Use of adenosine antagonists in the treatment of bradyarrhythmias and hemodynamic depression associated with cardiopulmonary resucitation and/or cardiovascular collapse

• US 4,980,379 A
• Filed: 06/30/1988
• Issued: 12/25/1990
• Est. Priority Date: 06/30/1988
• Status: Expired due to Term

• Current Assignee: University of Virginia Alumni Patents Foundation The Towers BLDG Ste 6-211 1224 West Main St Charlottesville VA
• Original Assignee: University of Virginia
• Inventors: Belardinelli, Luiz, Wesley, Robert C. Jr.
• Primary Examiner(s): Killos, Paul J.
• Application Number:
  US07/213,937
• Time in Patent Office: 908 Days
• Field of Search: 424/263, 514/821
• US Class Current: 514/263.34
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine

Abstract

A method to enhance the efficacy of cardioversion, defibrillation, cardiac pacing, and cardiopulmonary resuscitation and to treat post-resuscitation asystole, bradyarrhythmias, electromechanical dissociation, and hemodynamic collapse by administering to a human or animal an effective amount of an adenosine antagonist that competitively inhibits adenosine or that reduces the level of adenosine present in myocardial and vascular tissues and associated fluids.

Claims

1. A method of enhancing the efficacy of cardiopulmonary resuscitation, comprising:

administering to a human or animal with post-resuscitation asystole or cardiac arrhythmia an amount of an adenosine antagonist sufficient to alleviate said asystole and cardiac arrhythmia wherein said antagonist competitively inhibits adenosine or reduces the level of adenosine present in myocardial tissue and associated fluids.

2. The method of claim 1, wherein said antagonist is a xanthine derivative or non-xanthine derivative.

3. The method of claim 2, wherein said antagonist is a methylxanthine.

4. The method of claim 3, wherein said methylxanthine is selected from the group consisting of 1,3,7-trimethylxanthine;

3,7-dimethylxanthine;

1,3-dimethylxanthine;

aminophylline; and

8-(p-sulfophenyl)theophylline.

5. The method of claim 2, wherein said antagonist is a propylxanthine.

6. The method of claim 2, wherein said antagonist is (E)-4-(1,2,3,6-tetrahydro-l,3-dimethyl-2,6-dioxo-9H-purin-8-yl)cinnamic acid or (E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-l,3-dipropyl-9H-purine-8-yl)cinnamic acid.

7. The method of claim 2, wherein said antagonist is a non-xanthine derivative.

8. The method of claim 7, wherein said non-xanthine derivative is selected from the group consisting of imidazopyrimidine, pyrazolopyridine, etazolate, pyrazoloquinoline and triazoloquinazoline.

9. The method of claim 1, wherein said antagonist is administered in a dose of about 0.1-20 mg/kg.

10. The method of claim 9, wherein said antagonist is administered in a dosage of from about 0.45-10 mg/kg.

11. The method of claim 9, wherein said antagonist is administered in a dosage of about 3-5 mg/kg.

12. The method of claim 1, wherein said administration is selected from the group consisting of intravenous injection, oral ingestion, local release and insertion of a suppository.

13. The method of claim 12, wherein said administration is by intravenous injection.

14. The method of claim 13, wherein said intravenous injection is a continuous intravenous injection.

15. The method of claim 14, wherein said continuous intravenous injection is at a rate of about 0.45 mg/kg/hr.

16. The method of claim 1, wherein said administering occurs concurrently with an α

-adrenergic, β

-adrenergic or dopaminergic agent.

17. The method of claim 16, wherein said adrenergic or dopaminergic agent is administered in a ratio of about 0.01:

1.0 to 1.0;

0.01 relative to said antagonist.

18. The method of claim 1, wherein said enhancing comprises enhancing the effectiveness of cardioversion, defibrillation, and cardiac pacing within the setting of resuscitation.

19. A method for the treatment of post-resuscitation asystole, bradyarrhythmias, electro-mechanical dissociation, and hemodynamic collapse, comprising:

administering to a human or animal with post-resuscitation asystole or cardiac arrhythmia an amount of an adenosine antagonist sufficient to alleviate said asystole and cardiac arrhythmia wherein said antagonist competitively inhibits adenosine or reduces the level of adenosine present in myocardial tissue and associated fluids.

20. The method of claim 19, wherein said antagonist is a xanthine derivative or a non-xanthine derivative.

21. The method of claim 20, wherein said antagonist is a methylxanthine.

22. The method of claim 21, wherein said methylxanthine is selected from the group consisting of 1,3,7-trimethylxanthine;

3,7-dimethylxanthine;

1,3-dimethylxanthine;

aminophylline; and

8-(p-sulfophenyl)theophylline.

23. The method of claim 19, wherein said antagonist is a propylxanthine.

24. The method of claim 23, wherein said propylxanthine is (E)-4-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purin-8-yl)cinnamic acid or (E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-1,3-dipropyl-9H-purine-8-yl)cinnamic acid.

25. The method of claim 20, wherein said antagonist is a non-xanthine derivative.

26. The method of claim 25, wherein said non-xanthine is selected from the group consisting of imidazopyrimidine, pyrazolopyridine, etazolate, pyrazoloquinoline and triazoloquinazoline.

27. The method of claim 19, wherein said antagonist is administered in a dose of about 0.1-20 mg/Kg.

28. The method of claim 27, wherein said antagonist is administered in a dose of from about 0.45-10 mg/Kg.

29. The method of claim 27, wherein said antagonist is administered in a dose of about 3-5 mg/Kg.

30. The method of claim 19, wherein said administration is selected from the group consisting of intravenous injection, oral ingestion, local release and insertion of a suppository.

31. The method of claim 30, wherein said administration is by intravenous injection.

32. The method of claim 31, wherein said intravenous injection is a continuous intravenous injection.

33. The method of claim 32, wherein said continuous intravenous injection is at a rate of about 0.45 mg/Kg/hr.

34. The method of claim 19, wherein said administering occurs concurrently with an α

-adrenergic, β

-adrenergic or dopaminergic agent.

35. The method of claim 34, wherein said adrenergic or dopaminergic agent is administered in a ratio of about 0.01:

1.0 to about 1.0-0.01 relative to said antagonist.