
(ii) a therapeutically effective amount of a class I antiarrhythmic agent,
wherein said therapeutically effective amount of said β1-selective adrenergic receptor blocker and said therapeutically effective amount of said class I antiarrhythmic agent, when both are administered via inhalation to an experimental subject suffering from said atrial arrhythmia in a clinical study, induce cardioversion in said experimental subject and induce a greater reduction in average ventricular rate during said cardioversion in said experimental subject as compared to:
(a) administering said therapeutically effective amount of said β1-selective adrenergic receptor blocker via inhalation to a control subject suffering from said atrial arrhythmia in said clinical study without a class I antiarrhythmic agent; or
(b) administering said therapeutically effective amount of said class I antiarrhythmic agent via inhalation to a control subject suffering from said atrial arrhythmia in said clinical study without a β1-selective adrenergic receptor blocker; and
wherein said inhalation administration of both said therapeutically effective amount of said β1-selective adrenergic receptor blocker and said therapeutically effective amount of said class I antiarrhythmic agent slows atrioventricular node conduction during said cardioversion.
16. The method of claim 15 , wherein said administering of both said therapeutically effective amount of said β1-selective adrenergic receptor blocker and said therapeutically effective amount of said class I antiarrhythmic agent prolongs PR interval in said experimental subject during said cardioversion as measured by electrocardiograph.
17. The method of claim 16 , wherein said PR interval in said experimental subject is prolonged by at least 5%.
18. The method of claim 15 , wherein said administering of both said therapeutically effective amount of said β1-selective adrenergic receptor blocker and said therapeutically effective amount of said class I antiarrhythmic agent reduces average ventricular rate in said experimental subject during said cardioversion by at least 10%.
19. The method of claim 15 , comprising administering about 1 mg to about 4 mg of said β1-selective adrenergic receptor blocker.
20. The method of claim 15 , wherein said β1-selective adrenergic receptor blocker is administered at a concentration of about 2 mg/mL to about 30 mg/mL.
21. The method of claim 15 , wherein said β1-selective adrenergic receptor blocker comprises metoprolol or a pharmaceutically acceptable salt or solvate thereof.
22. The method of claim 21 , comprising administering about 1 mg to about 4 mg metoprolol or a pharmaceutically acceptable salt or solvate thereof at a concentration of about 2 mg/mL to about 30 mg/mL.
23. The method of claim 15 , wherein said β1-selective adrenergic receptor blocker comprises nebivolol or a pharmaceutically acceptable salt or solvate thereof.
24. The method of claim 15 , wherein said β1-selective adrenergic receptor blocker is administered up to about 90 minutes earlier than said dosage therapeutically effective amount of said class I antiarrhythmic agent.
25. The method of claim 15 , wherein said β1-selective adrenergic receptor blocker is administered concurrently with said class I antiarrhythmic agent.
26. The method of claim 15 , comprising administering about 1 mg to about 4 mg metoprolol or a pharmaceutically acceptable salt or solvate thereof at a concentration of about 2 mg/mL to about 30 mg/mL up to 90 minutes prior to administering about 20 mg to about 150 mg flecainide or a pharmaceutically acceptable salt or solvate thereof via aerosolization.
27. The method of claim 15 , comprising administering concurrently via aerosolization about 1 mg to about 4 mg metoprolol or a pharmaceutically acceptable salt or solvate thereof at a concentration of about 2 mg/mL to about 30 mg/mL and about 20 mg to about 150 mg flecainide or a pharmaceutically acceptable salt or solvate thereof.
28. The method of claim 15 , wherein said atrial arrhythmia comprises atrial fibrillation.
29. The method of claim 1 , wherein said slowing of said atrioventricular node conduction is evidenced by electrocardiograph.
30. The method of claim 15 , wherein said slowing of said atrioventricular node conduction is evidenced by electrocardiograph.