Treatment of arrhythmias via inhibition of a multifunctional calcium/calmodulin-dependent protein kinase

• US 6,518,245 B1
• Filed: 01/30/1998
• Issued: 02/11/2003
• Est. Priority Date: 01/31/1997
• Status: Expired due to Fees

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Anderson, Mark E., Braun, Andrew P., Schulman, Howard, Sung, Ruey J.
• Primary Examiner(s): Brumback, Brenda
• Assistant Examiner(s): Gupta, Anish
• Application Number:
  US09/016,145
• Time in Patent Office: 1,838 Days
• Field of Search: 514/601, 514/602, 514/604, 514/14, 564/1, 564/80, 564/84, 564/90, 564/91, 530/327
• US Class Current: 514/16.4
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 9/06 Antiarrhythmics

Abstract

This invention provides a method for treating or preventing arrhythmias in a human subject comprising the administration of an effective amount of a calcium/calmodulin-dependent protein kinase inhibitor. Also provided are pharmaceutical compositions comprising a calcium/calmodulin-dependent protein kinase inhibitor and a pharmaceutically acceptable carrier and methods for identifying agents useful for the treatment of arrhythmias.

Claims

1. A method for treating arrhythmia in a human subject comprising the administration of a direct inhibitor of a multifunctional Ca²⁺/calmodulin-dependent protein kinase in an amount sufficient to suppress early afterdepolarizations, delayed afterdepolarizations, or intracellular calcium overload.

2. A method of claim 1, wherein said inhibitor is a CaM kinase II inhibitor.

3. A method of claim 1, wherein said inhibitor is 2[N-(2hydroxyethyl)-N-(4-methoxy-benezenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methylbenzylamine.

4. A method of claim 1, wherein said inhibitor is the peptide of the sequence KKALHRQEAVDCL (SEQ ID NO:

1).

5. A method of claim 1, wherein said administration is by a means selected from the group consisting of intravenous infusion, parenteral pump infusion, transcutaneous administration, intracoronary artery infusion, and intrapericardial infusion.

6. A method of claim 1, wherein said arrhythmia is ventricular tachycardia.

7. A method of claim 1, wherein said arrhythmia is ventricular fibrillation.

8. A method of claim 1, wherein said arrhythmia is atrial fibrillation.

9. A method of claim 1, wherein said inhibitor is administered in a dose of from about 0.05 mg to about 5.0 mg per kilogram of body weight.

10. A method of claim 1, wherein said inhibitor is administered in a dose of from about 0.3 mg to about 3.0 mg per kilogram of body weight.

11. A method of claim 1, wherein said method further comprises the administration of an effective amount of a second antiarrhythmic agent.

12. A method of claim 11, wherein said second antiarrhythmic agent is a potassium channel antagonist.

13. A method of claim 11, wherein said second antiarrhythmic agent is selected from the group consisting of a potassium channel blocker, β

adrenergic receptor antagonist, and a calcium channel blocker.

14. A method of claim 1, wherein said method further comprises treatment with an antiarrhythmic device.

15. A method of claim 14, wherein said antiarrhythmic device is selected from the group consisting of a permanent pacing system, an atrial implantable cardioverter defibrillator, and a ventricular implantable cardioverter defibrillator.

16. A method for preventing arrhythmia in a human subject comprising the administration of a direct inhibitor of a multifunctional Ca²⁺/calmodulin-dependent protein kinase in an amount effective to suppress early afterdepolarizations, delayed afterdepolarizations, or intracellular calcium overload.

17. A method of claim 16, wherein said inhibitor is a CaM kinase II inhibitor.

18. A method of claim 16, wherein said inhibitor is 2[N-(2hydroxyethyl)-N-(4-methoxy-benezenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methylbenzylamine.

19. A method of claim 16, wherein said inhibitor is the peptide of the sequence KKALHRQEAVDCL (SEQ ID NO:

1).

20. A method of claim 16, wherein said administration is by a means selected from the group consisting of intravenous infusion, parenteral pump infusion, transcutaneous administration, intracoronary artery infusion, and intrapericardial infusion.

21. A method of claim 16, wherein said arrhythmia is ventricular tachycardia.

22. A method of claim 16, wherein said arrhythmia is ventricular fibrillation.

23. A method of claim 16, wherein said arrhythmia is atrial fibrillation.

24. A method of claim 16, wherein said inhibitor is administered in a dose of from about 0.05 mg to about 5.0 mg per kilogram of body weight.

25. A method of claim 16, wherein said inhibitor is administered in a dose of from about 0.3 mg to about 3.0 mg per kilogram of body weight.

26. A method of claim 16, wherein said method further comprises the administration of an effective amount of a second antiarrhythmic agent.

27. A method of claim 26, wherein said second antiarrhythmic agent is a potassium channel antagonist.

28. A method of claim 26, wherein said second antiarrhythmic agent is selected from the group consisting of a potassium channel blocker, a β

adrenergic receptor antagonist, and a calcium channel blocker.

29. A method of claim 16, wherein said method further comprises treatment with an antiarrhythmic device.

30. A method of claim 29, wherein said antiarrhythmic device is selected from the group consisting of a permanent pacing system, an atrial implantable cardioverter defibrillator, and a ventricular implantable cardioverter defibrillator.

31. A method for treating arrhythmia in a human subject, wherein said method comprises directly decreasing the Ca²⁺/calmodulin-dependent kinase activity level in said subject.

32. A method of claim 31, comprising the administration of a Ca²⁺/calmodulin-dependent kinase inhibitor to said subject.